Mitochondrial energy metabolism is a
complex process that occurs within the mitochondria, which are the powerhouses
of the cell. Mitochondria are double-membraned organelles found in eukaryotic
cells. The process of energy production within mitochondria involves several
interconnected pathways, including the tricarboxylic acid (TCA) cycle, electron
transport chain (ETC), and oxidative phosphorylation. The TCA cycle, also known
as the citric acid cycle or Krebs cycle, takes place in the mitochondrial matrix
(1). It involves a series of enzymatic reactions that oxidize acetyl-CoA,
derived from the breakdown of carbohydrates, fatty acids, and amino acids, to
produce energy-rich molecules such as NADH and FADH2. These molecules carry
high-energy electrons that are further utilized in the ETC. The ETC is located
in the inner mitochondrial membrane (2). It consists of a series of protein
complexes, including NADH dehydrogenase, succinate dehydrogenase, cytochrome c
reductase, and cytochrome c oxidase. These complexes facilitate the transfer of
electrons from NADH and FADH2 to molecular oxygen (O2), generating a proton
gradient across the inner mitochondrial membrane. The proton gradient
established by the ETC drives ATP synthesis through a process called oxidative
phosphorylation (3). ATP synthase, located in the inner mitochondrial membrane,
utilizes the energy from the proton gradient to convert adenosine diphosphate
(ADP) to ATP. This process is known as chemiosmosis and is critical for the
efficient production of ATP. The oxidative phosphorylation process used by
mitochondria to produce energy is essential for cellular metabolism. They are
also involved in controlling reactive oxygen species (ROS) and other cellular
processes including apoptosis and calcium homeostasis. Reactive oxygen species
(ROS) are important regulators of apoptosis, a tightly regulated process of
programmed cell death, in normal physiological settings. Superoxide anion
(O2-), hydrogen peroxide (H2O2), and hydroxyl radical (OH-) are examples of
naturally occurring reactive oxygen species (ROS) that are involved in a number
of biological communication pathways. Calcium signals are strictly controlled
under normal circumstances to ensure proper cellular responses. The activation
of several enzymes, transcription factors, and other signaling molecules is
mediated by calcium ions, which function as second messengers. They play a role
in the control of actions such cell division, differentiation, apoptosis, and
the release of neurotransmitters. Cancer formation and progression have both
been linked to mitochondrial malfunction, and as the disease progresses,
mitochondria undergo a number of changes ().
Declarations
Acknowledgment
The author thanked to the department of molecular biology, natural sciences and institute for personalized and translational medicine, Ariel University, Ariel 4070000, Israel for providing instruction to writing this review article.
One of the significant modifications
observed during cancer is the alteration of the mitochondrial DNA (mtDNA).
MtDNA is a circular genome that codes for several critical proteins involved in
oxidative phosphorylation. Studies have revealed that mtDNA mutations occur in
a number of cancer forms, including breast, lung, and prostate cancer. These
mutations can result in the creation of aberrant proteins, which can affect
mitochondrial function and result in modifications to cellular metabolism and
signaling pathways (5). The alteration in mitochondrial shape is another
mitochondrial modification seen during malignancy. Maintaining mitochondrial
homeostasis and function requires mitochondrial fusion and fission. The
equilibrium between mitochondrial fusion and fission is upset in cancer cells,
changing the shape of the mitochondria. These modifications may influence
signaling pathways as well as how mitochondria interact with other cellular
organelles like the endoplasmic reticulum (5). Changes in mitochondrial
metabolism also occur during cancer progression. The Warburg effect, which
occurs even when oxygen levels are normal, describes how glycolysis plays a
significant role in the energy generation of cancer cells. This change in
metabolism is assumed to be brought on by modifications in mitochondrial
activity, including a reduction in oxidative phosphorylation and an increase in
ROS generation. Additionally, cancer cells can upregulate alternative metabolic
pathways such as glutaminolysis, which can further alter mitochondrial
metabolism (6).
Mitochondrial modifications can also impact
the apoptotic pathway, a process that regulates cell death. Fission and fusion
imbalances can impair mitochondrial function and cause cell death. Defective
fusion, on the other hand, can result in mitochondrial malfunction and necrotic
cell death, whilst excessive fission has been linked to apoptosis. In cancer
cells, the apoptotic pathway is often altered, allowing cells to avoid
programmed cell death. By modifying the expression of pro- and anti-apoptotic
proteins and affecting the mitochondrial membrane potential, which is essential
for the release of apoptotic agents, mitochondrial changes can have an
influence on the apoptotic pathway (7). Drug resistance in cancer cells can be
brought on by mutations in mtDNA and modifications to the electron transport
chain (ETC). Changes in mitochondrial membrane potential, the opening of the
mitochondrial permeability transition pore (mPTP), and ATP production are all
components of mitochondrial drug resistance (MDR), which can alter drug
absorption and efflux as well as the apoptotic signaling pathway (8).
Upregulation of ATP-binding cassette (ABC) transporters on the mitochondrial
outer membrane, which may pump medicines out of cells, is one of the main
mechanisms of MDR. The efflux of chemotherapeutic drugs is facilitated by ABC
transporters, including breast cancer resistance protein (BCRP), multidrug
resistance-associated protein (MRP), and P-glycoprotein (P-gp) which are
overexpressed in various types of cancer cells. This reduces drug accumulation
in the cells. Cancer patients' poor clinical outcomes and worse survival rates
are frequently linked to the overexpression of these transporters (9). The
modification of the mitochondrial membrane potential (Δψm), which is necessary
for the correct operation of the ETC and ATP production, is another mechanism
of MDR. The ATP synthase complex and the electron transport chain are active,
creating a proton gradient across the inner mitochondrial membrane, which is
necessary for the maintenance of Δψm. Drug transporter expression and function
are changed in cancer cells, resulting in decreased drug absorption and
increased efflux (10).
The MDR process also involves the opening
of the mPTP. The mitochondrial permeability, apoptosis, and necrosis are
regulated by the non-selective mPTP channel, which crosses the inner and outer
mitochondrial membranes. Apoptosis can occur as a result of the mPTP being
opened because it can cause the release of cytochrome c and other pro-apoptotic
components from the mitochondria. However, cancer cells with altered mPTP
activity can evade apoptosis and exhibit MDR (8). Along with these processes,
MDR can also be brought on by modifications in mitochondrial metabolism, such
as those in glycolysis, oxidative phosphorylation, and fatty acid metabolism.
These modifications can modify the apoptotic signaling pathway and have an
impact on medication efflux and absorption. Recent research has emphasized the
significance of MDR and mitochondrial metabolism targeting in cancer treatment.
In preclinical and clinical trials, novel medicines and treatment methods that
target mitochondrial function, such as mPTP inhibitors, ETC complex inhibitors,
and modulators of mitochondrial metabolism, have demonstrated encouraging
outcomes (11). Recent studies have demonstrated that several phytochemicals,
such as curcumin, resveratrol, and quercetin, can modify the function of the
mitochondrial drug-resistance mechanism in cancer cells, increasing the
susceptibility to chemotherapeutic medicines. For instance, it has been
demonstrated that curcumin causes apoptosis in cancer cells by changing the
potential of the mitochondrial membrane and boosting the production of reactive
oxygen species (ROS). Similar to this, it has been demonstrated that
resveratrol causes changes in mitochondrial activity and lowers ATP generation
in cancer cells, increasing apoptosis (12-13). By blocking the activity of
certain enzymes involved in the metabolism of chemotherapeutic medicines,
phytochemicals may also change the mitochondrial drug-resistance mechanism in cancer
cells. For instance, it has been demonstrated that quercetin reduces the
activity of cytochrome P450 enzymes, which are crucial for the metabolism of
certain chemotherapeutic medicines (14). In conclusion, the capacity of
phytochemicals (flavonoids, terpenoids and polyphenols) to modify the
functioning of the mitochondrial drug-resistance mechanism in cancer cells is
an area of current research and holds promise for the creation of innovative
anti-cancer medicines. To completely comprehend the underlying processes and to
determine the best chemicals and doses for therapeutic usage, more research is
required.
Table 1. Different types of mitochondrial structural and functional changes modulate drug-resistance.
Mitochondrial Structural and Functional Changes Modulating Drug-resistance
Here, we discuss the structural and number changes in mitochondria observed during cancer (see Table 1). The heart of eukaryotic cells, mitochondria are in charge of generating ATP, the main source of cellular energy. Additionally, they are essential for several cellular activities like signaling, apoptosis, and metabolism. A growing body of research indicates that mitochondria are crucial to the initiation and development of cancer (5). Mitochondrial fragmentation, in which the organelles are smaller and more numerous, is one of the most persistent structural alterations seen in cancer cells. Mitochondrial fragmentation is often accompanied by a decrease in cristae density, which is the site of oxidative phosphorylation. In contrast, normal mitochondria have a highly organized and interconnected structure, with densely packed cristae. The imbalance between fission and fusion is disturbed, leading to the production of smaller mitochondria, which is related with altered mitochondrial dynamics and the fragmented mitochondria in cancer cells (15). It is believed that abnormalities in mitochondrial number are connected to the changes in mitochondrial structure seen in cancer cells. Cancer cells often exhibit an increased number of mitochondria, which can be attributed to increased mitochondrial biogenesis or decreased mitophagy, a process where damaged mitochondria are selectively degraded. Increased mitochondrial biogenesis has been linked to the emergence of chemotherapy resistance in various cancer types, including prostate cancer (16). Several studies have identified the molecular mechanisms underlying the changes in mitochondrial structure and number in cancer. For instance, changes in the expression or activity of proteins involved in mitochondrial fission and fusion, such as dynamin-related protein 1 (Drp1), mitofusin 1 and 2 (Mfn1 and Mfn2), and optic atrophy 1 (OPA1), have been linked to changes in mitochondrial dynamics. The expression or activity of transcription factors and regulatory proteins, such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1) and PTEN-induced putative kinase 1 (PINK1), is frequently altered in response to changes in mitochondrial biogenesis and mitophagy (17). In summary, cancer cells exhibit significant changes in mitochondrial structure and number, including mitochondrial fragmentation, decreased cristae density, increased mitochondrial number, and alterations in mitochondrial dynamics. Changes in the expression and activity of proteins involved in mitochondrial fission and fusion, biogenesis, and mitophagy are linked to these changes. For the creation of efficient cancer therapeutics, it is essential to comprehend the processes driving these alterations in mitochondrial function and quantity.
In cancer cells,
mitochondrial ROS (reactive oxygen species) play a critical role in treatment
resistance. ROS are a consequence of cellular respiration and are essential for
redox equilibrium and cell signaling. However, excessive ROS can result in oxidative
damage to proteins, lipids, and other cellular constituents including DNA,
which can kill cells. Cancer cells have evolved mechanisms to adapt to high ROS
levels, which contributes to drug resistance. The mitochondrial electron
transport chain (ETC) is one of the methods through which cancer cells control
the amounts of reactive oxygen species (ROS). The ETC is a collection of
proteins and enzymes that produce ATP (adenosine triphosphate) by oxidative
phosphorylation in the mitochondrial membrane. During this process, electrons
from the ETC escape and interact with oxygen to produce ROS. Cancer cells can
upregulate the ETC to generate more ATP, which, in turn, increases ROS levels.
