Bisdemethoxycurcumin sensitizes the response of cisplatin resistant non-small cell lung carcinoma cell lines by activating apoptosis and autophagy

Abstract

Lung cancer belongs to the most frequent and deadliest cancer types worldwide, non-small cell lung carcinoma (NSCLC) being the most frequent type. Development of chemoresistance in NSCLC patients is common and responsible for bad outcome. Curcuminoids are naturally occurring substances with prominent cytotoxic effects in different cancer cells. Here we analyzed influence of bisdemethoxycurcumin (BDMC) on phenotype and molecular mechanisms in cisplatin-sensitive NSCLC cell lines (A549 and H460) and their cisplatin-resistant counterparts. NSCLC cell lines were exposed to BDMC and analyzed by cell viability, proliferation, and motility assays, as well as fluorescence-activated cell sorting. Immunoblotting was assessed to detect apoptosis and autophagy. Colony-formation assay and multicellular tumor spheroid model were used to investigate the effects of BDMC. Expression levels of different Hedgehog-pathway genes were determined by RT-qPCR analysis. We identified substantial cytotoxic effects of BDMC on NSCLC cells in general and on cisplatin-resistant NSCLC cells in special. BDMC markedly decreased the cell viability by inducing apoptosis and autophagy in a cell-type specific manner. BDMC emphasized cisplatin-induced cell death and inhibited cell cycle progression of cisplatin-resistant NSCLC cells. Scratch-closure, colony formation, and multicellular spheroid growth in cisplatin-resistant NSCLC cell lines were inhibited by BDMC. Expression profile analyses of different Hedgehog-pathway regulatory genes showed that Gli1, the mean transcriptional regulator of this pathway, was markedly decreased upon the BDMC treatment, this decrement being most prominent in cisplatin-resistant cells. Our data identified BDMC as a potent substance that may be suitable for combined cisplatin-based therapy in cisplatin-resistant subpopulation of NSCLC patients.