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Chemotherapy-Associated Oxidative Stress: Impact on Chemotherapeutic Effectiveness:

Chemotherapy-Associated Oxidative Stress: Impact on Chemotherapeutic Effectiveness: Conklin 10.1177/1534735404270335 Conklin Chemotherapy-Associated Oxidative Stress Chemotherapy-Associated Oxidative Stress: Impact on Chemotherapeutic Effectiveness Kenneth A. Conklin, MD, PhD Antineoplastic agents induce oxidative stress in biological and react with molecular oxygen to form superoxide systems. During cancer chemotherapy, oxidative stress- radicals. Although superoxide is not highly toxic, induced lipid peroxidation generates numerous electro- mitochondrial superoxide dismutase generates philic aldehydes that can attack many cellular targets. These hydrogen peroxide from superoxide radicals, and, in products of oxidative stress can slow cell cycle progression the presence of reduced iron or copper, the highly of cancer cells and cause cell cycle checkpoint arrest, effects toxic hydroxyl radical is formed via Fenton or Haber- that may interfere with the ability of anticancer drugs to kill We iss r eact ions. T he cyt o chrome P450 cancer cells. The aldehydes may also inhibit drug-induced monooxygenase system of the hepatic endoplasmic apoptosis (programmed cell death) by inactivating death re- reticulum (microsomes) also generates a substantial ceptors and inhibiting caspase activity. These effects would amount of ROS in the process of metabolizing a chem- also diminish the efficacy of the treatment. The use of anti- ically diverse group of compounds that includes most oxidants during chemotherapy may enhance therapy by reducing the generation of oxidative stress-induced of the drugs that we administer as well as environmen- aldehydes. tal substances. The plasma and nuclear membranes are less active sites of ROS production, and enzyme systems, such as the xanthine-xanthine oxidase Keywords: antioxidants; apoptosis; chemotherapy; oxidative stress system, can also generate ROS. ROS can interact with cellular macromolecules, including DNA, protein, and lipids, and interfere with vital cellular functions. Mutations caused by ROS can Reactive oxygen species (ROS) are essential for life result in malignant transformation and the develop- because of their role in many vital processes such as ment of cancer. ROS are also implicated in the etiol- signal transduction and the ability of phagocytes to ogy and progression of many other diseases. Under carry out their bactericidal activity. ROS include free normal conditions, antioxidant mechanisms, includ- radicals, such as hydroxyl and superoxide radicals, ing small-molecular-weight antioxidants and antioxi- which are substances with one or more orbital elec dant enzyme systems, scavenge ROS and protect the trons with unpaired spin states, and nonradicals, organism from the damaging effects of oxidative including hydrogen peroxide and singlet oxygen stress. However, under conditions of excessive oxida- (Table 1). Although carefully controlled processes tive stress, for example, those which occur with the regulate the production of ROS for their essential administration of certain drugs, cellular antioxidant functions, many cellular processes result in the gener mechanisms may be unable to prevent the adverse ation of ROS. An important site of this nonessential impact of ROS on critical cellular processes. In cancer generation of ROS, which constitutes oxidative stress, cells, processes such as the ordered progression is the electron transport system (ETS; Figure 1) that through the cell cycle and intact apoptotic processes resides within the inner membrane of mitochondria. are necessary for antineoplastic agents to exert their Normally, electrons are transferred from complex I optimal cytotoxic activity. Since many antineoplastic (NADH dehydrogenase) and complex II (succinate agents are capable of producing oxidative stress in dehydrogenase) to coenzyme Q10 and then to com- plex III, cytochrome c, and complex IV. Finally, 4 elec- trons are transferred to oxygen with the formation of KAC is at the Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles. water. In the process, coupling of electron transport to Correspondence: Kenneth A. Conklin, MD, PhD, Department of oxidative phosphorylation results in adenosine Anesthesiology, David Geffen School of Medicine at UCLA, Box triphosphate generation. Although this process is very 951778, Los Angeles, CA 90095-1778. E-mail: kconklin@ efficient, about 2% of the electrons escape the ETS mednet.ucla.edu. DOI: 10.1177/1534735404270335 294 INTEGRATIVE CANCER THERAPIES 3(4); 2004 pp. 294-300 Chemotherapy-Associated Oxidative Stress Table 1. Mediators of Oxidative Stress A T P Reactive oxygen species Complex I Free radicals Hydroxyl radical: HO NADH ⋅ Complex III Complex IV Superoxide radical: O dHase Nonradicals Cyt. b, c Cyt.a, a Hydrogen peroxide: H O 1 Cyt.c 3 2 2 CoQ O 1 10 2 Singlet oxygen: O Lipid peroxidation products Peroxyl radical: ROO· Succ. Alkoxyl radical: RO· dHase Secondary products Malondialdehyde Complex II 4-hydroxyalkenals Figure 1 The electron transport system. Electrons flow from com- From Conklin KA. Dietary polyunsaturated fatty acids: impact on plex I (NADH dehydrogenase) and complex II (succinate cancer chemotherapy and radiation. Altern Med Rev. 2002;7:4-21. dehydrogenase) to coenzyme Q10, then to complex III, Reprinted with permission. cytochrome c, and complex IV. The