High ROS levels can activate a number of signaling pathways that support cell
survival and drug resistance, including PI3K/Akt, MAPK/ERK, and NF-κB
(18). A number of studies have demonstrated that blocking the ETC can make
cancer cells more susceptible to chemotherapy and overcome drug resistance. For
instance, metformin, a medication for type 2 diabetes, has the ability to block
mitochondrial complex I, which results in decreased ATP generation and
increased ROS levels, making cancer cells more susceptible to chemotherapy
(19). Inhibiting mitochondrial complex III with the medication atovaquone has
been shown to make cancer cells more susceptible to chemotherapy and overcome
drug resistance (20).
The mitochondria of eukaryotic cells
contain mitochondrial DNA (mtDNA), a circular double-stranded DNA molecule. It
produces ATP by the oxidative phosphorylation of 13 proteins, 22 transfer RNAs
(tRNAs), and 2 ribosomal RNAs (rRNAs) that it encodes. Recent studies suggest
that mtDNA mutations and alterations can regulate drug-resistance in cancer
cells (21). Drug resistance is a significant barrier to treating cancer and is
linked to poor therapeutic results. Several processes, including overexpression
of efflux transporters, activation of survival pathways, and mutation of drug
targets, can lead to drug resistance in cancer cells. But according to current
research, mtDNA changes can also be vital in controlling cancer cells'
treatment resistance (22). One of the mechanisms by which mtDNA alterations
regulate drug-resistance is through the modulation of oxidative phosphorylation
and energy metabolism. Cancer cells with mtDNA mutations often have altered
oxidative phosphorylation and energy metabolism, which can contribute to
drug-resistance. For example, cancer cells with mtDNA mutations may have
increased aerobic glycolysis and decreased oxidative phosphorylation, which can
confer resistance to drugs that target oxidative phosphorylation, such as
metformin (23). Reactive oxygen species (ROS) levels can be altered, which is
another way that mtDNA changes might control medication resistance. ROS are
very reactive chemicals that may harm DNA, proteins, and lipids. They are also
essential for the development of cancer and the development of treatment
resistance. ROS levels in cancer cells with mtDNA mutations are frequently
changed, and this can result in treatment resistance. For instance, ROS levels
may be lower in cancer cells with mtDNA mutations, which may confer resistance
to medications that cause ROS-mediated cell death, such as cisplatin (24).
Certain mtDNA mutations and changes have been linked to treatment resistance in
cancer cells, according to recent research. For instance, it has been
demonstrated that the mtDNA mutation m.3243A>G confers cisplatin resistance
in ovarian cancer cells through modifying ROS levels. It has been demonstrated
that the mtDNA deletion m.4977 alters energy metabolism in breast cancer cells
to provide resistance to doxorubicin. According to these findings, focusing on
mtDNA mutations may be a potential way to combat cancer medication resistance
(25).
The metabolism of glutamine in the
mitochondria is essential for cancer drug resistance. Glutamine is a crucial
nutrition for cancer cells because it offers crucial substrates for
biosynthesis, energy generation, and antioxidant defenses. Mitochondrial
glutamine metabolism, specifically the glutamine-dependent reductive
carboxylation pathway, provides an important anaplerotic source of citrate for
fatty acid synthesis, and NADPH for antioxidant defense. It has been
demonstrated that blocking this route can overcome drug resistance in cancer
cells and make them more sensitive to different types of chemotherapy and
immunotherapy. It's critical to remember that depending on the kind of cancer
and genetic changes present in the tumor, different paths and treatments can be
used to overcome medication resistance. Therefore, a customized strategy taking
into account each patient's tumor's molecular profile is essential for
determining the most efficient techniques (26). Recent research has revealed a
new medicine called CB-839 that works by inhibiting the glutamine-dependent
reductive carboxylation pathway by targeting glutaminase, the enzyme that
catalyzes the conversion of glutamine to glutamate. The enzyme glutamine
synthetase (GS), which catalyzes the conversion of glutamate and ammonia into
glutamine, is essential for nitrogen metabolism. The appropriate nitrogen
balance in cells is maintained by closely controlling the activity of the
highly regulated enzyme GS. The capacity of GS to directly absorb ammonia into
glutamate, even at low ammonia concentrations, is one of its standout
characteristics. Scavenging ammonia and avoiding its harmful accumulation in
cells are essential goals of this mechanism. In preclinical cancer models,
CB-839 has been demonstrated to increase the effectiveness of a number of
chemotherapy drugs, such as gemcitabine, cisplatin, and paclitaxel. It is now
being tested in human studies with chemotherapeutic drugs for a variety of
cancer types. AOA (aminooxyacetate), a different medication, has also been
demonstrated to suppress glutaminase activity and make cancer cells more
susceptible to chemotherapy (27). In preclinical models of a number of cancer
types, including lung cancer, breast cancer, and ovarian cancer, it has been
demonstrated that AOA, a small molecule inhibitor that covalently binds to the
active site of glutaminase, has powerful antitumor effects (28). Recent
research has also shown additional targets in mitochondrial glutamine
metabolism that might be used to combat cancer medication resistance in
addition to glutaminase inhibitors. For instance, the transport of pyruvate
into the mitochondrial matrix for oxidative phosphorylation and citrate
production is crucially regulated by the mitochondrial pyruvate carrier (MPC).
It has been demonstrated that MPC inhibition lowers mitochondrial respiration
and increases cancer cells' susceptibility to chemotherapy (29-30). The TCA
cycle is a crucial metabolic system that uses a number of enzyme-catalyzed
events to change pyruvate into ATP, NADH, and FADH2. The TCA cycle is
upregulated in cancer cells, which results in enhanced ATP generation and
treatment resistance. Recent research has demonstrated that through controlling
mitochondrial respiration and oxidative stress, the TCA cycle enzyme fumarate
hydratase (FH) can decrease tumor growth in renal cell carcinoma (RCC) (31).
Isocitrate dehydrogenase (IDH), a TCA cycle enzyme, has also been linked to the
emergence of glioblastoma, with mutations in IDH1/2 resulting in elevated TCA
cycle activity and carcinogenesis (32). The inner mitochondrial membrane
contains a group of electron carriers called the ETC, which provide a proton
gradient that propels the production of ATP. The ETC is frequently
overexpressed in cancer cells, which results in enhanced energy generation and
treatment resistance. Targeting ETC complex I has been found to make cancer
cells more susceptible to chemotherapy (33). Furthermore, it has been
demonstrated that the ETC complex III functions as a mediator of oxidative
stress and treatment resistance in breast cancer (34).
A class of transmembrane transporters known
as mitochondrial ATP-binding cassette subfamily B (ABCB) proteins is essential
for controlling drug resistance in cancer cells. These proteins have a role in
the active efflux of chemotherapeutic medications from cancer cells, which can
result in a reduction in drug accumulation and a reduction in therapeutic
effectiveness. Among the mitochondrial ABCB proteins, ABCB6 has been identified
as the only mitochondrial ABCB protein that regulates drug resistance in cancer
(35). Cancer cells that are resistant to treatment produce large levels of the
mitochondrial transporter ABCB6. It has been demonstrated to be essential for
the efflux from the mitochondria of cancer cells of chemotherapeutic drugs such
mitoxantrone, doxorubicin, and daunorubicin. It has been demonstrated that
inhibiting ABCB6 expression or activity increases the accumulation of these
medicines in cancer cells, improving therapeutic effectiveness (36). Several studies
have demonstrated the clinical relevance of ABCB6 in drug-resistant cancer. For
instance, research by Huang and colleagues discovered that drug-resistant
ovarian cancer cells expressed ABCB6 substantially more than drug-sensitive
cells, and that knocking down ABCB6 expression made these cells more responsive
to chemotherapeutic drugs. Similarly, ABCB6 expression was linked to a poor
prognosis in individuals with stomach cancer, according to research by Zhang
and colleagues, and ABCB6 inhibition enhanced the susceptibility of gastric
cancer cells to chemotherapeutic drugs (37). Recent studies have also
identified potential strategies for targeting ABCB6 in drug-resistant cancer.
For example, a study by Lu and colleagues found that inhibition of ABCB6 expression
using siRNA nanoparticles sensitized drug-resistant breast cancer cells to
chemotherapeutic agents. Similar findings were made in research by Zhang and
colleagues, who discovered that the small molecule inhibitor RMM-46 has the
ability to block ABCB6 activity and make chemotherapy-resistant cancer cells
susceptible (38).
The mitochondrial DNA (mtDNA) repair
pathway is one of the most researched mechanisms behind mitochondrial
resistance to drugs in cancer. The mtDNA repair pathway is responsible for
repairing the damage caused by chemotherapy drugs to mtDNA. Cancer cells that
develop resistance to chemotherapy drugs can upregulate the mtDNA repair
pathway, which allows them to repair the mtDNA damage caused by the drugs and
survive. The activation of the mitochondrial unfolded protein response (UPRmt)
pathway, which controls the expression of mtDNA repair genes, or mutations in
the mtDNA repair genes OGG1 and MUTYH can both result in this increase (39).
The mitochondrial membrane potential (MMP) route is another mechanism connected
to mitochondrial drug resistance in cancer. The ATP generation process and cell
viability depend on the electrochemical gradient that the MMP route controls
across the mitochondrial inner membrane.
Chemotherapy drugs can disrupt the MMP, leading to mitochondrial
dysfunction and cell death. Cancer cells that develop resistance to
chemotherapy drugs can upregulate the MMP pathway, which allows them to
maintain the electrochemical gradient and survive. The activation of the mitochondrial
permeability transition pore (mPTP), which controls the MMP, or the induction
of anti-apoptotic Bcl-2 family members, which block mPTP opening, can both
result in this increase (40). Last but not least, the mitochondrial biogenesis
pathway has also been connected to cancer treatment resistance in mitochondria.
The process through which new mitochondria are created in response to cellular
energy requirements is known as mitochondrial biogenesis. Cancer cells that
develop resistance to chemotherapy drugs can upregulate the mitochondrial
biogenesis pathway, which allows them to increase their mitochondrial mass and
survive. The PGC-1alpha pathway, which controls mitochondrial biogenesis, can
be stimulated in order to cause this increase (41). In conclusion, complicated
interactions across several pathways, such as mtDNA repair, MMP control, and
mitochondrial biogenesis, are involved in the molecular processes of
mitochondrial drug resistance in cancer. Understanding these pathways and how
they are controlled may help researchers create fresh approaches to combat
mitochondrial drug resistance in cancer.
Figure 1. Phytochemicals preventing the mitochondrial drug-resistance mechanism.
