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

Abstract

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 g/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.

Dietary Administration of the Proapoptotic Vitamin E Analogue α-Tocopheryloxyacetic Acid Inhibits Metastatic Murine Breast Cancer

“…These drawbacks have fueled efforts to develop novel anticancer agents that are toxic to tumor cells while sparing normal host cells. In this respect, the antitumor properties of the vitamin E [atocopherol (a-TOH)] derivatives a-tocopheryl succinate (a-TOS) and a-tocopheryloxyacetic acid (a-TEA) have recently sparked interest (1) because they have been shown to exhibit selective toxicity toward tumor cells (1)(2)(3)(4)(5) and to suppress tumor growth in various rodent and human xenograft tumor models (2,3,(5)(6)(7)(8)(9). a-TOS and a-TEA are semisynthetic derivatives of vitamin E that structurally share the phytyl tail and the chroman head with vitamin E (Fig.…”

“…4). Because this succinate group is linked to the chroman head by an ester bond, a-TOS is sensitive to hydrolytic cleavage by intestinal esterases (5). In contrast, a-TEA has an acetic acid moiety attached via a nonhydrolyzable ether bond to the chroman head at this position ( Fig.…”

Tocotrienol inhibits proliferation of human Tenon’s fibroblasts in vitro: a comparative study with vitamin E forms and mitomycin C

“…Involvement of transforming growth factor β-, Fas-, and c-Jun-NH 2 -terminal kinase signaling pathways is suggested [3]. In the years 1999 and 2000, Larrosa, Pinilla and colleagues published in vitro, animal model and histologic studies evaluating the potential application of α-tocopheryl succinate and acetate in glaucoma surgery [21,22,37,38].…”

In vitro and In vivo Anticancer Effects of the Novel Vitamin E Ether Analogue RRR-α-Tocopheryloxybutyl Sulfonic Acid in Prostate Cancer

“…Consistently, it has been reported that the resistance of ovarian carcinoma cp70 cells to VES-induced apoptosis was due to high levels of cellular esterase. This conclusion is based on the observation that VES did not induce apoptosis in cp70 cells unless the cells were pretreated with the esterase inhibitor bis-(p-nitrophenyl) phosphate (13). Thus, the bioavailability of VES is a major concern for its application in chemoprevention.…”