Dehydrobruceine B enhances the cisplatin-induced cytotoxicity through regulation of the mitochondrial apoptotic pathway in lung cancer A549 cells

Dehydrobruceine B (DHB) is a quassinoid isolated from Brucea javanica. We have shown previously that DHB induced Apoptosis on two kinds of lung Cancer cell lines, A549 and NCI-H292. In the present study, we investigated the interactions of DHB and cisplatin (CDDP) on apoptotic-related Cancer cell death. Synergistic effects on cell proliferation and Apoptosis were observed when A549 cells were treated with DHB plus CDDP. DHB combined CDDP exposure increased depolarization of mitochondrial membrane potential (MMP) and release of cytochrome c from mitochondria into the cytoplasm. The combination treatment also enhanced protein expression of Bax, reduced the protein levels of Bcl-xL and Bcl-2, and increased the cleavage of Caspase-3, caspase-9 and poly (ADP-ribose) polymerase (PARP). These results indicated that DHB sensitized A549 cells to cisplatin by regulating the mitochondrial apoptotic pathway. High constitutive expression of Nrf2 was found in A549 cells, which enhance the resistance of Cancer cells to chemotherapeutic agents including cisplatin. DHB reduced the protein levels of Nrf2 and its target genes, which may contribute to the increase of intracellular ROS level, consequently, induced mitochondria Apoptosis. These results generated a rationale for further investigation of DHB combined with CDDP as a potential therapeutic strategy in lung Cancer.

Chemotherapy resistance; Cisplatin; Dehydrobruceine B; Lung cancer; Nrf2.