Dietary Polyunsaturated Fatty Acids:
Impact on Cancer Chemotherapy and Radiation

This section is compiled by Frank M. Painter, D.C.
Send all comments or additions to:    Frankp@chiro.org

FROM: Alternative Medicine Review 2002 (Feb);   7 (1):   4–21 ~ FULL TEXT

Kenneth A. Conklin, MD, PhD


Introduction

Interpreting Reactive Oxygen Species (ROS) Mediated Mechanisms

Interpreting the results of studies designed to assess the impact of polyunsaturated fatty acids (PUFAs) on chemotherapy and radiation is difficult because PUFAs alone can affect cancer cell growth and viability. PUFAs create oxidative stress (Table 1) in biological systems as they undergo lipid peroxidation, forming free radicals such as peroxyl and alkoxyl radicals. Although these lipid hydroperoxides are relatively short-lived, their breakdown results in the formation of secondary products of lipid peroxidation (aldehydes such as malondialdehyde and the 4-hydroxyalkenals) that are longer-lived and can attack a variety of cellular targets.

Low concentrations of these aldehydes affect the cell cycle (Figure 1) in ways that reduce the rate of cell proliferation. These effects include inhibiting the transition of cells from the G0 phase to the G1 phase, prolonging the G1 phase, slowing progression through the S phase by inhibiting the activity of DNA polymerases, inhibiting cell cycle progression through the restriction point, and causing arrest at cycle cell checkpoints. [1,2] These effects that retard cell cycle progression will impact proliferating cells such as those in culture and those of certain animal tissues, including neoplasms, bone marrow, and the intestinal epithelium. Whereas low-level PUFA-induced oxidative stress is cytostatic, higher levels of oxidative stress result in apoptosis (programmed cell death), and still higher levels cause cellular necrosis. [3-5]

Many investigators have demonstrated that omega-6 (n-6) and omega-3 (n-3) PUFAs ­ including linoleic acid (LA), gamma-linolenic acid (GLA), dihommogamma-linolenic acid (DGLA), arachidonic acid (AA), alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) ­ inhibit growth and are cytotoxic to cancer cells in vitro; [6-15] that the effects are associated with the production of lipid peroxides and aldehydes; [8-13] and that the cytotoxicity of the added PUFAs is reduced by the addition of antioxidants. [8-13] Studies with laboratory animals have also demonstrated that feeding a diet containing peroxidation products of fish oil1 [6] reduces tumor growth, and that the effect is reduced by administering antioxidants. [17,18]

However, the effects in vitro are observed at PUFA concentrations (30 microM and above in most studies) exceeding normal plasma free fatty acid (FFA) levels. PUFAs in culture medium undergo lipid peroxidation more readily than those of plasma or tissues because: (1) culture medium, compared to plasma, contains lower levels of albumin that binds FFAs [19] and sequesters iron and copper that promote lipid peroxidation; (2) culture medium generally contains fewer antioxidants than plasma; (3) PUFAs in plasma lipoproteins are protected by antioxidants within the lipoproteins; and (4) cellular PUFAs are protected from lipid peroxidation by multiple antioxidants. Additionally, growth inhibition in vitro does not necessarily correlate with the degree of lipid peroxidation [13] and antioxidants preventing lipid peroxidation in vitro do not completely reverse the effects of certain PUFAs on cell growth. [11,12,14]

Researchers found that administering LA without antioxidants also reverses the suppressive effects of fish oil on the growth of colon adenocarcinoma in mice. [20] Further research has found that preventing lipid peroxidation in experimental diets by the addition of antioxidants does not interfere with the growth inhibitory effects of fish oil on primary tumor growth or the development of metastases in nude mice with transplanted human breast and prostate cancer cells. [21-23] These results suggest PUFAs are cytostatic and cytotoxic in vitro and in vivo when conditions allow lipid peroxidation to occur, but that certain PUFAs in the absence of oxidative stress also have inhibitory effects on tumor cell growth.

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PUFAs, Oxidative Stress, and Cancer Therapies

Supplementing the diet with PUFAs creates oxidative stress, reflected by reduced levels of antioxidants, e.g., vitamin E, [96] if supplementation is not accompanied by the administration of antioxidants. As noted above, oxidative stress can impact the proliferation of cancer cells by slowing cell cycle progression (prolonging the G1 phase or causing cells to enter the G0 phase) and inducing cell cycle checkpoint arrest.1-5 Although these effects may slow cancer growth and progression, they may also reduce the cytotoxicity of chemotherapy and radiation.

Many cancer chemotherapeutic agents act only during certain phases of the cell cycle. Examples include DNA synthesis inhibitors (some purine and pyrimidine analogues) and topoisomerase inhibitors (anthracyclines, epipodophyllotoxins, and camptothecins) that act during the S-phase, and antimitotic agents (taxanes and vinca alkaloids) that act during the M-phase. Thus, halting cell cycle progression in the G1 phase or causing cells to be quiescent (G0 phase) will reduce the effectiveness of these drugs. However, drugs that exhibit phase-nonspecific activities, such as alkylating agents and platinum coordination complexes, are also more cytotoxic when cells exhibit unrestricted progression through the cell cycle than when they remain in the G1 or G0 phase. Oxidative stress, by causing checkpoint arrest that normally does not occur in cancer cells, may further impair chemotherapeutic effectiveness by allowing repair of damage caused by the drugs.

