Dendrobine targeting JNK stress signaling to sensitize chemotoxicity of cisplatin against non-small cell lung cancer cells in vitro and in vivo

Background: Lung cancer is a leading cause of cancer-related death worldwide. Cisplatin-based chemotherapy is the standard treatment for lung cancer, but chemoresistance and adverse effects especially cardiotoxicity limit its efficacy. Purpose: The efficacy of combination treatment of dendrobine, a plant alkaloid isolated from Dendrobium nobile, with cisplatin was examined as a possible anti-non-small cell lung cancer strategy. Methods: The cytotoxicity of dendrobine and cisplatin against A549 lung cancer cells was analyzed by MTT and colony formation assays. Apoptosis was measured by annexin V/PI double staining. Apoptosis-related proteins were assessed by western blotting and qPCR analysis. In vivo efficacy was determined using A549 xenograft in nude mice. JNK and Bim inhibition were achieved by siRNA knockdown and/or chemical inhibition. Cardiotoxicity was assessed by serum creatine phosphokinase activity assay. Results: Dendrobine induced apoptotic cell death through mitochondrial-mediated pathway. Combination treatment of dendrobine with cisplatin showed enhanced cytotoxicity through stimulation of JNK/p38 stress signaling pathways and, consequently, the induction of apoptosis involving pro-apoptotic proteins Bax and Bim. In addition, dendrobine attenuated the body weight reduction and cardiotoxicity induced by cisplatin in nude mice. Conclusion: The combination treatment showed enhanced anticancer activity toward non-small cell lung cancer cells without aggravating the cardiotoxic effects of cisplatin suggesting that the combination strategy deserves further investigation for human lung cancer treatment.