final transfer is a 4- electron transfer to oxygen with the formation of water. The electron transport system is coupled at 3 sites to biological systems, ROS generated during cancer oxidative phosphorylation that results in the formation of adenosine triphosphate (ATP). chemotherapy may interfere with the efficacy of the treatment. Chemotherapy-Associated chondria of all cells. In cardiac cells, doxorubicin can penetrate the outer mitochondrial membrane and en- Oxidative Stress ter the cytosol where it is reduced by the cytosolic Antineoplastic agents have been shown to produce ox- NADH dehydrogenase. Intramolecular rearrange- idative stress in patients who receive these drugs dur- 1-11 ment results in formation of the lipophilic deoxy- ing cancer chemotherapy. This is evident by the aglycone of doxorubicin that penetrates the inner elevation of lipid peroxidation products; the reduc- membrane. There it competes with coenzyme Q10 tion of total radical-trapping capacity of blood plasma; (both are structurally quinones) as an electron accep- the reduction in plasma levels of antioxidants such as tor, diverting electrons to molecular oxygen with the vitamin E, vitamin C, and β-carotene; and the marked formation of superoxide radicals. reduction of tissue glutathione levels that occurs dur- In contrast to the above groups of antineoplastic ing chemotherapy. Those agents that generate high agents, taxanes (eg, paclitaxel and docetaxel), vinca levels of ROS include the anthracyclines (eg, alkaloids (eg, vincristine and vinblastine), anti- doxorubicin, epirubicin, and daunorubicin), alky- metabolites such as the antifolates, and nucleoside lating agents, platinum coordination complexes (eg, and nucleotide analogues generate only low levels of cisplatin, carboplatin, and oxaliplatin), epi oxidative stress (Figure 2). However, all antineoplastic podophyllotoxins (eg, etoposide and teniposide), and agents generate some ROS as they induce apoptosis in the camptothecins (eg, topotecan and irinotecan; Fig cancer cells. This is because one of the pathways of ure 2). The anthracyclines generate by far the highest drug-induced apoptosis involves the release of levels of oxidative stress. This is due to their ability to cytochrome c from mitochondria. When this occurs, divert electrons from the ETS of cardiac mitochon electrons are diverted from the ETS to oxygen by dria, resulting in formation of superoxide radicals, in NADH dehydrogenase and reduced coenzyme Q10, addition to generating ROS at other cellular sites. resulting in the formation of superoxide radicals. Doxorubicin, the most studied anthracycline, pos Oxidative stress interferes with cellular processes sesses a sugar moiety attached to a tetracycline ring (cell cycle progression and drug-induced apoptosis; that contains a quinone structure. Disruption of the see below) that are necessary for antineoplastic agents ETS by doxorubicin can occur only following reduc to exert their optimal cytotoxicity on cancer cells, and tion of the quinone to its semiquinone. Doxorubicin is modest levels of oxidative stress have been shown to hydrophilic and, in mitochondria of most cells, it can 15,16 reduce the cytotoxicity of anticancer drugs. Thus, not penetrate the inner membrane and be reduced by the formation of ROS that occurs when anticancer NADH dehydrogenase (complex I), which is located drugs are administered may diminish the effectiveness on the inner (matrix) surface. However, the structure of the treatment. In addition, since some side effects of the cardiac mitochondria inner membrane is caused by antineoplastic agents appear to be pre- unique in that it possesses an NADH dehydrogenase vented by certain antioxidants, administering these on the outer (cytosolic) surface in addition to the ma- supplements during chemotherapy may diminish the trix NADH dehydrogenase that is present in mito- INTEGRATIVE CANCER THERAPIES 3(4); 2004 295 Conklin OXIDATIVE STRESS AND OXIDATIVE STRESS AND CHE CHEM MOT OTH HE ERAP RAPY Y Hig High h A An ntth hr ra acy cyc clliin nes es Pt Pt- -co com mp plle ex xe es s Alkylating agents Alkylating agents Epi Epipod podoph ophy yllllo otto ox xiin ns s C Ca am mp pto toth the ec ciin ns s Pu Pur riin ne e//Py Pyr riim miid diin ne e Antimetabolites Antimetabolites Lo Low w T Ta axa xane nes s Vi Vin nca ca a allk ka alo loid ids s Figure 2 Oxidative stress and chemotherapy. The highest level of oxidative stress induced by antineoplastic agents is seen with the anthracyclines. This is due to their unique ability to generate reactive oxygen species in cardiac mitochondria. Platinum coordination complexes, al k y l ati n g agents, epi podophy l l o tox i ns, and camptothecins also generate high levels of oxidative Figure 3 The cell cycle. G1 = preparation for DNA synthesis; S = stress at multiple cellular sites. Nucleoside and nucleo- DNA synthesis; G2 = preparation for mitosis; M = mito- tide analogues, antifolates, taxanes, and vinca alkaloids sis. The cell cycle safeguards include the restriction generate only low levels of oxidative stress, which point (R) and the checkpoints (C). The restriction point is occurs primarily as a result of drug-induced apoptosis. passed only when all requirements for DNA synthesis are met. Checkpoint arrest occurs in response to cellular damage and leads either to repair of the damage or apoptosis if the damage is too severe to repair. development of side effects as well as improve the From Conklin KA. Dietary polyunsaturated fatty acids: impact on response to therapy. This contention is supported by cancer chemotherapy and radiation. Altern Med Rev. 2002;7:4-21. 