Gamma-tocotrienol acts as a BH3 mimetic to induce apoptosis in neuroblastoma SH-SY5Y cells super([starf)

• Published in: The Journal of nutritional biochemistry 2016-05, Vol.31, p.28-37
• Main Authors: Tana, Jen-Kit, Thenb, Sue-Mian, Mazlanc, Musalmah, Rahmand, Raja Noor Zaliha Raja Abdul, Jamala, Rahman, Ngaha, Wan Zurinah Wan
• Format: Article
• Language: English
• ISSN: 0955-2863
• DOI: 10.1016/j.jnutbio.2015.12.019

Bcl-2 family proteins are crucial regulators of apoptosis. Both pro- and antiapoptotic members exist, and overexpression of the latter facilitates evasion of apoptosis in many cancer types. Bcl-2 homology domain 3 (BH3) mimetics are small molecule inhibitors of antiapoptotic Bcl-2 family members, and these inhibitors are promising anticancer agents. In this study, we report that gamma-tocotrienol ( gamma T3), an isomer of vitamin E, can inhibit Bcl-2 to induce apoptosis. We demonstrate that gamma T3 induces cell death in human neuroblastoma SH-SY5Y cells by depolarising the mitochondrial membrane potential, enabling release of cytochrome c to the cytosol and increasing the activities of caspases-9 and -3. Treatment of cells with inhibitors of Bax or caspase-9 attenuated the cell death induced by gamma T3. Simulated docking analysis suggested that gamma T3 binds at the hydrophobic groove of Bcl-2, while a binding assay showed that gamma T3 competed with a fluorescent probe to bind at the hydrophobic groove. Our data suggest that gamma T3 mimics the action of BH3-only protein by binding to the hydrophobic groove of Bcl-2 and inducing apoptosis via the intrinsic pathway in a Bax- and caspase-9-dependent manner.