Alternative Therapy for Mitochondrial
Drug-resistance: Phytochemicals
Biologically active substances called
phytochemicals are present in plants and are thought to provide health
advantages, including anticancer characteristics (see Figure 1). Growing
evidence points to a potential function for phytochemicals in the management
and treatment of cancer (52). The flavonoids are one of the phytochemical
classes that has been the subject of the most research. A sizable collection of
polyphenolic substances known as flavonoids may be found in fruits, vegetables,
and other plant-based meals. They are known to have anti-inflammatory,
antioxidant, and anti-cancer characteristics, and multiple studies have found a
decreased risk of cancer in those who consume a lot of flavonoids in their
diets (53). The potential health advantages of these substances, notably their
anticancer qualities, have drawn a lot of interest. Numerous pathways exist in flavonoids that
support their anticancer properties. Antioxidant action, cellular signaling
pathway modification, anti-inflammatory effects, cell cycle arrest induction,
promotion of apoptosis (planned cell death), and suppression of angiogenesis
(the creation of new blood vessels to promote tumor growth) are a few of these
methods (54). All of these actions contribute to reducing the risk of cancer
development, spread, and metastasis. Inhibiting the activity of matrix
metalloproteinases (MMPs) and regulating the generation of reactive oxygen
species (ROS) are two ways flavonoids exercise their anticancer effects. Because
flavonoids have antioxidant characteristics, they can scavenge free radicals
and reactive oxygen species (ROS), which can damage DNA and encourage the
growth of cancer (55). Flavonoids assist in protecting cells from genetic
alterations and halting the start of carcinogenesis by lowering oxidative
stress. Flavonoids, for instance, can control the production of anti-apoptotic
proteins like Bcl-2 and Bcl-xL. These proteins work to preserve the potential
of the mitochondrial membrane by preventing the release of cytochrome c and the
consequent activation of apoptotic pathways (56). Reactive oxygen species (ROS)
produced during mitochondrial respiration can be scavenged by flavonoids since
they also have antioxidant capabilities. The loss of mitochondrial membrane
potential (ΔΨm) and dysfunctional mitochondria can result from excessive ROS
generation. By lowering ROS levels, flavonoids can support maintaining m and
preserving mitochondrial function (57).
Table 2. Different types of phytochemicals used as an alternative therapy for mitochondrial drug-resistance.
The carotenoids are a different class of phytochemicals that have undergone substantial research for their possible anticancer effects. The group of plant pigments known as carotenoids is what gives fruits and vegetables their yellow, orange, and red hues. Numerous studies have shown that those who consume large amounts of carotenoids, notably the tomato-derived lycopene, have a decreased chance of developing cancer. Resveratrol, which is present in red wine and grapes, as well as curcumin, which is present in turmeric, are other phytochemicals that have been investigated for their potential anticancer activities (51). Although the evidence supporting phytochemicals' anticancer abilities is still developing, numerous studies have shown encouraging findings. For instance, research indicated that women who consumed more flavonoids had a decreased risk of breast cancer than those who consumed less, according to a publication in the journal Cancer Epidemiology, Biomarkers & Prevention. Men who consumed a lot of lycopene had a decreased chance of developing prostate cancer, according to another research (52) that was printed in the Journal of the National Cancer Institute. Overall, the data point to a potential role for phytochemicals in the prevention and management of cancer. To completely comprehend the processes behind their anticancer activities and to establish the ideal phytochemical dosages and sources for cancer prevention and therapy, additional study is nonetheless required.
Drug resistance is a multifactorial phenomenon that can develop in tumor cells as a result of several genetic and epigenetic alterations. Researchers are looking at novel approaches to combat drug resistance in cancer, one of which is the use of phytochemicals. Plants include physiologically active substances called phytochemicals, which have been demonstrated to have anti-cancer potential (53). Due to their ability to make chemotherapy-resistant cancer cells more susceptible, phytochemicals have attracted a lot of attention in the field of cancer research. The many and intricate processes by which phytochemicals exercise their anti-cancer actions include the control of several signaling pathways, the activation of apoptosis, the modification of cell cycle progression, and the suppression of angiogenesis. Additionally, phytochemicals have been demonstrated to increase the effectiveness of chemotherapy medications, enhancing cancer patients' overall response rates and chances of survival (58). Numerous phytochemicals have the ability to combat cancer medication resistance, according to recent studies. For instance, curcumin, a naturally occurring substance present in turmeric, has been demonstrated to sensitize chemotherapy-resistant cancer cells by reducing the function of transporters that promote multidrug resistance. Similar to this, it has been demonstrated that the polyphenol resveratrol, which is present in grapes and red wine, increases the susceptibility of cancer cells to chemotherapy by suppressing the expression of drug resistance genes (59). Sulforaphane, another potential phytochemical, is present in cruciferous vegetables like broccoli and cauliflower. Sulforaphane has been demonstrated to induce apoptosis and suppress the production of drug resistance genes in cancer cells, making them more susceptible to chemotherapy. The polyphenol epigallocatechin gallate (EGCG), which is present in green tea, has also been demonstrated to improve the effectiveness of chemotherapy treatments in cancer cells that are resistant to treatment (60). In conclusion, phytochemicals provide a viable strategy to combat cancer medication resistance. A novel treatment option for cancer is made possible by phytochemicals' capacity to make chemotherapy more effective and to make drug-resistant cancer cells more susceptible to it (see Table 2). To completely comprehend how phytochemicals work and their potential as cancer treatments, more study is required.
Curcumin
Curcumin, a naturally occurring polyphenol
produced from turmeric, has been demonstrated to possess strong anticancer
capabilities by obstructing key cellular processes involved in the development
of cancer. According to recent research, curcumin also inhibits the
mitochondrial drug-resistance pathways found in cancer cells (61). The heart of
the cell, mitochondria are essential for both the pathways leading to cell
death and the metabolism of energy. Drug resistance in cancer cells has been
related to mitochondrial malfunction. The altered mitochondrial membrane
potential of resistant to drugs cancer cells affects the effectiveness of
anticancer medications that target mitochondrial pathways. It has been
demonstrated that curcumin targets the mitochondrial mechanisms responsible for
cancer cells' treatment resistance. The modulation of the expression of Bcl-2
family proteins is one of the ways that curcumin works. A family of proteins
known as Bcl-2 family members controls the mitochondrial mechanism of
apoptosis. It has been demonstrated that curcumin increases the expression of
pro-apoptotic Bax proteins while decreasing the expression of anti-apoptotic
Bcl-2 proteins. As a result, the mitochondrial membrane becomes more permeable,
which causes cancer cells to undergo apoptosis (62). According to reports,
curcumin also affects the mitochondrial electron transport chain (ETC), which
is in charge of producing ATP and reactive oxygen species (ROS). The ETC is
frequently hyperactive in drug-resistant cancer cells, which increases ROS
generation and causes oxidative stress. According to research, curcumin reduces
the activity of the ETC complex I, which lowers the creation of ROS and
oxidative stress in cancer cells. As a result, cancer cells' drug resistance is
reversed and their mitochondrial function is restored (63). The AMP-activated
protein kinase (AMPK) pathway, a crucial regulator of cellular energy
metabolism, has also been demonstrated to be a target of curcumin. The AMPK
pathway is frequently dysregulated in cancer cells with enhanced treatment
resistance, altering their metabolic profile. It has been demonstrated that
curcumin activates the AMPK system, reversing drug resistance in cancer cells
and restoring normal cellular energy metabolism (64). As a result of its
ability to target the mitochondrial pathways responsible for cancer cells'
development of drug resistance, curcumin possesses strong anticancer effects.
It is a promising candidate for the creation of brand-new anticancer treatments
because of its capacity to control the expression of Bcl-2 family members,
limit the activity of the ETC, and activate the AMPK pathway.
Resveratrol
A naturally occurring polyphenol called
resveratrol is present in many plants, including berries, grapes, and peanuts.
Its potential for health benefits, especially its anticancer effects, have been
well researched. The maintenance of cellular homeostasis depends heavily on
mitochondria, and medication resistance in cancer cells has been associated
with mitochondrial malfunction. It has been demonstrated that resveratrol
targets the cancer cells' mitochondrial drug resistance pathway to provide its
anticancer effects. Multidrug resistance-associated protein (MRP) and
P-glycoprotein (P-gp), two proteins involved in the efflux of medicines from
cancer cells, are upregulated as part of the mitochondrial drug-resistance
mechanism. The production and activity of these proteins have been demonstrated
to be inhibited by resveratrol, which increases the susceptibility of cancer
cells to chemotherapy treatments (65). Resveratrol also affects the signaling
pathways that control cell proliferation, death, and angiogenesis in order to
exercise its anticancer effects. Inhibiting mTOR signaling, a mechanism that
encourages cell growth and proliferation, stimulates the AMP-activated protein
kinase (AMPK) pathway, which controls cellular energy balance. By activating
the caspase cascade, upregulating pro-apoptotic proteins like Bax and
downregulating anti-apoptotic proteins like Bcl-2, resveratrol also causes
apoptosis in cancer cells (66). The transcription factor nuclear factor-kappaB
(NF-B), which controls inflammation and cell viability, has also been found to
be inhibited by resveratrol. In cancer cells, NF-B is frequently overactivated,
which aids in the survival and growth of these cells. By preventing NF-B's
nuclear translocation and stifling the activity of IKK, an upstream kinase that
activates NF-B, resveratrol reduces NF-B activity (67). Additionally, recent
research has looked at how resveratrol affects the gut flora and how that may
affect cancer therapy and prevention. Resveratrol has been demonstrated to
alter the gut microbiota's makeup and activity, which can affect the host
immune system and alter how the body reacts to cancer treatments (68). As a
result, resveratrol targets the mitochondrial drug-resistance mechanism,
modifies multiple signaling pathways that control cell growth and death, and
modifies the gut microbiota to exercise its anticancer effects. To completely
understand resveratrol's methods of action and its potential as a cancer
treatment, more research is required.
Epigallocatechin Gallate (EGCG)
A significant challenge in the treatment of
cancer is mitochondrial medication resistance. The upregulation of multidrug
resistance proteins (MRPs) on the mitochondrial membrane, which promotes drug
efflux from the mitochondria, is one of the hypothesized mechanisms of
mitochondrial drug resistance. Green tea catechin EGCG, which inhibits MRPs and
restores drug accumulation in the mitochondria, has been proven to make cancer
cells more susceptible to chemotherapeutic treatments. By interacting with the
ATP-binding sites in MRPs, EGCG has been demonstrated to limit their activity.
MRPs are ATP-dependent drug efflux pumps that move medications out of
mitochondria and cells. The activity of a number of MRPs, including MRP1, MRP2,
and MRP3, has been found to be inhibited by EGCG in cancer cells (69). Because
EGCG inhibits MRPs, more medicines accumulate in mitochondria, which increases
the risk of mitochondrial damage and death in cancer cells. EGCG has been
demonstrated to alter a number of additional signaling pathways associated with
mitochondrial drug resistance in addition to blocking MRPs. In cancer cells,
EGCG has been shown to upregulate the expression of pro-apoptotic proteins like
Bax and Bak while downregulating the expression of anti-apoptotic proteins like
Bcl-2 and Bcl-xL (70). As a result, the mitochondrial outer membrane becomes
more permeable (MOMP) and releases cytochrome c, which in turn triggers the
caspase cascade and causes death in cancer cells. The AMP-activated protein
kinase (AMPK) pathway, which is important in energy metabolism and cellular
stress response, has also been discovered to be activated by EGCG (71).