17,18 Reprinted with permission. many preclinical and some clinical studies. Mediators of Oxidative Stress The Cell Cycle Free radicals (Table 1) generated during oxidative The cell cycle (Figure 3) consists of 4 phases: G1, S, G2, stress have many cellular targets, although one of the and M. During G1, the cell prepares for DNA synthe- primary targets is cellular lipids. Lipid peroxidation of sis. The S phase is the phase of DNA synthesis. During polyunsaturated fatty acids results in the formation of G2, the cell prepares for mitosis. The M phase is the peroxyl and alkoxyl radicals. These primary products phase of mitosis during which the cell divides into 2 of lipid peroxidation, which are highly reactive and daughter cells. The major regulatory points and safe- relatively short-lived, undergo further reactions to guards of the cell cycle include the restriction point form secondary products of lipid peroxidation that in (R) and the checkpoints (C). A cardinal feature of the clude a variety of aldehydes (Table 1) such as malondi normal cell cycle is strict control of the cellular deci- aldehyde, the 4-hydroxyalkenals, and acrolein. The sion to advance to another round of DNA synthesis. In aldehydes are more stable than the primary products the presence of mitogens and when other require- and can diffuse throughout the cell where they dam ments, such as the presence of adequate nutrients, are age cellular components and interfere with cellular met, the cell will pass the restriction point and is com- functions. Because of their electrophilic character, the mitted to another round of DNA synthesis. The check- aldehydes bind to nucleophilic groups of amino acids, points, which ensure that the integrity of the genome such as cysteine, lysine, histidine, serine, and tyrosine, is maintained, include the G1 and G2 checkpoints, which are critical components of enzyme active sites which arrest the cell cycle if DNA damage is detected; or are necessary for maintaining the tertiary structure the S phase checkpoint, which arrests the cell cycle if a of proteins. The binding of aldehydes to proteins, problem with DNA replication occurs; and the M which results in enzyme inhibition and alteration of phase checkpoint, which arrests the cell cycle if a prob- the structure of cellular receptors, may account for the lem with mitotic spindle assembly occurs. When the impact of oxidative stress on the cytotoxicity of anti- cell cycle arrests at a checkpoint, the cell either cor- neoplastic agents. 296 INTEGRATIVE CANCER THERAPIES 3(4); 2004 Chemotherapy-Associated Oxidative Stress rects the defect that is detected (eg, by repairing damaged DNA) or undergoes apoptosis. Oxidative stress reduces the rate of cell prolifera- tion by inhibiting the transition of cells from the G0 to the G1 phase, prolonging the G1 phase, slowing pro- gression through the S phase by inhibiting DNA syn- thesis, inhibiting cell cycle progression through the restriction point, and causing arrest at cell cycle check- 19-25 points. Thus, the rate of proliferation of cells in cul- ture (normal cells and cancer cells) decreases during 26-36 periods of oxidative stress, and oxidative stress slows 37-39 the growth of tumors in laboratory animals. The 4- hydroxyalkenals, specifically, have been shown to inhibit tumor cell growth in culture and in laboratory animals. Other studies clearly demonstrate that high 42,43 rates of growth of normal tissue (liver) and 20,44 tumors are associated with low levels of lipid peroxidation. Thus, it is not surprising that tumor cells have diminished levels of pro-oxidant enzymes and efficient antioxidant systems so that they can maintain a low level of intracellular oxidative stress 45-50 Figure 4 Cyclin-dependent kinases. The cyclin-dependent kin and a rapid rate of proliferation. The effects of oxi- ases (CDK1, CDK2, etc) are enzymes that ensure an dative stress on cell proliferation are most likely attrib- ordered progression through the cell cycle. The CDKs are the catalytic subunits that are activated when they utable to inhibition of critical enzymes by the alde- combine with their appropriate cyclins, which are the hydes, and selective inhibition of DNA polymerases by regulatory subunits of the enzymes. Once activated, the 21,51-53 4-hydroxyalkenals has been demonstrated. The CDKs phosphorylate their protein substrates, which allows the cell cycle to proceed. cyclin-dependent kinases (CDKs) are other likely tar- gets of the aldehydes. These enzymes (Figure 4) may enhance the repair processes and diminish the ensure an ordered progression through the phases of 54-56 efficacy of the treatment. In this regard, checkpoint the cell cycle, and their inhibition, for example, by the abrogation, the opposite of what occurs during oxida- CDK inhibitor p21 (the mediator of the p53 tumor tive stress, has been shown to enhance the cytotoxicity suppressor gene), prevents passage through the of most antineoplastic agents. By reducing the genera- restriction point and causes checkpoint arrest (Figure tion of aldehydes, antioxidants may counteract the 5). effects of chemotherapy-induced oxidative stress on Antineoplastic agents that exhibit cell cycle phase- the cell cycle and enhance the cytotoxicity of specific activities depend on cell cycle progression to antineoplastic