Paper Title
γ-Tocotrienol Enhances The Cytotoxic Potency of Jerantinine B on Human Brain Cancer Cells

Jerantinine B has been shown to induce cytotoxic effect against cancer cell lines in vitro with similar toxic effects also evident on non-cancerous cells. On the other hand, although tocotrienols isomers have demonstrated selective toxicity, metabolic degradation due to high dose delivery has limited the therapeutic potential. Therefore, combination treatment has been suggested as alternative to circumventing these limitations. Herein, a sub-effective concentration (IC20) of jerantinine B was combined with sub-effective concentration of δ- and γ-tocotrienol aimed at improving potency and minimizing non selective toxicity. Synergistic antiproliferative was determined using neutral red cell viability assay and combination index method. Histochemical staining, comet assay, flow cytometry and immunofluorescence assay were used for investigation of combined treatments on cell morphology, DNA damage, cell cycle and microtubule inhibition. Results revealed induction of synergistic antiproliferative effect on brain (U87MG) cells with improved selective toxicity towards MRC5 cells. This was characterised by morphological and biochemical hallmarks of apoptosis including cell shrinkage, chromatin fragmentation and condensation, double stranded DNA breaks. G0/G1 arrest was induced by IC50 of γ-tocotrienol and combined low concentration treatment with jerantinine B compared to G2/M arrest induced by IC50 of jerantinine B. Jerantinine B and the combined low concentration treatment caused disruption of microtubule networks. The apoptotic effects of individual and combined treatments was mediated via caspase 8,9 and 3 enzymatic activities. The combined treatment of jerantinine B with γ-tocotrienol at sub effective concentration demonstrated improved potency and selective toxicity towards non-cancerous cells that could be potentially used as future chemotherapeutic regimen against brain cancer