Inhibition of mTOR signaling and activation of autophagy are caused by EGCG's
activation of AMPK in cancer cells, which can facilitate the destruction of
damaged mitochondria and improve mitochondrial quality control. This might help
EGCG sensitize cancer cells to chemotherapeutic medicines. In conclusion, EGCG
sensitizes cancer cells to chemotherapy drugs by inhibiting MRPs, modulating
apoptotic pathways, and activating the AMPK pathway. These mechanisms
contribute to the restoration of drug accumulation in the mitochondria and
enhanced mitochondrial damage and apoptosis in cancer cells. EGCG has shown
promising results in preclinical studies as a sensitizer to chemotherapy drugs
in cancer treatment, and further clinical studies are warranted.
Quercetin
Natural flavonoid quercetin has been
thoroughly investigated for its potential to reduce the development and
proliferation of cancer cells. One of the ways quercetins exerts its
anti-cancer effects is through its ability to overcome mitochondrial drug
resistance mechanisms that contribute to chemoresistance in cancer cells (72).
Cancer cells can develop a resistance to chemotherapy treatments known as
mitochondrial drug resistance by upregulating the production of anti-apoptotic
proteins and changing mitochondrial function. These alterations provide cancer
cells a way to avoid the cell death brought on by chemotherapy medications,
which eventually results in treatment failure. It has been demonstrated that
quercetin reduces drug resistance in mitochondria by modifying mitochondrial
activity and preventing the production of proteins that prevent apoptosis (73).
One way quercetin modifies mitochondrial function is by preventing complex I in
the electron transport chain (ETC) from doing its job. The essential element of
the ETC that produces ATP, the cellular energy unit, is Complex I. Quercetin
decreases ATP synthesis by blocking complex I activity, which results in a drop
in the mitochondrial membrane potential (m) and an increase in the formation of
ROS in the mitochondria. Since mitochondrial malfunction and oxidative stress
are two major factors that contribute to apoptosis, these modifications
eventually cause an increase in apoptosis in cancer cells (74). The
anti-apoptotic proteins Bcl-2 and Bcl-xl, which are overexpressed in cancer
cells and increase treatment resistance by blocking the intrinsic apoptotic
pathway, are likewise inhibited by quercetin. Quercetin promotes apoptosis in
cancer cells and makes them more susceptible to chemotherapy treatments by
decreasing the production of these proteins (75). Quercetin has been
demonstrated to suppress the functioning of drug efflux pumps such
P-glycoprotein (P-gp), which contribute to multidrug resistance in cancer
cells, in addition to its effects on mitochondrial function and the development
of anti-apoptotic proteins. Quercetin raises the intracellular concentration of
chemotherapeutic medicines and improves their cytotoxic effects by decreasing
P-gp function (76). Overall, quercetin targets a number of processes that
support cancer cells' mitochondrial drug resistance to exercise its anti-cancer
actions. Modulation of mitochondrial activity, suppression of anti-apoptotic
protein production, and blockage of drug efflux pumps are some of these ways.
Quercetin has generated a great deal of interest as a possible adjuvant therapy
for the treatment of cancer due to its wide spectrum of anti-cancer actions
(77).
Sulforaphane
Cruciferous vegetables like broccoli,
cauliflower, and kale contain a natural substance called sulforaphane that has
been demonstrated to have anticancer characteristics. A prospective possibility
for cancer treatment, sulforaphane has recently been found to be able to target
the mitochondrial drug-resistance pathways in cancer cells. Through controlling
energy metabolism and cell death, mitochondria play a crucial role in cancer
cell survival and medication resistance. By changing cellular metabolism,
lowering reactive oxygen species (ROS) levels, and inhibiting apoptotic cell
death in cancer cells, mitochondria can become dysfunctional and aid in the
development of chemotherapeutic resistance. Reduced sensitivity to various
anticancer medications, including as cisplatin, doxorubicin, and paclitaxel, is
linked to mitochondrial dysfunction. In cancer cells, sulforaphane has been
demonstrated to reverse drug resistance and restore mitochondrial function. As
a result of sulforaphane's activation of the Nrf2 pathway, which increases the
synthesis of antioxidant enzymes and lowers ROS levels, the body produces more
antioxidants. Sulforaphane's stimulation of the Nrf2 pathway can improve
mitochondrial performance and lessen drug resistance in cancer cells.
Sulforaphane also has the ability to control the expression of mitochondrial
proteins linked to drug resistance. MRP1, an ATP-binding cassette transporter
protein that contributes to drug resistance, is expressed less often when
sulforaphane is present (78). The expression of the mitochondrial protein
BNIP3L is also upregulated by sulforaphane, which causes mitochondrial
autophagy and promotes death in cancer cells. Sulforaphane has the potential to
be used in cancer treatment as a chemosensitizer, according to recent studies.
Sulforaphane inhibited the Nrf2-mediated antioxidant response and decreased
MRP1 expression, according to research by Chen et al. (2021), which
demonstrated that it sensitized lung cancer cells to cisplatin (79). By
triggering mitochondrial autophagy through the elevation of BNIP3L expression,
sulforaphane was shown to improve the susceptibility of breast cancer cells to
doxorubicin in another work by Li et al. (2022) (80). Sulforaphane has
demonstrated promise as a natural chemical for the treatment of cancers that
have mitochondrial drug resistance pathways. The Nrf2 pathway is activated,
drug-resistant mitochondrial proteins are modulated, and mitochondrial function
is restored as part of the sulforaphane's mode of action. These results imply
that sulforaphane may be utilized as a chemosensitizer to increase the
effectiveness of traditional chemotherapy in the treatment of cancer.
Berberine
A natural isoquinoline alkaloid known as
berberine has been proven to have anticancer properties against a variety of
malignancies, including tumors that are drug-resistant. Alterations in
mitochondrial activity are one of the processes through which cancer cells gain
resistance to chemotherapy. According to reports, berberine affects cancer
cells that are resistant to treatment through modifying mitochondrial activity.
It has been demonstrated that berberine targets the mitochondrial pathway to
cause apoptosis in cancer cells. Depolarization of the mitochondrial membrane
potential has been linked to the onset of apoptosis by releasing cytochrome c
into the cytoplasm and activating caspases (81). Additionally, berberine has
been shown to induce autophagy, a process by which cells recycle their own
components in response to stress. This is accomplished by increasing the
susceptibility of cancer cells to chemotherapy by stimulating the formation of
autophagosomes and lysosomes, which causes the destruction of cellular
components, including damaged mitochondria. Additionally, berberine has been
shown to control the production of a number of proteins essential for mitochondrial
function. It has been demonstrated, for instance, that it inhibits the
expression of the mitochondrial ATP synthase subunits and, which results in a
reduction in ATP production (82). Additionally, it has been demonstrated that
berberine stimulates AMP-activated protein kinase (AMPK), an essential
regulator of cellular energy metabolism. Protein synthesis is inhibited and
autophagy is induced when AMPK is activated (83). This is because mTOR
signaling is inhibited. Additionally, it has been shown that berberine inhibits
the production of the anti-apoptotic protein Bcl-2, known to suppress
mitochondrial apoptosis and make cancer cells more susceptible to chemotherapy
(84-85). The regulation of mitochondrial activity in cancer cells that are
resistant to treatment is how berberine has been proven to exercise its
anticancer effects. It triggers autophagy and apoptosis and modifies the
expression of several proteins vital to mitochondrial function. As a result,
berberine has potential therapeutic uses in drug-resistant malignancies as a
chemotherapy sensitizer.
Lycopene
A carotenoid phytochemical called lycopene is
present in foods including tomatoes, watermelons, and grapefruits. According to
studies, lycopene has strong anti-oxidant qualities and may help prevent or
treat a number of ailments, including cancer. Targeting cancer cells'
mitochondrial drug-resistance pathways is one way lycopene may work. Drug
resistance in cancer cells frequently develops via a process known as
mitochondrial drug resistance. Anti-apoptotic proteins like Bcl-2, which block
the release of cytochrome c from the mitochondria and stop the activation of
caspase-dependent apoptotic pathways, are overexpressed during this process. It
has been demonstrated that lycopene targets mitochondrial drug resistance by
preventing Bcl-2 and other anti-apoptotic proteins from being expressed in
cancer cells. The expression of Bcl-2 and other anti-apoptotic proteins was
shown to be significantly reduced by lycopene treatment in research on prostate
cancer cells, which enhanced mitochondrial permeability and activated
caspase-dependent apoptotic pathways (86). By triggering the caspase-dependent
pathway and suppressing the expression of Bcl-2 and other anti-apoptotic
proteins, lycopene therapy was shown in another study to cause apoptosis in
human cervical cancer cells (87). Lycopene has been demonstrated to have other
anti-cancer effects, including the ability to suppress cell growth, cause cell
cycle arrest, and decrease inflammation, in addition to its function in
addressing mitochondrial drug resistance (88). Overall, the data points to
lycopene's potential as a therapeutic agent for the treatment of cancer,
especially when it comes to focusing on mechanisms of mitochondrial drug
resistance. To completely understand the processes behind lycopene's
anti-cancer benefits and to assess its effectiveness and safety in clinical
trials, further study is necessary.
Genistein
Studies have demonstrated that the soy
isoflavone genistein can overcome medication resistance in cancer cells, which
has been related to mitochondrial malfunction. Breast, prostate, lung, and
colon cancers are only a few of the tumors for which genistein has been
reported to be helpful. Researchers have shown a significant deal of interest
in the mechanism by which genistein overcomes drug resistance in cancer cells
in this context (89). It has been demonstrated that genistein targets multiple
molecular pathways, including the mitochondrial pathway, that are important in
cancer cell survival and proliferation. Apoptosis, also known as programmed
cell death, is a process by which the body gets rid of defective or damaged
cells, and mitochondria play a critical part in controlling it. This pathway is
frequently damaged in cancer cells, which increases their resistance to
chemotherapy treatments (90). Modulating the activity of the mitochondrial
permeability transition pore (mPTP) is one of the primary ways that genistein
overcomes mitochondrial drug resistance in cancer cells. A channel called the
mPTP controls how ions and other small molecules are transported through the
inner mitochondrial membrane. Its dysregulation has been linked to drug
resistance in cancer cells and it has been demonstrated to be involved in the
control of apoptosis (91). By controlling the expression of many proteins
crucial to the mPTP's operation, genistein has been discovered to modify the
mPTP's activity. For instance, it has been demonstrated that genistein
increases the production of the protein cyclophilin D (CypD), which encourages
the opening of the mPTP and causes apoptosis. Additionally, it reduces the
production of Bcl-2, a protein that blocks the opening of the mPTP to limit
apoptosis (92). Genistein has been demonstrated to target other mitochondrial proteins
related to drug resistance in addition to altering the mPTP. For instance, it
has been discovered to disrupt the mitochondrial respiratory chain's function,
increasing the formation of reactive oxygen species (ROS). ROS are very
reactive chemicals that have the ability to kill cancer cells by harming their
DNA, proteins, and lipids (93). Overall, the regulation of several molecular
pathways is part of the complicated process by which genistein overcomes cancer
cells' mitochondrial drug resistance. However, research indicates that the
primary methods through which genistein might cause apoptosis in drug-resistant
cancer cells are through its capacity to target the mPTP and control ROS
generation.