agents. exert their antineoplastic activity, and interference with this progression will diminish the cytotoxicity of the drugs. Examples of agents that exhibit phase-spe Drug-Induced Apoptosis cific activities include (1) anthracyclines and epipodophyllotoxins that inhibit topoisomerase II The 2 major cellular pathways of drug-induced activity and act in the S phase, (2) antifolates and apoptosis are the mitochondrial pathway, initiated by nucleotide/nucleoside analogues that interfere with release of cytochrome c, and the CD95 death receptor DNA synthesis and act in the S phase, (3) vinca alka pathway, initiated by ligation of the death receptor by 14,57,58 - - loids and taxanes that interfere with the mitotic pro its ligand CD95L (Figure 6). Following the initiat cess and act primarily during the M phase, and (4) ing event, the apoptotic process is carried out by a fam camptothecins that inhibit topoisomerase I activity ily of enzymes called caspases. Caspases (cysteine- and act in the S phase. Even platinum coordination dependent aspartate directed proteases) are proteas - - complexes and alkylating agents, which are not con es that have a cysteine residue at the active site and re sidered to be phase-specific agents, require cells to quire a reducing environment for optimal activity. T h e p roapopt o t i c s ign a ls of CD95 ligat ion progress through the S phase and G2 phase of the cell (antineoplastic agents upregulate the receptor or in- cycle for apoptosis to occur. In addition, repair of DNA duce expression of the ligand) or cytochrome c re- damage caused by platinum coordination complexes lease activate initiator caspases (caspases-8 and -9, and alkylating agents results in resistance to these respectively) that subsequently activate the effector drugs, and checkpoint arrest during oxidative stress INTEGRATIVE CANCER THERAPIES 3(4); 2004 297 Conklin Figure 5 The G1 checkpoint. DNA damage results in stabilization of the p53 protein, which is the product of the p53 tumor Figure 6 Duel apoptotic pathways of chemotherapy. Cellular suppressor gene. The elevated level of cellular p53 pro- damage by antineoplastic agents initiates the process of tein that results from its stabilization induces synthesis apoptosis by causing release of cytochrome c from mito- of p21 protein. The p21 protein mediates checkpoint chondria or by activation of death receptors. These arrest by inhibition of CDK (cyclin-dependent kinase) proapoptotic events result in activation of unique pro- CDK activity. Once the cell cycle is arrested, the DNA teases, caspase 8 and caspase 9, which are termed ini- damage is repaired or the cell undergoes apoptosis if tiator caspases because they activate other caspases the damage is too severe to repair. (effector caspases) that carry out disassembly of the cell. From Conklin KA. Dietary polyunsaturated fatty acids: impact on cancer chemotherapy and radiation. Altern Med Rev. 2002;7:4-21. caspases (caspases-3, -6, and -7) that carry out disas- Reprinted with permission. sembly of the cell. Oxidative stress can induce apoptosis by causing 15,16 agents during oxidative stress. If so, antioxidants damage to cellular components (eg, DNA), and some may enhance the anticancer activity of cancer chemo- studies suggest that ROS are downstream mediators of therapy by reducing aldehyde generation during apoptosis. However, there is considerable evidence chemotherapy-induced oxidative stress. that apoptosis does not require ROS and that their Aldehydes generated by lipid peroxidation during generation is a late event after cells are already com- 61,62 chemotherapy-induced oxidative stress may also mitted to programmed cell death. Consistent with directly interfere with the CD95 death receptor path- this latter contention is the generation of ROS in mito- way of drug-induced apoptosis. The CD95 death chondria that occurs only after apoptosis is initiated by receptor has a cysteine-rich extracellular domain, cytochrome c release. making it a potential target for binding by strongly In contrast to oxidative stress-induced apoptosis, 63-65 electrophilic agents such as the aldehydes. Binding of excessive oxidative stress inhibits caspase activity 15,16 aldehydes to death receptors may mimic the effect of and drug-induced apoptosis, thereby interfering death receptor antibodies that bind the extracellular with the ability of antineoplastic agents to kill tumor 15,16 domain and interfere with ligand binding and drug- cells. Caspase inhibition by other means, such as induced apoptosis. Thus, antioxidants, by reducing that caused by the cowpox virus CrmA protein when it the level of aldehydes, may facilitate drug-induced is overexpressed in leukemia cells, has also been apoptosis via the CD95 pathway. shown to confer resistance to a variety of antineoplas- tic agents. Electrophilic aldehydes, such as the tetrapeptide aldehyde (acetyl-Tyr-Val-Ala-Asp-H) that Conclusion was used to characterize caspase-1, covalently bind to Oxidative stress interferes with many cellular func- the sulfhydryl group of the cysteine residue at the tions, such as cell cycle progression and apoptotic active site of caspases and inhibit their activity. Thus, pathways, that can reduce the ability of antineoplastic aldehyde generation, resulting in caspase inhibition, agents to kill cancer cells. 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Chemotherapy-Associated Oxidative Stress: Impact on Chemotherapeutic Effectiveness:

