Novel coumarin compounds potentiate the effect of cisplatin on lung cancer cells by enhancing pro-apoptotic gene expressions, G2/M cell arrest, oxidative and antiangiogenic effects

Coumarin is a functional compound with a pronounced wide range of biological activities and has recently been shown to have anticancer effects on various human cancer cells. Cisplatin is widely used in the treatment of many cancers but its effectiveness is limited due to acquired resistance and dose-related side effects. This study aimed to reveal the chemosensitizing ability of novel synthesized coumarin-triazole hybrid compounds (3a-f) alone or their combination with cisplatin in A549 cells.MTT assay was used for cytotoxic effects. Lactate dehydrogenase (LDH), antioxidant/oxidant status, DNA fragmentation were determined spectrophotometrically by using commercial kits. Muse™ Cell Analyzer was used to assess cell cycle progression. Pro/anti-apoptotic gene expressions were determined by Real-Time qPCR. The antiangiogenic activity was determined by VEGF expression and Hen's chorioallantoic membrane model. Compounds 3c, d, e, and f potentiated the cisplatin-induced cytotoxicity through the increase of LDH release and DNA fragmentation, induced G2/M cell cycle arrest, overproduction of oxidative stress, and decrease of cellular antioxidant levels. These compounds combined with cisplatin caused upregulation in the pro-apoptotic Bax, Bid, caspase-3, caspase-8, caspase-9, Fas, and p53 gene expressions while downregulating anti-apoptotic DFFA, NFkB1, and Bcl2 gene expressions. These combinations caused vascular loss and a reduction in VEGF expression. These results suggest that a combinational regimen of coumarin compounds with cisplatin overcome the acquired resistance of cancer cells to cisplatin and, considering compounds have relatively low toxicity in normal cells, decrease the dose requirement of cisplatin in cancer treatments.