The synthetic ajoene analog SPA3015 induces apoptotic cell death through crosstalk between NF-kappa B and PPAR gamma in multidrug-resistant cancer cells

Abstract

Multidrug resistance (MDR) caused by P-glycoprotein (P-gp) overexpression impedes successful cancer chemotherapy. In this study, we investigated the anticancer effects of SPA3015, a synthetic ajoene analog, in P-gp-overexpressing MDR cancer cells (KBV20C and MES-SA/DX5). Treatment with SPA3015 caused a dramatic decrease in the cell viabilities of both KBV20C and MES-SA/DX5 cells. This decrease was accompanied by apoptotic cell death without affecting the expression level or drug efflux function of P-gp. SPA3015 selectively suppressed NF-kappa B reporter gene activity, which led to decreased expression of NF-kappa B target genes such as CIAP1, CIAP2, XIAP, and Bcl-XL. Surprisingly, nuclear localization and DNA binding affinity of the p65 subunit were not affected by SPA3015, suggesting that SPA3015 inhibits the transcriptional activity of NF-kappa B at the nucleus. Indeed, SPA3015 treatment led to an increase in the physical interaction of p65 with PPAR gamma, which resulted in the inhibition of NF-kappa B activity. Our findings support the hypothesis that SPA3015 inhibits NF-kappa B transcriptional activity by facilitating the physical interaction of the p65 subunit and PPAR gamma, which leads to apoptotic cell death in MDR cancer cells. (C) 2016 Elsevier Ltd. All rights reserved.