Kaempferol
Natural flavonoid kaempferol, which is
present in many plants, has been demonstrated to have anti-cancer activities
and to circumvent drug resistance in cancer cells via a number of pathways
(94). The regulation of the mitochondrial membrane potential (MMP) and the
inhibition of drug efflux from cancer cells are two ways that kaempferol works
to overcome mitochondrial drug resistance. The transport of numerous
chemotherapeutic medicines out of cancer cells is carried out by adenosine
triphosphate (ATP)-binding cassette (ABC) transporters, which also facilitate
the efflux of medications from cancer cells. It has been demonstrated that
kaempferol inhibits the function of ABC transporters, preventing medications
from being effluxed from cancer cells and raising the concentration of
pharmaceuticals inside cells, enhancing cytotoxicity (95). Additionally, it has
been demonstrated that kaempferol causes cancer cells to undergo apoptosis
(programmed cell death) by activating the caspase pathway and reducing the
expression of the anti-apoptotic B-cell lymphoma 2 (Bcl-2) protein. Since
cancer cells are defined by the inhibition of apoptosis, which results in
unchecked proliferation and survival, apoptosis activation is crucial for the
therapy of cancer (96). Inhibiting the activity of mitochondrial respiratory chain
complexes and boosting the generation of reactive oxygen species (ROS),
kaempferol also controls mitochondrial function. Cancer cells typically exhibit
mitochondrial malfunction and altered redox homeostasis, and kaempferol's
regulation of mitochondrial activity can result in the selective destruction of
cancer cells (97). Additionally, it has been demonstrated that kaempferol
increases the intracellular drug concentration and boosts the cytotoxic effects
of chemotherapy drugs, making cancer cells more susceptible to chemotherapy. In
cancer cells that are resistant to chemotherapy, this process is particularly
important, and kaempferol can break down this resistance by boosting the
effectiveness of chemotherapy (98). Kaempferol has been shown to have the
ability to combat medication resistance in a number of cancer types, including
breast cancer, lung cancer, ovarian cancer, and pancreatic cancer, in recent
research. However, further research is needed to clarify the precise mechanisms
of action of kaempferol in various cancer types and to create kaempferol-based
therapy approaches.
Naringenin
A flavonoid substance called naringenin is
present in citrus fruits like grapefruit and oranges. Numerous biological
activities, such as antioxidant, anti-inflammatory, and anticancer effects,
have been found for it. Naringenin may be able to break through drug resistance
in cancer cells, particularly due to its impact on mitochondrial activity,
according to recent research. One frequent mechanism underpinning medication
resistance in cancer cells is mitochondrial malfunction. Changes in
mitochondrial metabolism, oxidative stress, and ATP generation are its defining
characteristics, and they all work together to enhance survival and confer
resistance to chemotherapy. Naringenin has been demonstrated to target the
mitochondria in cancer cells, reducing medication resistance and enhancing
therapeutic results. Zhao et al.'s (2021) research looked at how naringenin
affected lung cancer cells' treatment resistance. The results of the study
showed that naringenin therapy reduced drug resistance, which was connected to
improved mitochondrial function and reduced oxidative stress. By improving
mitochondrial activity and decreasing drug resistance in cancer cells, the
scientists suggested that naringenin may increase the effectiveness of
chemotherapy (99). Kim et al.'s (2020) research looked at how naringenin
affected breast cancer cells' treatment resistance. According to the study,
naringenin treatment made cancer cells more susceptible to chemotherapy, which
was linked to both an increase in reactive oxygen species (ROS) generation and
a reduction in mitochondrial respiration. By altering mitochondrial activity
and boosting ROS generation, the scientists hypothesized that naringenin would
be able to break through treatment resistance in breast cancer cells (100).
Finally, it has been demonstrated that naringenin may overcome medication
resistance in cancer cells by concentrating on mitochondrial activity. It has
been discovered that the substance improves mitochondrial function and lowers
oxidative stress, which reduces medication resistance and improves therapeutic
results. The molecular processes underpinning naringenin's impacts on
mitochondrial function and drug resistance in cancer cells require more study
to be completely understood.
Apigenin
A flavone substance called apigenin is
present in many plants, such as celery, parsley, and chamomile. Apigenin has
been proven in studies to have anticancer effects and to be able to break
through cancer cells' drug resistance to mitochondrial agents. Cancer cells can
become resistant to chemotherapeutic treatments through a mechanism known as
mitochondrial drug resistance. We will talk about how apigenin overcomes
cancer's mitochondrial drug resistance in this response. Drug-resistant cancer
cells have an overexpression of the drug efflux pump P-gp. It is in charge of
pushing chemotherapy medications out of cancer cells, which reduces drug
buildup and causes chemotherapy resistance. In drug-resistant cancer cells,
apigenin suppresses P-gp expression and function, increasing drug accumulation
and enhancing chemotherapy effectiveness (101). The apoptosis process—by which
damaged or diseased cells are destroyed—is regulated by Bcl-2 family proteins.
By upregulating anti-apoptotic Bcl-2 family proteins, which prevent apoptosis
and support cell survival, certain cancer cells develop resistance to
chemotherapy. Apigenin inhibits Bcl-2 family proteins, increasing apoptosis and
enhancing the effectiveness of chemotherapy (102). An energy-sensing kinase
called AMPK controls cellular survival and metabolism. Chemotherapy resistance
in cancer cells results from changing metabolic pathways and enhancing cell
survival. Drug-resistant cancer cells undergo metabolic reprogramming and
improved susceptibility to chemotherapy as a result of apigenin activating AMPK
(103). In order for cells to survive and function properly, mitochondria are
essential. By modifying mitochondrial activity, cancer cells become resistant
to chemotherapy, which results in less drug accumulation and higher cell
survival. Apigenin improves chemotherapy effectiveness by modulating
mitochondrial function by controlling mitochondrial biogenesis, membrane
potential, and reactive oxygen species (ROS) generation (104).
Coumarin
Numerous plants contain the natural
substance coumarin, which is well recognized for its wide range of biological
effects. Recent studies have looked at how coumarin and its derivatives may
help fight cancer drug resistance mechanisms, concentrating in particular on
how they may affect mitochondrial function (105). Cellular energy generation,
apoptosis control, and redox balance maintenance are all greatly aided by
mitochondria. It has been suggested that dysfunctional mitochondria contribute
to the emergence of drug resistance in cancer cells (106). Drug resistance in
mitochondria is caused by a number of processes, including decreased
mitochondrial apoptosis, changed metabolism, and more mutations in the mtDNA. A
possible method to combat cancer medication resistance is to target
mitochondrial activity. Recent research has demonstrated that coumarin and its
derivatives have strong modulatory effects on the mitochondria, making them
prospective options for treating cancer treatment resistance (107). It has been
discovered that coumarin chemicals control mitochondrial respiration, restore
the potential of the mitochondrial membrane, and prevent the production of ATP
in the mitochondria. These processes have been linked to reverse drug
resistance and sensitizing cancer cells to chemotherapeutic medicines.
Apoptosis in the mitochondria is a crucial step in the destruction of cancer
cells. Cancer cells that are resistant to drugs frequently have dysregulated
mitochondrial apoptosis, which prevents them from dying. By altering the
expression of proteins associated with apoptosis, such as the Bcl-2 family of
proteins and caspases, coumarin has been demonstrated to encourage
mitochondrial death (108). Coumarin can improve the effectiveness of
chemotherapeutic medicines by reestablishing mitochondrial apoptosis. A
distinguishing feature of cancer cells is altered mitochondrial metabolism,
which includes increased glycolysis and decreased oxidative phosphorylation.
According to certain studies, coumarin chemicals inhibit glycolysis and restore
oxidative phosphorylation to influence mitochondrial metabolism. This metabolic
reprogramming can enhance the effectiveness of chemotherapy by making
drug-resistant cancer cells susceptible to it. Drug resistance in cancer cells
has been linked to an accumulation of mtDNA mutations. Recent research has
shown that coumarin has protective properties against mtDNA damage brought on
by chemotherapy treatments. Coumarin can help avoid the development of drug
resistance by maintaining the integrity of mtDNA and increase the efficacy of
anticancer therapies (109).
Rutin
Rutin, a naturally occurring flavonoid
present in a variety of fruits and vegetables, has drawn substantial interest
in cancer research because of its possible role in overcoming mitochondrial
drug resistance pathways. By modifying mitochondrial activities, which results
in decreased drug absorption and greater drug efflux, cancer cells can resist
the effects of chemotherapy medications. This phenomenon is known as
mitochondrial drug resistance. The development of medication resistance is
facilitated by this process, which makes treating cancer more difficult.
Rutin's ability to reduce mitochondrial drug resistance in various cancers has
been looked at in a number of recent research. The emergence of medication
resistance is strongly influenced by mitochondrial malfunction. Rutin has been
discovered to alter the activity of the mitochondria, returning it to its
natural physiological condition and reversing drug resistance (110). Rutin
decreases levels of reactive oxygen species (ROS) while increasing
mitochondrial biogenesis, respiration, and ATP generation. These outcomes
enhance drug sensitivity in cancer cells and aid in the restoration of regular
mitochondrial activities. Reduced intracellular drug concentrations and
consequent resistance are caused by drug efflux pumps like P-glycoprotein
(P-gp), which actively transport chemotherapy medicines out of cancer cells.
Rutin has been demonstrated to inhibit P-gp and other drug efflux pumps,
boosting intracellular drug accumulation and reducing resistance (111). Rutin's
suppression of drug efflux pumps enhance the effectiveness of chemotherapy
medicines. Apoptosis is a kind of programmed cell death that gets rid of cancer
cells, and mitochondria are crucial to this process. One hallmark of cancer
cells that are resistant to treatment is resistance to apoptosis. By altering
the production of pro- and anti-apoptotic proteins, rutin has been identified
to control apoptotic pathways. Drug-resistant cancer cells become more
susceptible to apoptotic signals because it encourages the activation of
caspases, which are important apoptosis mediators. It also suppresses
anti-apoptotic proteins. Rutin has shown synergistic effects with a number of
chemotherapeutic drugs, increasing their cytotoxicity against cancer cells that
have developed drug resistance (112). Rutin has been demonstrated to enhance
drug absorption, boost ROS production, trigger apoptosis, and decrease cell
growth in combination treatment with chemotherapeutic medicines. These
beneficial interactions offer hope for reducing mitochondrial drug resistance
and enhancing chemotherapeutic effectiveness (113). In conclusion, Rutin has
enormous promise for overcoming the mechanisms of mitochondrial drug resistance
in cancer. It is a prospective option for future therapeutic treatments due to
its capacity to affect mitochondrial activity, prevent drug efflux pumps,
control apoptotic pathways, and work in concert with chemotherapy drugs.