Oxidative stress has also been shown to alter the mode of chemotherapy-induced cell death, usually occurring by apoptosis following cellular damage by antineoplastic agents. [97,98] Oxidative stress inhibits drug-induced apoptosis and results in cell death by necrosis,3-5 an effect that reduces the cytotoxicity of chemotherapeutic agents, including doxorubicin, etoposide, cisplatin, and cytosine arabinoside [.99,100] Certain antioxidants have been shown to prevent the oxidative stress-induced inhibition of apoptosis by antineoplastic agents and to enhance the drugs' cytotoxicity. [100] Thus, administering antioxidants with PUFAs during chemotherapy may enhance the effectiveness of the treatment. Antioxidant administration during chemotherapy can also reduce or prevent the development of certain side effects. [94]

As with chemotherapy, the cytotoxic effects of radiation are less when cells are in the G1 or G0 phase of the cell cycle; checkpoint arrest may lead to repair of cell damage caused by the treatment; and oxidative stress may interfere with radiotherapy-induced apoptosis. Thus, administering PUFAs during radiotherapy may enhance the effectiveness of the treatment, although concerns have been expressed because antioxidants may counteract the free radical-inducing impact of low linear energy transfer radiation (beta-radiation, gamma-radiation, and x-rays). In mice with transplanted squamous carcinoma, an exceptionally high intraperitoneal dose of vitamin E (1 g/kg dl-alpha-tocopherol) administered 30 minutes before irradiation has been shown to protect tumors from the lethal effect of x-rays. [101] However, in rats with transplanted sarcomas or hepatomas, the intramuscular injection of 50, 250, or 500 mg/kg of dl-alpha-tocopherol seven days before treatment, or 50 mg/kg injected both seven days and one day before treatment, enhanced the lethal effect of tumor irradiation; whereas, a 1-g/kg dose injected seven days before treatment resulted in no change in the tumor response. [102-104] The mechanism whereby vitamin E (500 mg/kg or less) enhanced the impact of tumor irradiation may be by enhancing blood tumor flow and oxygenation (free radical generation by radiotherapy is proportional to the oxygen tension). [24,105-107] Additionally, studies in mice have shown that supplementation with other antioxidants, including retinol palmitate (150,000 IU/kg diet), and beta-carotene (90 mg/kg diet),108 enhanced the antitumor response of radiation therapy. Results of clinical studies also suggest administering antioxidants during radiation therapy may be beneficial. [93]

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Commentary

Dietary supplementation with certain PUFAs, including EPA, DHA, and GLA (which is rapidly elongated to DGLA), may provide a means of enhancing the response to cancer therapies. Altering the physical and functional properties of tumor cell membranes by enrichment with these PUFAs may increase the response to chemotherapy and radiation, and may, to some degree, reverse the resistance of cancer cells to certain chemotherapeutic agents. Although there is a lack of clinical data to support the contention that certain PUFAs enhance the response to cancer therapies, preclinical data suggest PUFA supplementation is beneficial. Certainly, clinical studies need to be conducted to confirm the preclinical data.

Although many effects of PUFA supplementation may enhance the impact of cytotoxic antineoplastic agents and radiation, aldehydes generated by PUFA-induced oxidative stress may reduce the efficacy of these treatments by slowing cell cycle progression, inducing cell cycle checkpoint arrest, and altering the mode of cell death in response to these treatments (Table 3). Supplementation with antioxidants may enhance the effects of PUFA administration during chemotherapy and radiation by reducing oxidative stress and the generation of aldehydes, a contention supported by the results of Yam et al, [82] which demonstrate that antioxidants added to a fish oil diet enhance the antineoplastic activity of cisplatin more than the fish oil diet alone.

Unanswered questions remain regarding the impact of antioxidants, since few clinical studies have been done, and, although a substantial amount of preclinical data supports the contention that antioxidants can improve the response to antineoplastic agents which have mechanisms of action that do not involve reactive oxygen species,94,109,110 far less data is available regarding the impact of antioxidants on radiotherapy. Additionally, reactive oxygen species, generated during oxidative stress, have been implicated as downstream mediators of apoptosis. [111] If reactive oxygen species are mediators, antioxidants could interfere with apoptosis, although there is considerable evidence that reactive oxygen species are not necessary for apoptosis to occur, [112,113] and that the generation of reactive oxygen species is a late event that occurs after cells are already committed to apoptosis. [114] Also, inhibition of caspases, cysteine proteases that carry out disassembly of the cell following proapoptotic signals, [115] by oxidative stress3 or other inhibitors, [116] interferes with drug-induced apoptosis and reduces the cytotoxicity of multiple chemotherapeutic agents. [99,100,116] Although the mechanism whereby oxidative stress inhibits caspase activity is unclear, aldehydes, generated following the oxidation of PUFAs, are strong electrophiles that bind to nucleophilic moieties such as cysteine residues of proteins. Tetrapeptide aldehydes have been shown to be potent inhibitors of caspases. [117] Strong electrophiles such as the aldehydes resulting from PUFA oxidation may also bind to cysteine-rich extracellular domains of death receptors [118] and interfere with apoptotic signals initiated by death ligands. Although cellular damage by chemotherapeutic agents and radiation is generally considered to cause caspase activation and apoptosis by mechanisms that involve cytochrome C release from mitochondria, death receptors are implicated in apoptosis induced by certain cytotoxic agents (Figure 2). [119] Certainly, many aspects of oxidative stress as it relates to chemotherapy- and radiotherapy-induced apoptosis need to be elucidated.

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