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Differential Response of Human Ovarian Cancer Cells to Induction of Apoptosis by Vitamin E Succinate and Vitamin E Analogue, -TEA

¹ School of Biological Sciences/C0900 and ² Division of Nutrition/A2703, University of Texas at Austin, Austin, Texas, and ³ Department of Chemistry, Brock University, St. Catharines, Ontario, Canada

A vitamin E derivative, vitamin E succinate (VES; RRR--tocopheryl succinate), and a vitamin E analogue, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy acetic acid (-TEA), induce human breast, prostate, colon, lung, cervical, and endometrial tumor cells in culture to undergo apoptosis but not normal human mammary epithelial cells, immortalized, nontumorigenic breast cells, or normal human prostate epithelial cells. Human ovarian and cervical cancer cell lines are exceptions, with -TEA exhibiting greater proapoptotic effects. Although both VES and -TEA can induce A2780 and subline A2780/cp70 ovarian cancer cells to undergo DNA synthesis arrest within 24 h of treatment, only -TEA is an effective inducer of apoptosis. VES or -TEA treatment of cp70 cells with 5, 10, or 20 µg/ml for 3 days induced 5, 6, and 19% versus 9, 36, and 71% apoptosis, respectively. Colony formation data provide additional evidence that cp70 cells are more sensitive to growth inhibition by -TEA than VES. Differences in stability of the ester-linked succinate moiety of VES versus the ether-linked acetic acid moiety of -TEA were demonstrated by high-performance liquid chromatography analyses that showed -TEA to remain intact, whereas VES was hydrolyzed to the free phenol, RRR--tocopherol. Pretreatment of cp70 cells with bis-(p-nitrophenyl) phosphate, an esterase inhibitor, before VES treatment, resulted in increased levels of intact VES and apoptosis. Taken together, these data show -TEA to be a potent and stable proapoptotic agent for human ovarian tumor cells and suggest that endogenous ovarian esterases can hydrolyze the succinate moiety of VES, yielding RRR--tocopherol, an ineffective apoptotic-inducing agent.

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