Integrative Cancer Therapies , Volume 3 (4): 7 – Jul 25, 2016

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Abstract

Conklin 10.1177/1534735404270335 Conklin Chemotherapy-Associated Oxidative Stress Chemotherapy-Associated Oxidative Stress: Impact on Chemotherapeutic Effectiveness Kenneth A. Conklin, MD, PhD Antineoplastic agents induce oxidative stress in biological and react with molecular oxygen to form superoxide systems. During cancer chemotherapy, oxidative stress- radicals. Although superoxide is not highly toxic, induced lipid peroxidation generates numerous electro- mitochondrial superoxide dismutase generates philic aldehydes that can attack many cellular targets. These hydrogen peroxide from superoxide radicals, and, in products of oxidative stress can slow cell cycle progression the presence of reduced iron or copper, the highly of cancer cells and cause cell cycle checkpoint arrest, effects toxic hydroxyl radical is formed via Fenton or Haber- that may interfere with the ability of anticancer drugs to kill We iss r eact ions. T he cyt o chrome P450 cancer cells. The aldehydes may also inhibit drug-induced monooxygenase system of the hepatic endoplasmic apoptosis (programmed cell death) by inactivating death re- reticulum (microsomes) also generates a substantial ceptors and inhibiting caspase activity. These effects would amount of ROS in the process of metabolizing a chem- also diminish the efficacy of the treatment. The use of anti- ically diverse group of compounds that includes most oxidants during chemotherapy may enhance therapy by reducing the generation of oxidative stress-induced of the drugs that we administer as well as environmen- aldehydes. tal substances. The plasma and nuclear membranes are less active sites of ROS production, and enzyme systems, such as the xanthine-xanthine oxidase Keywords: antioxidants; apoptosis; chemotherapy; oxidative stress system, can also generate ROS. ROS can interact with cellular macromolecules, including DNA, protein, and lipids, and interfere with vital cellular functions. Mutations caused by ROS can Reactive oxygen species (ROS) are essential for life result in malignant transformation and the develop- because of their role in many vital processes such as ment of cancer. ROS are also implicated in the etiol- signal transduction and the ability of phagocytes to ogy and progression of many other diseases. Under carry out their bactericidal activity. ROS include free normal conditions, antioxidant mechanisms, includ- radicals, such as hydroxyl and superoxide radicals, ing small-molecular-weight antioxidants and antioxi- which are substances with one or more orbital elec dant enzyme systems, scavenge ROS and protect the trons with unpaired spin states, and nonradicals, organism from the damaging effects of oxidative including hydrogen peroxide and singlet oxygen stress. However, under conditions of excessive oxida- (Table 1). Although carefully controlled processes tive stress, for example, those which occur with the regulate the production of ROS for their essential administration of certain drugs, cellular antioxidant functions, many cellular processes result in the gener mechanisms may be unable to prevent the adverse ation of ROS. An important site of this nonessential impact of ROS on critical cellular processes. In cancer generation of ROS, which constitutes oxidative stress, cells, processes such as the ordered progression is the electron transport system (ETS; Figure 1) that through the cell cycle and intact apoptotic processes resides within the inner membrane of mitochondria. are necessary for antineoplastic agents to exert their Normally, electrons are transferred from complex I optimal cytotoxic activity. Since many antineoplastic (NADH dehydrogenase) and complex II (succinate agents are capable of producing oxidative stress in dehydrogenase) to coenzyme Q10 and then to com- plex III, cytochrome c, and complex IV. Finally, 4 elec- trons are transferred to oxygen with the formation of KAC is at the Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles. water. In the process, coupling of electron transport to Correspondence: Kenneth A. Conklin, MD, PhD, Department of oxidative phosphorylation results in adenosine Anesthesiology, David Geffen School of Medicine at UCLA, Box triphosphate generation. Although this process is very 951778, Los Angeles, CA 90095-1778. E-mail: kconklin@ efficient, about 2% of the electrons escape the ETS mednet.ucla.edu. DOI: 10.1177/1534735404270335 294 INTEGRATIVE CANCER THERAPIES 3(4); 2004 pp. 294-300 Chemotherapy-Associated Oxidative Stress Table 1. Mediators of Oxidative Stress A T P Reactive oxygen species Complex I Free radicals Hydroxyl radical: HO NADH ⋅ Complex III Complex IV Superoxide radical: O dHase Nonradicals Cyt. b, c Cyt.a, a Hydrogen peroxide: H O 1 Cyt.c 3 2 2 CoQ O 1 10 2 Singlet oxygen: O Lipid peroxidation products Peroxyl radical: ROO· Succ. Alkoxyl radical: RO· dHase Secondary products Malondialdehyde Complex II 4-hydroxyalkenals Figure 1 The electron transport system. Electrons flow from com- From Conklin KA. Dietary polyunsaturated fatty acids: impact on plex I (NADH dehydrogenase) and complex II (succinate cancer chemotherapy and radiation. Altern Med Rev. 2002;7:4-21. dehydrogenase) to coenzyme Q10, then to complex III, Reprinted with permission. cytochrome c, and complex IV. The final transfer is a 4- electron transfer to oxygen with the formation of water. The electron transport