Studies of natural vitamin E forms and their synthetic derivatives for potential anticancer application in human breast cancer cell lines and mouse tumor models
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Vitamin E is a group of naturally occurring fat soluble compounds which consists of eight distinct forms of tocopherols and tocotrienols. Although a well-defined physiological function of vitamin E is as an antioxidant, beneficial effects of individual vitamin E compounds on chronic human diseases such as cancer need to be better understood. Studies in this dissertation investigated potential application of gamma-tocopherol (gamma-T), gamma-tocotrienol (gamma-T3) or synthetic derivatives of tocotrienols as anticancer agents in comparison to alpha-tocopherol (alpha-T), its redox-silent acetic acid derivative (alpha-TEA) or alpha-tocotrienol (alpha-T3). Redox-silent derivatives of alpha- and gamma-T3; namely alpha-T3EA and gamma-T3EA exhibited potent anti-proliferative and proapoptotic activities in a murine mammary cancer cell line as well as in human breast cancer cell lines. Moreover, studies using human vascular endothelial cells in cell culture showed that the tocotrienol derivatives exhibited strong antiangiogenic activities which were markedly improved over those of the parent compounds. An antitumor efficacy study using the 66cl-4-GFP syngeneic mouse mammary tumor model showed that each tocotrienol derivative, when delivered in the diet, significantly suppressed mammary tumor growth; however serum and tissue concentrations of these novel compounds were lower than those of alpha-TEA, suggesting that the next generation of vitamin E derivatives will need to be modified to improve bioavailability. On the other hand, some natural-source vitamin E forms, especially gamma-forms, display anticancer activities without any chemical modification in both in vitro cell culture studies and in vivo animal models. Dietary delivery of gamma-T3 suppressed tumor growth in a syngeneic implantation mouse mammary cancer model by inhibiting cell proliferation and inducing apoptosis. Cell culture studies using human breast cancer cells showed that gamma-T3 triggered apoptosis by inducing endoplasmic reticulum (ER)-stress mediated by acid sphingomyelinase (ASMase) action. Activation of stress-activated mitogen-activated protein kinases (MAPKs), JNK and p38, was associated with gamma-T3-induced ER stress followed by upregulation of extrinsic death receptor-5 (DR5) expression in a CHOP transcription factor dependent manner. Gamma-T also triggered extrinsic apoptosis signaling by increasing DR5 mRNA, protein and cell surface expression levels followed by mitochondria-dependent apoptotic signaling. In agreement with in vitro studies, gamma-T delivered in the diet suppressed the tumor growth of MDA-MB-231-GFP human breast cancer cells in a xenograft model but the antitumor activity of gamma-T was hampered by co-administration of alpha-T. The preferential tissue retention of alpha-T over gamma-T could be overcome by use of sesamin, a dietary source of human cytochrome P450 inhibitor. Based on data presented, gamma-T and gamma-T3 show preclinical potential for cancer treatment either as single agents or in combination with other agents.