Two naturally occurring dietary sources of vitamin E [i.e. RRR-α-tocopherol (αT), and RRR-γ-tocopherol (γT)], the manufactured synthetic form of vitamin E, all-racemic-α-tocopherol (all-rac-αT), as well as, a potent antitumor analog of vitamin E, RRR-α-tocopherol ether-linked acetic acid analog (α-TEA) were assessed for anticancer actions. Data showed that γT, all-rac-αT and α-TEA but not αT or αT + γT significantly inhibited tumor burden of human MDA-MB-231 cells in nude mice. Immunohistochemical analyses of tumor tissue showed that all-rac-αT and α-TEA increased apoptosis and decreased proliferation in tumor cells while γT was associated with increased tumor cell apoptosis only. In vitro data showed α-TEA and γT but not all-rac-αT or αT to inhibit colony formation and induce apoptosis. Anticancer actions of α-TEA and γT involved DR5 protein upregulation, Survivin protein downregulation and PARP cleavage all of which were blocked by co-treatment with αT. In summary, both γT and α-TEA exhibited promising anticancer properties in vivo and in vitro, whereas all-rac-αT exhibited promising anticancer properties in vivo only. Importantly, αT not only failed to exhibit anticancer properties but it reduced anticancer actions of γT in vivo and γT and α-TEA in vitro.
Taken together, data show that both γT and γT3 induce apoptosis via de novo ceramide synthesis dependent activation of JNK/CHOP/DR5 pro-apoptotic signaling.
Despite multimodal treatment that includes surgery, radiation and chemotherapy, virtually all glioblastomas (GBM) recur, indicating that these interventions are insufficient to eradicate all malignant cells. To identify potential new therapeutic targets in GBMs, we examined the expression and function of proteins that are associated with therapy resistance and cancer cell survival. We measured the expression of eight such proteins in 50 GBM samples by immunohistochemistry and analyzed patient survival. We report that GBM patients with high expression of ABCG2 (also called BCRP) or XIAP at the protein level had worse survival than those with low expression. The adjusted hazard ratio for ABCG2 was 2.35 and for XIAP was 2.65. Since glioma stem cells (GSCs) have been shown to be more resistant than bulk tumor cells to anti-cancer therapies and to express high levels of these proteins, we also sought to determine if ABCG2 and XIAP have functional roles in GSCs. We used small molecule inhibitors to treat patient-derived GBM tumorspheres in vitro and observed that inhibitors of ABCG2, Ko143 and fumitremorgin, significantly reduced self-renewal. These results suggest that ABCG2 and XIAP proteins may be useful indicators of patient survival and that inhibition of ABCG2 may be a promising therapeutic target in GBMs.
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