The anticancer effects of vitamin E derivative alpha-tea in human hematological malignancies

Abstract

alpha-TEA (alpha-tocopherol ether linked acetic acid) has been shown to induce apoptosis in human prostate, ovarian and breast cancer cells in culture and in xenograft models by promoting pro-apoptotic pathways and inhibiting anti-apoptotic pathways. Studies investigated the ability of alpha-TEA to induce apoptosis in human hematological malignant cell lines Jurkat, Raji and U266, representing T cell leukemia, B cell lymphoma and multiple myeloma, respectively. The three cell lines were cultured in the presence of different concentrations of alpha-TEA for different time periods, and examined for apoptosis by annexin V – FITC analyses, DAPI staining, and western blotting for poly (ADP-ribose) polymerase cleavage. alpha-TEA induced apoptosis in all three cell lines in a dose and time dependent manner. Levels of pro-apoptotic molecules DR5, c-Jun N-terminal protein kinase (JNK), C/EBP homologous protein (CHOP), caspase 9, and caspase 3 were upregulated in alpha-TEA treated cells in comparison to vehicle controls. Caspase 8 was activated in Jurkat and U266 cells but not in Raji cells. Apoptosis and pro-death signaling mediators were blocked by ceramide inhibitor, desipramine. The anti-apoptotic nuclear factor kappa B (NF-[kappa]B) signaling pathway was down-regulated in alpha-TEA treated Raji and U266 cells. Combinations of omega-3 fatty acid docosahexaenoic (DHA) and alpha-TEA significantly enhanced apoptosis in Jurkat cells in comparison to single treatments and vehicle control. In summary, alpha-TEA induced apoptosis in the malignant hematological cell lines is via shared and distinct pathways. ASMase/ceramide-mediated JNK activation and endoplasmic reticulum (ER) stress mitochondrial dependent apoptosis are involved in alpha-TEA induced apoptosis in the three cell lines; however, the cell lines exhibit cell type-specific responses to alpha-TEA: activation of death receptor/caspase 8 pathway is involved in Jurkat cells, suppression of NF-[kappa]B signaling is involved in Raji cells, and the U266 cells share both of these pathways for the induction of apoptosis.