The use of antioxidant therapies during chemotherapy

Drisko JA, Chapman J, Hunter VJ.

Gynecol Oncol. 2003 Mar;88(3):434-9.

OBJECTIVE: At the present time, many cancer patients combine some form of complementary and alternative medicine therapies with their conventional therapies. The most common choice of these therapies is the use of antioxidants.

RESULTS: A review of four common antioxidants is undertaken, which includes vitamin E (mixed tocopherols and tocotrienols), beta-carotene (natural mixed carotenoids), vitamin C (ascorbic acid), and vitamin A (retinoic acid). Antioxidants act as electron acceptors as well as therapeutic biologic response modifiers. Despite the fact that chemotherapy-induced formation of free radicals is well-demonstrated, chemotherapy-induced cytotoxicity in general does not seem to depend on formation of reactive oxygen species.

CONCLUSIONS: Currently, evidence is growing that antioxidants may provide some benefit when combined with certain types of chemotherapy. Because of the potential for positive benefits, a randomized controlled trial evaluating the safety and efficacy of adding antioxidants to chemotherapy in newly diagnosed ovarian cancer is underway at the University of Kansas Medical Center.

Role of caspase-8 activation in mediating vitamin E-induced apoptosis in murine mammary cancer cells

Shah S, Gapor A, Sylvester PW.

Nutr Cancer. 2003;45(2):236-46. March-April

The vitamin E family of compounds is divided into two subgroups, tocopherols and tocotrienols. However, tocotrienols display more potent apoptotic activity in mammary cancer cells. Although the mechanism(s) mediating tocotrienol-induced apoptosis is presently unknown, apoptosis is carried out by activation of initiator caspases (caspase-8 or -9) that subsequently activate effector caspases (caspase-3, -6, or -7). Studies were conducted to determine whether tocotrienol-induced apoptosis is mediated by activation of the caspase-8 and/or caspase-9 pathway. Highly malignant +SA mouse mammary epithelial cells were grown in culture and maintained on serum-free media. Treatment with tocotrienol-rich-fraction of palm oil (TRF) and g-tocotrienol, but not a-tocopherol, induced a dose-dependent decrease in +SA cell viability. TRF- and g-tocotrienol-induced cell death resulted from apoptosis, as determined by DNA fragmentation and positive TUNEL assay staining. Additional studies showed that treatment with 50 mM TRF or 20 mM g-tocotrienol increased intracellular activity and levels of processed caspase-8 and -3 but not caspase-9. Furthermore, treatment with specific caspase-8 or -3 inhibitors, but not caspase-9 inhibitor, completely blocked the tocotrienol-induced apoptosis in +SA cells. These findings demonstrate that tocotrienol-induced apoptosis in +SA mammary cancer cells is mediated through activation of the caspase-8 signaling pathway and is independent of caspase-9 activation.

Palm oil alleviates 12-O-tetradecanoyl-phorbol-13-acetate-induced tumor promotion response in murine skin

Kausar H, Bhasin G, Zargar MA, Athar M.

Cancer Lett. 2003 Mar 31;192(2):151-60.

Palm oil is a rich source of vitamin E, carotenoids, tocotrienols and tocopherols which are natural antioxidants and act as scavengers of oxygen free radicals. 12-O-Tetradecanoyl-phorbol-13-acetate (TPA) is a known oxidant that promotes tumorigenesis in mouse skin through the elaboration of oxidative stress. In this study we therefore assessed the anti-tumor promoting potential of palm oil against TPA-mediated skin tumorigenesis in 7,12-dimethylbenz[a]anthracene-initiated Swiss albino mice. Topical application of palm oil 1 h prior to application of TPA resulted in a significant protection against skin tumor promotion. The animals pre-treated with palm oil showed a decrease in both tumor incidence and tumor yield as compared to the TPA (alone)-treated group. Palm oil application also reduced the development of malignant tumors. Since TPA-induced epidermal ornithine decarboxylase (ODC) activity and [(3)H]thymidine incorporation are conventionally used markers of skin tumor promotion, we also assessed the effect of pre-application of palm oil on these parameters, and it was observed that the application of palm oil prior to the application of TPA alleviated both these TPA-induced markers of tumor promotion. The effect of pre-application of palm oil on TPA-mediated depletion in the non-enzymatic and enzymatic molecules was also assessed and it was observed that palm oil application prior to TPA application resulted in the recovery of TPA-mediated depletion in the levels of these molecules viz. glutathione, glutathione peroxidase, glutathione reductase, glutathione-S-transferase and catalase. Similarly, palm oil also exhibited a protective effect against Fe(2+)-ascorbate-induced lipid peroxidation in the epidermal microsomes. The results of the present study thus suggest that palm oil possesses anti-skin tumor promoting effects, and that the mechanism of such effects may involve the inhibition of tumor promoter-induced epidermal ODC activity, [(3)H]thymidine incorporation and cutaneous oxidative stress.

Comparative study on the action of tocopherols and tocotrienols as antioxidant: chemical and physical effects

Yoshida Y, Niki E, Noguchi N

Chem Phys Lipids, 2003;123(1):63-75

Alpha-Tocopherol is known as the most abundant and active form of vitamin E homologues in vivo, but recently the role of other forms of vitamin E has received renewed attention. The antioxidant properties were compared for alpha-, beta-, gamma- and delta-tocopherols and tocotrienols. The following results were obtained: (1). the corresponding tocopherols and tocotrienols exerted the same reactivities toward radicals and the same antioxidant activities against lipid peroxidation in solution and liposomal membranes; (2). tocopherols gave more significant physical effect than tocotrienols on the increase in rigidity at the membrane interior; (3). tocopherols and tocotrienols showed similar mobilities within the membranes, but tocotrienols were more readily transferred between the membranes and incorporated into the membranes than tocopherols; (4). alpha-tocopherol and alpha-tocotrienol, but not the other forms, reduced Cu(II) to give Cu(I) together with alpha-tocopheryl and alpha-tocotrienyl quinones, respectively and exerted prooxidant effect in the oxidation of methyl linoleate in SDS micelles.

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