system is coupled at 3 sites to biological systems, ROS generated during cancer oxidative phosphorylation that results in the formation of adenosine triphosphate (ATP). chemotherapy may interfere with the efficacy of the treatment. Chemotherapy-Associated chondria of all cells. In cardiac cells, doxorubicin can penetrate the outer mitochondrial membrane and en- Oxidative Stress ter the cytosol where it is reduced by the cytosolic Antineoplastic agents have been shown to produce ox- NADH dehydrogenase. Intramolecular rearrange- idative stress in patients who receive these drugs dur- 1-11 ment results in formation of the lipophilic deoxy- ing cancer chemotherapy. This is evident by the aglycone of doxorubicin that penetrates the inner elevation of lipid peroxidation products; the reduc- membrane. There it competes with coenzyme Q10 tion of total radical-trapping capacity of blood plasma; (both are structurally quinones) as an electron accep- the reduction in plasma levels of antioxidants such as tor, diverting electrons to molecular oxygen with the vitamin E, vitamin C, and β-carotene; and the marked formation of superoxide radicals. reduction of tissue glutathione levels that occurs dur- In contrast to the above groups of antineoplastic ing chemotherapy. Those agents that generate high agents, taxanes (eg, paclitaxel and docetaxel), vinca levels of ROS include the anthracyclines (eg, alkaloids (eg, vincristine and vinblastine), anti- doxorubicin, epirubicin, and daunorubicin), alky- metabolites such as the antifolates, and nucleoside lating agents, platinum coordination complexes (eg, and nucleotide analogues generate only low levels of cisplatin, carboplatin, and oxaliplatin), epi oxidative stress (Figure 2). However, all antineoplastic podophyllotoxins (eg, etoposide and teniposide), and agents generate some ROS as they induce apoptosis in the camptothecins (eg, topotecan and irinotecan; Fig cancer cells. This is because one of the pathways of ure 2). The anthracyclines generate by far the highest drug-induced apoptosis involves the release of levels of oxidative stress. This is due to their ability to cytochrome c from mitochondria. When this occurs, divert electrons from the ETS of cardiac mitochon electrons are diverted from the ETS to oxygen by dria, resulting in formation of superoxide radicals, in NADH dehydrogenase and reduced coenzyme Q10, addition to generating ROS at other cellular sites. resulting in the formation of superoxide radicals. Doxorubicin, the most studied anthracycline, pos Oxidative stress interferes with cellular processes sesses a sugar moiety attached to a tetracycline ring (cell cycle progression and drug-induced apoptosis; that contains a quinone structure. Disruption of the see below) that are necessary for antineoplastic agents ETS by doxorubicin can occur only following reduc to exert their optimal cytotoxicity on cancer cells, and tion of the quinone to its semiquinone. Doxorubicin is modest levels of oxidative stress have been shown to hydrophilic and, in mitochondria of most cells, it can 15,16 reduce the cytotoxicity of anticancer drugs. Thus, not penetrate the inner membrane and be reduced by the formation of ROS that occurs when anticancer NADH dehydrogenase (complex I), which is located drugs are administered may diminish the effectiveness on the inner (matrix) surface. However, the structure of the treatment. In addition, since some side effects of the cardiac mitochondria inner membrane is caused by antineoplastic agents appear to be pre- unique in that it possesses an NADH dehydrogenase vented by certain antioxidants, administering these on the outer (cytosolic) surface in addition to the ma- supplements during chemotherapy may diminish the trix NADH dehydrogenase that is present in mito- INTEGRATIVE CANCER THERAPIES 3(4); 2004 295 Conklin OXIDATIVE STRESS AND OXIDATIVE STRESS AND CHE CHEM MOT OTH HE ERAP RAPY Y Hig High h A An ntth hr ra acy cyc clliin nes es Pt Pt- -co com mp plle ex xe es s Alkylating agents Alkylating agents Epi Epipod podoph ophy yllllo otto ox xiin ns s C Ca am mp pto toth the ec ciin ns s Pu Pur riin ne e//Py Pyr riim miid diin ne e Antimetabolites Antimetabolites Lo Low w T Ta axa xane nes s Vi Vin nca ca a allk ka alo loid ids s Figure 2 Oxidative stress and chemotherapy. The highest level of oxidative stress induced by antineoplastic agents is seen with the anthracyclines. This is due to their unique ability to generate reactive oxygen species in cardiac mitochondria. Platinum coordination complexes, al k y l ati n g agents, epi podophy l l o tox i ns, and camptothecins also generate high levels of oxidative Figure 3 The cell cycle. G1 = preparation for DNA synthesis; S = stress at multiple cellular sites. Nucleoside and nucleo- DNA synthesis; G2 = preparation for mitosis; M = mito- tide analogues, antifolates, taxanes, and vinca alkaloids sis. The cell cycle safeguards include the restriction generate only low levels of oxidative stress, which point (R) and the checkpoints (C). The restriction point is occurs primarily as a result of drug-induced apoptosis. passed only when all requirements for DNA synthesis are met. Checkpoint arrest occurs in response to cellular damage and leads either to repair of the damage or apoptosis if the damage is too severe to repair. development of side effects as well as improve the From Conklin KA. Dietary polyunsaturated fatty acids: impact on response to therapy. This contention is supported by cancer chemotherapy and radiation. Altern Med Rev. 2002;7:4-21. 