Simvastatin in combination with bergamottin potentiates TNF-induced apoptosis through modulation of NF-kappa B signalling pathway in human chronic myelogenous leukaemia

Context Simvastatin (SV) and bergamottin (BGM) are known to exhibit diverse anti-cancer and anti-inflammatory activities. Objective Very little is known about the potential efficacy of combination of these two agents to potentiate TNF-induced apoptosis in human chronic myelogenous leukaemia (CML). Materials and methods In the present study, we investigated whether SV combined with BGM mediates its effect through suppression of NF-kappa B-signalling pathway. Results We found that the combination treatment enhanced cytotoxicity and potentiated the apoptosis induced by TNF as indicated by intracellular esterase activity, Annexin V staining and caspase activation. This effect of co-treatment correlated with down-regulation of various gene products that mediate cell proliferation (cyclin D1), cell survival (cIAP-1, Bcl-2, Bcl-xL and Survivin), invasion (MMP-9) and angiogenesis (VEGF); all known to be regulated by NF-kappa B. SV combined with BGM also produced TNF-induced cell-cycle arrest in S-phase and this arrest correlated with a concomitant increase in the levels of cyclin-dependent inhibitor p21 and p27. The combination therapy inhibited TNF-induced NF-kappa B activation, IkB alpha degradation and p65 translocation to the nucleus as compared with the treatment with individual agents alone. Besides, SV combined with BGM did not significantly potentiate apoptotic effect induced by TNF in p65(-/-)cells, as compared with wild-type fibroblasts. Discussion and conclusion Our results provide novel insight into the role of SV and BGM in potentially preventing and treating cancer through modulation of NF-kappa B signalling pathway and its regulated gene products.