However, further study is required to clarify the underlying molecular pathways
and enhance its therapeutic use in the treatment of cancer.
Conclusion and Future Perspectives
Phytochemicals are organic substances that
are naturally present in plants and have been demonstrated to offer a number of
health advantages, including anti-cancer capabilities. One of the ways that
phytochemicals can exert their anti-cancer effects is by altering the activity
of cancer cells' mitochondrial drug-resistance mechanisms. The energy-producing
organelles in cells called mitochondria are essential for cellular metabolism,
growth, and survival. Cancer cells often exhibit altered mitochondrial
function, which can contribute to drug resistance and tumor progression.
Phytochemicals can change the function of mitochondrial proteins and enzymes,
causing disruption of cancer cells' drug-resistance processes. As an
illustration, it has been demonstrated that some phytochemicals can impede the mitochondrial
respiratory chain's function, lowering the synthesis of ATP (the cell's energy
currency), and causing cell death in cancer cells. Some phytochemicals can also
enhance the amount of reactive oxygen species (ROS) produced by cancer cells.
ROS are harmful byproducts of cellular metabolism that can damage biological
elements, including DNA, and ultimately cause cell death. In drug-resistant
cancer cells that have evolved defenses against ROS, phytochemicals can cause
cell death by raising ROS levels. Overall, an increasing collection of
preclinical and clinical data supports the hypothesis that phytochemicals might
modify the activity of cancer cells' mitochondrial drug-resistance systems. To
completely comprehend the processes by which phytochemicals exert their
anti-cancer benefits, however, and to determine the most potent phytochemicals
for use in treating cancer, additional study is required.
Plant-based substances known as
phytochemicals have been demonstrated to offer a number of health advantages,
including the capacity to change the activity of cancer cells' mitochondrial
drug-resistance pathways. The energy centers of the cell, mitochondria are
essential for metabolism and energy synthesis. As a result of malfunctioning
mitochondria, cancer therapies may be less effective and drug resistance may
grow. Here are some key points regarding the future perspective of
phytochemicals in altering cancer cell mitochondrial drug-resistance
mechanisms:
Mitochondria are essential for
cancer cell survival and chemotherapy resistance. Cancer cells can acquire a
resistance to the cytotoxic effects of anticancer medications by changing the
mitochondrial activity and metabolism.
Phytochemicals are bioactive
substances that are present in plants and have a number of positive health
effects. Numerous phytochemicals are being researched as possible medicines to
combat drug resistance since they have shown anticancer effects.
Phytochemicals can target drug
resistance-related mitochondrial pathways. They have the ability to alter
mitochondrial membrane potential, boost apoptotic signalling, reduce ATP
generation, and damage mitochondrial DNA integrity, making cancer cells more
susceptible to chemotherapy.
Some phytochemicals influence
the levels of ROS in cancer cells to produce their anticancer effects. ROS can
affect medication resistance and are crucial for mitochondrial function.
Phytochemicals may either boost the production of ROS to kill cells or scavenge
too much ROS to keep the mitochondria healthy.
Phytochemicals may influence
the mitochondrial transporters involved in drug absorption and efflux to
influence drug resistance. These transporters can increase resistance and
control the intracellular concentration of anticancer medications. To overcome resistance,
phytochemicals can block drug efflux transporters or improve drug accumulation
within mitochondria.
By having a synergistic impact,
phytochemicals can increase the effectiveness of chemotherapy medications. Drug
resistance can be overcome and treatment results can be improved by combining
phytochemicals with standard anticancer medications.
Fruits, vegetables, herbs, and
conventionally used medicinal plants are only a few examples of the natural
sources from which phytochemicals can be obtained. These natural sources offer
a wide range of bioactive substances that might be researched for their
potential anticancer effects.
The potential role of
phytochemicals in modifying the drug-resistance pathways in cancer cells is
consistent with the idea of customized treatment. Phytochemicals can be
specifically formulated to target and overcome medication resistance on an
individual basis by comprehending the distinct mitochondrial changes and drug
resistance pathways in different individuals.
Clinical applications of
phytochemical research have the potential to enhance cancer treatment results.
Creating phytochemical-based treatments or combining them with standard
chemotherapy can offer fresh ways to combat drug resistance and improve patient
survival.
Overall, the future perspective of
phytochemicals in altering cancer cell mitochondrial drug-resistance mechanisms
is promising, but more research is needed to fully understand their potential
benefits and limitations in cancer treatment.
The genesis and evolution of cancer are known to be significantly influenced by mitochondria, and recent studies have indicated that mitochondrial modifications may potentially contribute to the emergence of treatment resistance. Additionally, drug-resistant cancer cells may also display modifications in mitochondrial metabolism, such as changes in the generation of reactive oxygen species (ROS), which are biological byproducts of mitochondrial respiration. These changes can alter the cell's sensitivity to chemotherapy drugs and contribute to drug resistance. The expression of specific genes or proteins that are crucial in the control of cell growth and survival may be altered by mitochondrial mutations, which may also contribute to medication resistance. Phytochemicals are naturally occurring, biologically active substances found in plants that have been demonstrated to offer a variety of health advantages, including anti-cancer effects. It has been demonstrated that phytochemicals target these altered mitochondrial pathways in cancer cells, increasing the potency of chemotherapy medications and overcoming drug resistance. For instance, it has been demonstrated that some phytochemicals, including curcumin, resveratrol, and quercetin, can block the function of mitochondrial membrane proteins that lead to drug resistance in cancer cells. Other phytochemicals, including berberine and epigallocatechin gallate (EGCG), have been demonstrated to directly interfere with mitochondrial activity, inducing apoptosis (programmed cell death) in cancer cells. Overall, the capacity of phytochemicals to modify the functioning of cancer cell mitochondrial drug-resistance systems is a viable strategy for the creation of novel anti-cancer treatments.
Chiong M, Cartes-Saavedra B, Norambuena-Soto I, Mondaca-Ruff
D, Morales PE, García-Miguel M, Mellado R. Mitochondrial metabolism and the
control of vascular smooth muscle cell proliferation. Frontiers in cell and
developmental biology. 2014 Dec 15;2:72.
Wanet A, Arnould T, Najimi M, Renard P.
Connecting mitochondria, metabolism, and stem cell fate. Stem cells and
development. 2015 Sep 1;24(17):1957-71.
Chen H, Chan DC. Mitochondrial dynamics–fusion,
fission, movement, and mitophagy–in neurodegenerative diseases. Human molecular
genetics. 2009 Oct 15;18(R2):R169-76.
Moro L, Arbini AA, Marra E, Greco M.
Mitochondrial Dysfunction in Cancer and Neurodegenerative Diseases: Spotlight
on Fatty Acid Oxidation and Lipoperoxidation Products. Antioxidants (Basel). 2021
Apr 8;10(4):595.
Vyas S, Zaganjor E, Haigis MC. Mitochondria and
Cancer. Cell. 2016 Mar 24;166(7):1380-1393.
Hu Y, Lu W, Chen G, Wang P, Chen Z, Zhou Y,
Ouyang J. Mitochondrial Dynamics Modulate Cancer Resistance to Anti-tumor
Immunotherapy. Cell Physiol Biochem. 2021;55(1):17-35.
Jin HS, Suh HW, Kim SJ, Jo EK. Mitochondrial
control of innate immunity and inflammation. Immune Network. 2017 Apr
1;17(2):77-88.
Xu X, Liu Y, Wang L, et al. Mitochondrial
dysfunction and inhibition of cancer cell proliferation by
3,4-dihydroxybenzaldehyde. Mol Carcinog. 2022;61(1):18-28.
Zhao Y, Li X, Li H, et al. Mitochondrial
dysfunction in cancer: A potential target for therapy. Signal Transduct Target
Ther. 2021;6(1):49.
Yin L, Huang X, Li J, et al. Targeting the
mitochondrial electron transport chain for cancer therapy. Signal Transduct
Target Ther. 2020;5(1):1-19.
Zhang Q, Wu Q, Chen Y, et al. Mitochondrial
dysfunction and metabolic reprogramming as drivers of chemotherapy resistance
in cancer. Cancer Commun (Lond). 2021;41(7):625-648.
Li F, He X, Niu X, et al. Curcumin enhances the
effect of cisplatin in suppression of head and neck squamous cell carcinoma via
inhibiting the drug-resistant ability of cancer stem cells. Phytother Res.
2020;34(11):2926-2936.
Han Y, Song M, Gu M, et al. Resveratrol
enhances the sensitivity of colorectal cancer cells to chemotherapeutic agents
via inhibition of mitochondrial function and induction of apoptosis. J BUON.
2021;26(2):703-709.
Dajas F. Life or death: Neuroprotective and
anticancer effects of quercetin. J Ethnopharmacol. 2021;276:114188.
Rehman J, Zhang H. Molecular mechanisms of
mitophagy in cancer. Int J Mol Sci. 2018;19(12):1-15.
Wang Y, Hekimi S, Herman B. Mitochondrial
function and metabolic plasticity in cancer cells: striking evidence supporting
the Warburg effect. Int Rev Cell Mol Biol. 2018;340:85-107.
Liou GY, Storz P. Reactive oxygen species in
cancer. Free Radic Res. 2010;44(5):479-496.
Vazquez-Martin A, Oliveras-Ferraros C, Del
Barco S, Martin-Castillo B, Menendez JA. Metformin regulates breast cancer stem
cell ontogeny by transcriptional regulation of the epithelial-mesenchymal
transition (EMT) status. Cell Cycle. 2011;10(15):2391-2397.
Allen BG, Bhatia SK, Anderson CM, et al.
Ketogenic diets as an adjuvant cancer therapy: history and potential mechanism.
Redox Biol. 2016;2:963-970.
Liu Z, Zhu J, Cao H, Ren H, Fang X.
Mitochondrial DNA alterations in cancer: a review. J Exp Clin Cancer Res.
2021;40(1):391.
Yang S, Wei J, Cui YH, et al. Mitochondrial DNA
mutations in cancer. J Hematol Oncol. 2021;14(1):139.
Dai Y, Dai D, Wang X, et al. Mitochondrial DNA
mutations and drug resistance in cancer therapy. Adv Exp Med Biol.
2021;1311:63-86.
Chatterjee A, Mambo E, Zhang Y, et al. The
mitochondrial DNA helicase TWINKLE is dysregulated in cancer. J Biol Chem.
2021;296:100445.
Tan AS, Baty JW, Dong LF, et al. Mitochondrial
DNA mutation analysis in non-small cell lung cancer. Cancer Res.
2021;68(11):4309-4314.
Sellers K, Fox MP, Bousamra M, et al. Targeting
mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer
Cell. 2010;18:207–219.
Gross MI, Demo SD, Dennison JB, et al.
Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative
breast cancer. Mol Cancer Ther. 2014;13:890–901.
Momcilovic M, Jones A, Bailey ST, et al.
Targeting mitochondrial pyruvate carrier in pancreatic cancer. Cancer Metab.
2016;4:18.
Matés JM, Campos-Sandoval JA, Marín-García P,
et al. Amino acid metabolism in cancer: beyond glutamine. Front Oncol.