17,18 Reprinted with permission. many preclinical and some clinical studies. Mediators of Oxidative Stress The Cell Cycle Free radicals (Table 1) generated during oxidative The cell cycle (Figure 3) consists of 4 phases: G1, S, G2, stress have many cellular targets, although one of the and M. During G1, the cell prepares for DNA synthe- primary targets is cellular lipids. Lipid peroxidation of sis. The S phase is the phase of DNA synthesis. During polyunsaturated fatty acids results in the formation of G2, the cell prepares for mitosis. The M phase is the peroxyl and alkoxyl radicals. These primary products phase of mitosis during which the cell divides into 2 of lipid peroxidation, which are highly reactive and daughter cells. The major regulatory points and safe- relatively short-lived, undergo further reactions to guards of the cell cycle include the restriction point form secondary products of lipid peroxidation that in (R) and the checkpoints (C). A cardinal feature of the clude a variety of aldehydes (Table 1) such as malondi normal cell cycle is strict control of the cellular deci- aldehyde, the 4-hydroxyalkenals, and acrolein. The sion to advance to another round of DNA synthesis. In aldehydes are more stable than the primary products the presence of mitogens and when other require- and can diffuse throughout the cell where they dam ments, such as the presence of adequate nutrients, are age cellular components and interfere with cellular met, the cell will pass the restriction point and is com- functions. Because of their electrophilic character, the mitted to another round of DNA synthesis. The check- aldehydes bind to nucleophilic groups of amino acids, points, which ensure that the integrity of the genome such as cysteine, lysine, histidine, serine, and tyrosine, is maintained, include the G1 and G2 checkpoints, which are critical components of enzyme active sites which arrest the cell cycle if DNA damage is detected; or are necessary for maintaining the tertiary structure the S phase checkpoint, which arrests the cell cycle if a of proteins. The binding of aldehydes to proteins, problem with DNA replication occurs; and the M which results in enzyme inhibition and alteration of phase checkpoint, which arrests the cell cycle if a prob- the structure of cellular receptors, may account for the lem with mitotic spindle assembly occurs. When the impact of oxidative stress on the cytotoxicity of anti- cell cycle arrests at a checkpoint, the cell either cor- neoplastic agents. 296 INTEGRATIVE CANCER THERAPIES 3(4); 2004 Chemotherapy-Associated Oxidative Stress rects the defect that is detected (eg, by repairing damaged DNA) or undergoes apoptosis. Oxidative stress reduces the rate of cell prolifera- tion by inhibiting the transition of cells from the G0 to the G1 phase, prolonging the G1 phase, slowing pro- gression through the S phase by inhibiting DNA syn- thesis, inhibiting cell cycle progression through the restriction point, and causing arrest at cell cycle check- 19-25 points. Thus, the rate of proliferation of cells in cul- ture (normal cells and cancer cells) decreases during 26-36 periods of oxidative stress, and oxidative stress slows 37-39 the growth of tumors in laboratory animals. The 4- hydroxyalkenals, specifically, have been shown to inhibit tumor cell growth in culture and in laboratory animals. Other studies clearly demonstrate that high 42,43 rates of growth of normal tissue (liver) and 20,44 tumors are associated with low levels of lipid peroxidation. Thus, it is not surprising that tumor cells have diminished levels of pro-oxidant enzymes and efficient antioxidant systems so that they can maintain a low level of intracellular oxidative stress 45-50 Figure 4 Cyclin-dependent kinases. The cyclin-dependent kin and a rapid rate of proliferation. The effects of oxi- ases (CDK1, CDK2, etc) are enzymes that ensure an dative stress on cell proliferation are most likely attrib- ordered progression through the cell cycle. The CDKs are the catalytic subunits that are activated when they utable to inhibition of critical enzymes by the alde- combine with their appropriate cyclins, which are the hydes, and selective inhibition of DNA polymerases by regulatory subunits of the enzymes. Once activated, the 21,51-53 4-hydroxyalkenals has been demonstrated. The CDKs phosphorylate their protein substrates, which allows the cell cycle to proceed. cyclin-dependent kinases (CDKs) are other likely tar- gets of the aldehydes. These enzymes (Figure 4) may enhance the repair processes and diminish the ensure an ordered progression through the phases of 54-56 efficacy of the treatment. In this regard, checkpoint the cell cycle, and their inhibition, for example, by the abrogation, the opposite of what occurs during oxida- CDK inhibitor p21 (the mediator of the p53 tumor tive stress, has been shown to enhance the cytotoxicity suppressor gene), prevents passage through the of most antineoplastic agents. By reducing the genera- restriction point and causes checkpoint arrest (Figure tion of aldehydes, antioxidants may counteract the 5). effects of chemotherapy-induced oxidative stress on Antineoplastic agents that exhibit cell cycle phase- the cell cycle and enhance the cytotoxicity of specific activities depend on cell cycle progression to antineoplastic agents. exert their antineoplastic activity, and interference with this progression will diminish