title: Gamma-tocotrienol acts as a BH3 mimetic to induce apoptosis in neuroblastoma SH-SY5Y cells.
abstract: 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 (γT3), an isomer of vitamin E, can inhibit Bcl-2 to induce apoptosis. We demonstrate that γT3 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 γT3. Simulated docking analysis suggested that γT3 binds at the hydrophobic groove of Bcl-2, while a binding assay showed that γT3 competed with a fluorescent probe to bind at the hydrophobic groove. Our data suggest that γT3 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.
authors.affiliation: UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia Medical Center, 56000, Cheras, Kuala Lumpur, Malaysia. Electronic address: tanjenkit@gmail.com.
authors.forename: Jen-Kit
authors.initials: JK
authors.lastname: Tan
authors.affiliation: Department of Biomedical Sciences, Faculty of Sciences, The University of Nottingham Malaysia Campus, 43500, Semenyih, Selangor, Malaysia. Electronic address: then.sue-mian@nottingham.edu.my.
authors.forename: Sue-Mian
authors.initials: SM
authors.lastname: Then
authors.affiliation: Faculty of Medicine, Universiti Teknologi MARA, 47000, Sungai Buluh, Selangor, Malaysia. Electronic address: musalmah6393@salam.uitm.edu.my.
authors.forename: Musalmah
authors.initials: M
authors.lastname: Mazlan
authors.affiliation: Enzyme and Microbial Technology Research Center, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia; Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia. Electronic address: rnzaliha@upm.edu.my.
authors.forename: Raja Noor Zaliha
authors.initials: RN
authors.lastname: Raja Abdul Rahman
authors.affiliation: UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia Medical Center, 56000, Cheras, Kuala Lumpur, Malaysia. Electronic address: rahmanj@ppukm.ukm.edu.my.
authors.forename: Rahman
authors.initials: R
authors.lastname: Jamal
authors.affiliation: UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia Medical Center, 56000, Cheras, Kuala Lumpur, Malaysia; Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Center, 56000, Cheras, Kuala Lumpur, Malaysia. Electronic address: wanzurinah@ppukm.ukm.edu.my.
authors.forename: Wan Zurinah
authors.initials: WZ
authors.lastname: Wan Ngah
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002839:Chromans / Q000494:pharmacology*; D006801:Humans; D018716:Molecular Mimicry; D009447:Neuroblastoma / Q000473:pathology*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000494:pharmacology*; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C474007:Bax protein (53-86); D002839:Chromans; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D014810:Vitamin E; C013649:plastochromanol 8
keywords: Apoptosis; BH3 mimetic; Bcl-2; Gamma-tocotrienol; Neuroblastoma; Vitamin E