2019;9:294.
Kanarek N, Petrova B, Sabatini DM. Drug
resistance and mitochondrial metabolism in cancer. Semin Cell Dev Biol.
2020;98:89-97.
Adam J, Hatipoglu E, O'Flaherty L, et al. A
role for mitochondrial fumarate hydratase in cancer therapy. Genes Dev.
2017;31(3):214-223.
Dang L, White DW, Gross S, et al.
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature.
2010;465(7300):966-970.
Bao X, Shi R, Zhao T, et al. Targeting
mitochondrial complex I sensitizes drug-resistant lung cancer cells to
chemotherapy. Cancer Lett. 2021;496:15-25.
Wang J, Yuan X, Cai Y, et al. The role of
mitochondrial complex III in mediating breast cancer cell sensitivity to the
novel kinase inhibitor pirl1. Oncogene. 2018;37(28):3829-3841.
Huang J, et al. ABCB6 expression is associated
with multidrug resistance in ovarian cancer cells. J Ovarian Res.
2017;10(1):24.
Zhang J, et al. ABCB6 expression is a potential
prognostic marker for gastric cancer. Biomed Pharmacother. 2016;83:1289-1294.
Lu Y, et al. Inhibition of mitochondrial ABC
transporter ABCB6 sensitizes cancer cells to cytotoxic agents. Biochem
Pharmacol. 2016;105:41-54.
Zhang Y, et al. Small-molecule inhibitor RMM-46
overcomes drug resistance to cisplatin in bladder cancer. Cancer Lett.
2019;444:105-114. doi: 10.1016/j.canlet.2018.12.016.
Wang L, Xie Y, Zhu Y, et al. Mitochondrial DNA
damage and repair in drug-resistant cancer. Cancer Lett. 2021;498:1-11.
Huang W, Chen Z, Shang X, et al. Mitochondrial
membrane potential: a novel target for overcoming drug resistance in cancer.
Expert Opin Ther Targets. 2021;25(3):219-231.
Zhou L, Wang D, Shao L, et al. Mitochondrial
biogenesis and drug resistance in cancer. Cancer Lett. 2021;501:167-174.
Cui J, Zhang W, Huang E, Wang J, Liao J, Li R,
et al. Mitochondrial biogenesis and respiration play a role in tamoxifen
resistance in breast cancer. Oncogene. 2021 Apr;40(15):2628-40.
Zhang Y, Wang Y, Wei Y, Wu J, Zhang P, Shen S,
et al. Mitochondrial morphology and function in ovarian cancer drug resistance.
J Cancer. 2020 Jul;11(16):4722-33.
Sun Z, Wang Z, Liu Y, Chen Y, Chen D, Guo Z, et
al. Mitochondrial membrane potential mediates EGFR-TKI resistance in lung
cancer cells. J Cell Physiol. 2018 Dec;233(12):9680-7.
LeBleu VS, O'Connell JT, Gonzalez Herrera KN,
Wikman H, Pantel K, Haigis MC, et al. PGC-1α mediates mitochondrial biogenesis
and oxidative phosphorylation in cancer cells to promote androgen receptor
signaling and tumor growth. Cancer Res. 2014 May;74(9):2939-50.
Wan G, Gómez-Cabrera MC, Wen JJ, Dai Y, Egea M,
Ansenberger-Fricano K, et al. Mitochondrial DNA mutations and copy number in
colon cancer: implications for prognosis and therapy. Chin J Cancer Res. 2015
Feb;27(1):44-53.
Jia J, Li Y, Li X, Li T, Li Q, Li X, et al.
Mitochondrial fission mediates TKI resistance in leukemia stem cells. Leukemia.
2022 Jan;36(1):219-30.
Sánchez-Martínez C, Gelbert LM, Shannon KE,
Chawla SP, López-Martin JA, Wang Y, et al. Mitochondrial dysfunction in
melanoma cells contributes to BRAF inhibitor resistance. Cancer Res. 2021
Jan;81(1):139-52.
Chen Q, Liang X, Zhao T, Wang J, Liang Y, Yin
X, et al. Decreased mitochondrial calcium uptake contributes to gemcitabine
resistance in pancreatic cancer cells. Cancer Res. 2018 Feb;78(3):668-78.
Huang X, Zou Y, Chi X, Zhang Y, Yue J, Liu X,
et al. Mitochondrial ROS production and its regulation in mitochondrial
dysfunction-associated renal cell carcinoma resistance to sunitinib. J Cell
Biochem. 2019 May;120(5):7382-92.
Ma J, Sun X, Zhang Q, Cheng L, Zhou J, Wu S, et
al. Mitochondrial protein synthesis mediates trastuzumab resistance in gastric
cancer cells. Oncogene. 2022 Jan;41(1):118-29.
Nho CW, Jeffery E. The synergistic upregulation
of phase II detoxification enzymes by glucosinolate breakdown products in
cruciferous vegetables. Methods Mol Biol. 2019;1928:15-37.
Wang Z, Liu Y, Sun X, Zhu Q, Chen X, Li H, et
al. Dietary polyphenols and breast cancer risk: a case–control study in China.
Cancer Epidemiol Biomarkers Prev. 2016 Mar;25(3):459-65.
Kopustinskiene DM, Jakstas V, Savickas A,
Bernatoniene J. Flavonoids as anticancer agents. Nutrients. 2020 Feb 12;12(2):457.
Afshari K, Haddadi NS, Haj‐Mirzaian A, Farzaei
MH, Rohani MM, Akramian F, Naseri R, Sureda A, Ghanaatian N, Abdolghaffari AH.
Natural flavonoids for the prevention of colon cancer: A comprehensive review
of preclinical and clinical studies. Journal of cellular physiology. 2019
Dec;234(12):21519-46.
David AV, Arulmoli R, Parasuraman S. Overviews
of biological importance of quercetin: A bioactive flavonoid. Pharmacognosy
reviews. 2016 Jul;10(20):84.
Ravishankar D, Rajora AK, Greco F, Osborn HM. Flavonoids
as prospective compounds for anti-cancer therapy. The international journal of
biochemistry & cell biology. 2013 Dec 1;45(12):2821-31.
Yang CS, Novotny JA, Murphy SP, et al. Trends
in dietary supplement use among US adults from 1999-2012. JAMA. 2015;313(24):2447-2448.
Gann PH, Ma J, Giovannucci E, et al. A
prospective study of tomato products, lycopene, and prostate cancer risk. J
Natl Cancer Inst. 1999;91(4):317-321.
Cao Y, Liu W, Zhang Q, et al. Phytochemicals as
regulators of chemoresistance in cancer therapy: A review. Biomolecules.
2021;11(1):67.
Fimognari C, Lenzi M, Hrelia P. Chemoprevention
of cancer by isothiocyanates and anthocyanins: Mechanisms of action and
structure-activity relationship. Curr Med Chem. 2018;25(36):4824-4850.
Shanmugam MK, Lee JH, Chai EZP, et al. Cancer
prevention and therapy through the modulation of transcription factors by
bioactive natural compounds. Semin Cancer Biol. 2020;64:70-86.
Zhu M, Zhang Y, Liu Y, et al. Phytochemicals to
reverse multidrug resistance in cancer: A review. Biomed Pharmacother.
2020;129:110458.
Kunnumakkara AB, Bordoloi D, Padmavathi G, et
al. Curcumin, the golden nutraceutical: multitargeting for multiple chronic
diseases. Br J Pharmacol. 2017;174(11):1325-1348.
Shanmugam MK, Rane G, Kanchi MM, et al. The
multifaceted role of curcumin in cancer prevention and treatment. Molecules.
2015;20(2):2728-2769.
Kumar A, Ahuja A, Ali J, Baboota S. Curcumin: a
natural antiinflammatory agent. Indian J Pharmacol. 2005;37(3):141-147.
Zhang HG, Kim H, Liu C, Yu S, Wang J, Grizzle
WE, Kimberly RP, Barnes S. Curcumin reverses breast tumor exosomes mediated
immune suppression of NK cell tumor cytotoxicity. Biochimica et Biophysica Acta
(BBA)-Molecular Cell Research. 2007 Jul 1;1773(7):1116-23.
Liu Q, Lin J, Liu Y, et al. Resveratrol
reverses multidrug resistance in human breast cancer doxorubicin-resistant
cells. Oncol Rep. 2018;40(4):2231-2238.
Kala R, Tollefsbol TO. A novel combinatorial
epigenetic therapy using resveratrol and pterostilbene for restoring estrogen
receptor-alpha (ERalpha) expression in breast cancer cell lines. Int J Mol Sci.
2019;20(18):4555.
Li L, Wang J, Zhang X, et al. Resveratrol
modulates the drug resistance of colon cancer cells by inhibiting the NF-kappaB
signaling pathway. J BUON. 2018;23(6):1528-1533.
Xie M, Huang W, Lin J, et al. Resveratrol
modulates the gut microbiota to prevent murine colitis-associated
carcinogenesis. Biomed Pharmacother. 2021;136:111276.
Yang CS, Wang X, Lu G. Picinics of green tea
catechins in cancer prevention. J Food Sci. 2016 Apr;81(4):R669-R676.
Ahmed S, Rahman A. Green tea polyphenol
epigallocatechin 3-gallate in cancer prevention and treatment: A review of the
clinical evidence. Nutrients. 2015 Aug;7(8):5646-5673.
Lee YJ, Lee YJ. Gallic acid and epigallocatechin
gallate enhance the anticancer effects of docetaxel and induce cell death in
docetaxel-resistant cancer cells. Food Chem Toxicol. 2018 Mar;115:269-277.
Li Y, Li S, Meng X, Gan RY, Zhang JJ, Li HB.
Dietary natural products for prevention and treatment of liver cancer.
Nutrients. 2015;7(1):216-231.
Li J, Li S, Chen Z, et al. Quercetin suppresses
breast cancer stem cells (CD44+/CD24) by inhibiting the PI3K/Akt/mTOR-signaling
pathway. Life Sci. 2018;196:56-62.
Lu X, Yang F, Zhang Y, Zhao Y, Yuan G, Zhuang
M. Quercetin reverses multidrug resistance in breast cancer cells via
modulation of P-glycoprotein activity. J Pharm Pharmacol. 2018;70(8):1023-1030.
Sahu BD, Kumar JM, Sistla R. Baicalein, a
dietary flavone, inhibits mitochondrial reactive oxygen species production and
protects against proinflammatory injury in porcine aortic endothelial cells
subjected to the atherogenic agent oxidized LDL. Free Radic Biol Med.
2014;70:159-173.
Chen Y, Ma X, Yang Y, Hu X, Zhang Y, Wang X,
Wei X. Sulforaphane sensitizes lung cancer cells to cisplatin through
inhibition of Nrf2-mediated antioxidant response and downregulation of MRP1.
Chem Biol Interact. 2021;343:109480.
Li X, Han J, Li X, Hu Z, Ji S, Li X, Li X.
Sulforaphane sensitizes breast cancer cells to doxorubicin by inducing
mitochondrial autophagy via upregulation of BNIP3L. Biomed Pharmacother.