the cytotoxicity of the drugs. Examples of agents that exhibit phase-spe Drug-Induced Apoptosis cific activities include (1) anthracyclines and epipodophyllotoxins that inhibit topoisomerase II The 2 major cellular pathways of drug-induced activity and act in the S phase, (2) antifolates and apoptosis are the mitochondrial pathway, initiated by nucleotide/nucleoside analogues that interfere with release of cytochrome c, and the CD95 death receptor DNA synthesis and act in the S phase, (3) vinca alka pathway, initiated by ligation of the death receptor by 14,57,58 - - loids and taxanes that interfere with the mitotic pro its ligand CD95L (Figure 6). Following the initiat cess and act primarily during the M phase, and (4) ing event, the apoptotic process is carried out by a fam camptothecins that inhibit topoisomerase I activity ily of enzymes called caspases. Caspases (cysteine- and act in the S phase. Even platinum coordination dependent aspartate directed proteases) are proteas - - complexes and alkylating agents, which are not con es that have a cysteine residue at the active site and re sidered to be phase-specific agents, require cells to quire a reducing environment for optimal activity. T h e p roapopt o t i c s ign a ls of CD95 ligat ion progress through the S phase and G2 phase of the cell (antineoplastic agents upregulate the receptor or in- cycle for apoptosis to occur. In addition, repair of DNA duce expression of the ligand) or cytochrome c re- damage caused by platinum coordination complexes lease activate initiator caspases (caspases-8 and -9, and alkylating agents results in resistance to these respectively) that subsequently activate the effector drugs, and checkpoint arrest during oxidative stress INTEGRATIVE CANCER THERAPIES 3(4); 2004 297 Conklin Figure 5 The G1 checkpoint. DNA damage results in stabilization of the p53 protein, which is the product of the p53 tumor Figure 6 Duel apoptotic pathways of chemotherapy. Cellular suppressor gene. The elevated level of cellular p53 pro- damage by antineoplastic agents initiates the process of tein that results from its stabilization induces synthesis apoptosis by causing release of cytochrome c from mito- of p21 protein. The p21 protein mediates checkpoint chondria or by activation of death receptors. These arrest by inhibition of CDK (cyclin-dependent kinase) proapoptotic events result in activation of unique pro- CDK activity. Once the cell cycle is arrested, the DNA teases, caspase 8 and caspase 9, which are termed ini- damage is repaired or the cell undergoes apoptosis if tiator caspases because they activate other caspases the damage is too severe to repair. (effector caspases) that carry out disassembly of the cell. From Conklin KA. Dietary polyunsaturated fatty acids: impact on cancer chemotherapy and radiation. Altern Med Rev. 2002;7:4-21. caspases (caspases-3, -6, and -7) that carry out disas- Reprinted with permission. sembly of the cell. Oxidative stress can induce apoptosis by causing 15,16 agents during oxidative stress. If so, antioxidants damage to cellular components (eg, DNA), and some may enhance the anticancer activity of cancer chemo- studies suggest that ROS are downstream mediators of therapy by reducing aldehyde generation during apoptosis. However, there is considerable evidence chemotherapy-induced oxidative stress. that apoptosis does not require ROS and that their Aldehydes generated by lipid peroxidation during generation is a late event after cells are already com- 61,62 chemotherapy-induced oxidative stress may also mitted to programmed cell death. Consistent with directly interfere with the CD95 death receptor path- this latter contention is the generation of ROS in mito- way of drug-induced apoptosis. The CD95 death chondria that occurs only after apoptosis is initiated by receptor has a cysteine-rich extracellular domain, cytochrome c release. making it a potential target for binding by strongly In contrast to oxidative stress-induced apoptosis, 63-65 electrophilic agents such as the aldehydes. Binding of excessive oxidative stress inhibits caspase activity 15,16 aldehydes to death receptors may mimic the effect of and drug-induced apoptosis, thereby interfering death receptor antibodies that bind the extracellular with the ability of antineoplastic agents to kill tumor 15,16 domain and interfere with ligand binding and drug- cells. Caspase inhibition by other means, such as induced apoptosis. Thus, antioxidants, by reducing that caused by the cowpox virus CrmA protein when it the level of aldehydes, may facilitate drug-induced is overexpressed in leukemia cells, has also been apoptosis via the CD95 pathway. shown to confer resistance to a variety of antineoplas- tic agents. Electrophilic aldehydes, such as the tetrapeptide aldehyde (acetyl-Tyr-Val-Ala-Asp-H) that Conclusion was used to characterize caspase-1, covalently bind to Oxidative stress interferes with many cellular func- the sulfhydryl group of the cysteine residue at the tions, such as cell cycle progression and apoptotic active site of caspases and inhibit their activity. Thus, pathways, that can reduce the ability of antineoplastic aldehyde generation, resulting in caspase inhibition, agents to kill cancer cells. 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Journal

Integrative Cancer TherapiesSAGE

Published: Jul 25, 2016

Keywords: antioxidants; apoptosis; chemotherapy; oxidative stress

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