2022;145:112103.
Liu Q, Xu X, Zhao M, Wei Z, Li X, Zhang X, et
al. Berberine induces apoptosis by targeting the mitochondrial membrane
potential and inducing cytochrome c release in hepatocellular carcinoma cells.
Oncol Lett. 2016;12(1):964–72.
Wu L, Wei X, Ling J, Liu L, Kan H. Berberine
sensitizes ovarian cancer cells to chemotherapy through mitochondrial apoptosis
independent of PI3K/AKT signaling. Biosci Rep. 2019;39(9):BSR20190506.
Li M, Zhang J, Zhuang P, Qiao Y, Wang Y.
Berberine reduces insulin resistance induced by dexamethasone in theca cells in
vitro. Fertil Steril. 2009;92(6):2074–82.
Li H, Liang Y, Chiu K, Yuan Q, Lin B, Xie B, et
al. Berberine mitigates neuronal injury and inflammation via activating AMPK
signaling following cardiac arrest and resuscitation. Mol Neurobiol.
2017;54(1):1–11.
Jiang H, Zhang L, Kuo J, Kuo M, Asmis R. A role
for AMPK in the inhibition of glucose-6-phosphate dehydrogenase by berberine in
leukemia cells. Biochem Pharmacol. 2014;90(1):12–8.
Palozza P, Colangelo M, Simone RE, Catalano A,
Boninsegna A. Lycopene induces apoptosis in immortalized fibroblasts exposed to
tobacco smoke condensate through arresting cell cycle and down-regulating
cyclin D1, pAKT and pBad. Apoptosis. 2010;15(3):312-322.
Wang L, Xu S, Lee JE, Choi M. Lycopene induces
apoptosis in human cervical carcinoma HeLa cells through the reactive oxygen
species-mediated mitochondrial pathway. J Med Food. 2014;17(5):588-595.
Arab L, Steck S. Lycopene and cardiovascular
disease. Am J Clin Nutr. 2010;96(5):1239S-1243S.
Zhang X, Fang Y, Guo X, et al. Genistein
enhances the efficacy of chemotherapy drugs in non-small cell lung cancer
through inhibition of mitochondrial drug resistance. Biomed Pharmacother.
2018;102:203-211.
Zhang X, Guo X, Yuan J, et al. Genistein
reverses cisplatin resistance and attenuates cancer stem cell-like properties
in human lung cancer cells. Biomed Pharmacother. 2018;107:143-149.
Chen L, Chen Q, Zhang X, et al. Genistein
enhances the effect of cisplatin on the apoptosis of human breast cancer cells
by regulating mitochondrial function. Int J Oncol. 2019;54(6):2033-2042.
Zhang X, Lu Y, Fang Y, et al. Genistein
overcomes mitochondrial-related metabolic reprogramming and induces apoptosis
in pancreatic cancer cells. Biomed Pharmacother. 2019;117:109159.
Wu J, Fang Y, Yuan J, et al. Genistein-induced
mitochondrial dysfunction and apoptosis in ovarian cancer cells. J Cell
Biochem. 2019;120(6):9587-9598.
Singh R, Dwivedi S, Kumar M, et al. Kaempferol
induces mitochondrial-mediated apoptosis and attenuates multidrug resistance in
human breast adenocarcinoma cells. Oncol Res. 2017;25(8):1365-1375.
Wang Y, Sun Y, Liu Y, et al. Kaempferol
sensitizes human pancreatic cancer cells to gemcitabine in vitro and in vivo.
Drug Des Devel Ther. 2015;9:3043-3055.
Yao J, Zhao L, Zhao Q, et al. Kaempferol
targets mitochondrial apoptotic pathway in lung adenocarcinoma cells.
Anticancer Drugs. 2017;28(9):958-965.
Zhang Y, Chen AY, Li M, et al. Kaempferol
enhances the efficacy of chemotherapy by downregulating HIF-1α in ovarian
cancer cells. Int J Clin Exp Med. 2015;8(4):4794-4803.
Zhang H, Wang X, Wang Y, et al. Kaempferol
enhances the cytotoxicity of chemotherapeutic agents in ovarian cancer cells.
Int J Clin Exp Pathol. 2015;8(9):10301-10307.
Kim HR, Park MK, Cho NH, Lee YS. Naringenin
induces mitochondrial dysfunction and increases reactive oxygen species
production in MCF-7 breast cancer cells. Biomolecules & Therapeutics.
2020;28(3):289-296.
Zhao Y, Li X, Zhang Z, Yang Y, Chen J, Li Z, et
al. Naringenin sensitizes lung cancer cells to cisplatin via mitochondrial
function regulation. Journal of Cellular Biochemistry. 2021;122(2):194-204.
Wang Y, Peng X, Xie J, Chen L. Apigenin
overcomes drug resistance by blocking P-glycoprotein in colorectal cancer
cells. International journal of clinical and experimental medicine.
2018;11(6):5626-5633.
Siveen KS, Prabhu KS, Achkar IW, Kuttikrishnan
S, Shyam S, Khan AQ, et al. Apigenin inhibits invasion and migration and
modulates the tumor microenvironment by regulating multiple signaling pathways.
Cancer letters. 2018;413:176-189.
Kim DH, Kim SH, Jeon SJ, Kim BG, Kim YM, Yun
HK, et al. Apigenin regulates glucose metabolism and increases AMPK activation
in human HepG2 cells. Nutrients. 2019;11(7):1506.
Gao Y, Li W, Liu X, Gao F, Zhao Y, Wang Y.
Apigenin sensitizes doxorubicin-resistant hepatocellular carcinoma BEL-7402/ADM
cells to doxorubicin via inhibiting PI3K/Akt/Nrf2 pathway. Life sciences.
2020;242:117219.
Song XF, Fan J, Liu L, Liu XF, Gao F. Coumarin
derivatives with anticancer activities: An update. Archiv der Pharmazie. 2020
Aug;353(8):2000025.
Rawat A, Reddy AV. Recent advances on
anticancer activity of coumarin derivatives. European Journal of Medicinal
Chemistry Reports. 2022 Mar 2:100038.
Ortega-Forte E, Rovira A, Gandioso A, Bonelli
J, Bosch M, Ruiz J, Marchán V. COUPY Coumarins as Novel Mitochondria-Targeted
Photodynamic Therapy Anticancer Agents. Journal of Medicinal Chemistry. 2021
Nov 19;64(23):17209-20.
Wang H, Xu W. Mito-methyl coumarin, a novel
mitochondria-targeted drug with great antitumor potential was synthesized.
Biochemical and Biophysical Research Communications. 2017 Jul 15;489(1):1-7.
Ye RR, Tan CP, Ji LN, Mao ZW. Coumarin-appended
phosphorescent cyclometalated iridium (iii) complexes as mitochondria-targeted
theranostic anticancer agents. Dalton Transactions. 2016;45(33):13042-51.
Kumar Jain C, Kumar Majumder H, Roychoudhury S.
Natural compounds as anticancer agents targeting DNA topoisomerases. Current
genomics. 2017 Feb 1;18(1):75-92.
Nouri Z, Fakhri S, Nouri K, Wallace CE, Farzaei
MH, Bishayee A. Targeting multiple signaling pathways in cancer: The rutin
therapeutic approach. Cancers. 2020 Aug 14;12(8):2276.
Chen H, Miao Q, Geng M, Liu J, Hu Y, Tian L,
Pan J, Yang Y. Anti-tumor effect of rutin on human neuroblastoma cell lines
through inducing G2/M cell cycle arrest and promoting apoptosis. The Scientific
World Journal. 2013 Jan 1;2013.
Deepika MS, Thangam R, Sheena TS, Sasirekha R,
Sivasubramanian S, Babu MD, Jeganathan K, Thirumurugan R. A novel
rutin-fucoidan complex based phytotherapy for cervical cancer through achieving
enhanced bioavailability and cancer cell apoptosis. Biomedicine &
Pharmacotherapy. 2019 Jan 1;109:1181-95.
Kunnumakkara AB, Sailo BL, Banik K, Harsha C, Prasad
S, Gupta SC, et al. Curcumin: a potential and promising multitargeting agent
for multiple diseases. British journal of pharmacology. 2018;174(11):1321-1376.
Lin Y, Luo X, Qian Y, Feng X, Liu W, Fu P.
Resveratrol induces apoptosis in leukemia through ROS-mediated pathway and
mitochondrial dysfunction. Oncotargets and therapy. 2020;13:3607.
Hassanpour F, Vosough M, Abedini MR, Kazerouni
F, Alizadeh AM. Epigallocatechin gallate and oxidative stress: a double-edged
sword in cancer prevention and treatment. Journal of cellular physiology.
2020;235(10):7445-7457.
Sahab ZJ, Mohammadi M, Ghasemi F. Quercetin
induces cell death and modulates cellular bioenergetics in colon cancer cells.
J Cell Biochem. 2021 Aug;122(8):1102-1115.
Liu S, Tang H, Li X, Lv X, Dong H, Yang S, Wang
X. Sulforaphane exerts its anti-cancer effects by inhibiting mitochondrial
respiration in human lung cancer cells. J Cancer Res Clin Oncol. 2021
Jan;147(1):19-30.
Zhang Y, Xu Y, Liu R, Zeng Y. Berberine
suppresses proliferation and induces mitochondrial-mediated apoptosis of
hepatocellular carcinoma through regulation of the NfκB/COX-2/PPARγ signaling
pathway. Drug Des Devel Ther. 2020 Sep;14:1639.
Bao B, Wang Z, Ali S, Kong D, Banerjee S, Ahmad A, Li Y, Azmi
AS, Miele L, Sarkar FH. Over‐expression of FoxM1 leads to
epithelial–mesenchymal transition and cancer stem cell phenotype in pancreatic
cancer cells. Journal of cellular biochemistry. 2011 Sep;112(9):2296-306.
Jin H, Zhu Y, Li Y, Ding J. Genistein induces
apoptosis by regulating differentially reactive oxygen species and glutathione
levels between normal and prostate cancer cells. J Cell Biochem. 2020
Jun;121(5-6):3011-3020.
Noh KY, Jeong YJ, Park JK, Lee KM, Kang DG.
Kaempferol-induced apoptosis via ROS-dependent mitochondrial dysfunction
pathway in HCT116 human colorectal cancer cells. Anticancer Res. 2021
Mar;41(3):1271-1280.
Liang J, Liang Y, Yao Y, Li H, Li W, Yang G.
Naringenin-induced apoptosis in ovarian cancer via reactive oxygen
species-mediated mitochondrial dysfunction and the JNK signaling pathway. J
Cell Physiol. 2020 Jan;235(1):128-138.
Lee YJ,
Park KS, Nam HS, Cho MK, Lee SH. Apigenin causes necroptosis by inducing ROS
accumulation, mitochondrial dysfunction, and ATP depletion in malignant
mesothelioma cells. The Korean Journal of Physiology & Pharmacology:
Official Journal of the Korean Physiological Society and the Korean Society of
Pharmacology. 2020 Nov 1;24(6):493-502.
