Histone deacetylase inhibitor OBP801 and amrubicin synergistically inhibit the growth of squamous cell lung carcinoma by inducing mitochondrial ASK1dependent apoptosis

Squamous cell lung carcinoma (SQCLC) is an aggressive type of lung cancer. In contrast with the marked advances that have been achieved in the treatment of lung adenocarcinoma, there are currently no effective targeted therapies for SQCLC, for with cytotoxic drugs are still the main treatment strategy. Therefore, the present study aimed to develop novel combination therapies for SQCLC. The results demonstrated that a combined treatment with the potent histone deacetylase (HDAC) inhibitor OBP801 and the thirdgeneration anthracycline amrubicin synergistically inhibited the viability of SQCLC cell lines by inducing apoptosis signalregulating kinase 1 (ASK1)dependent, as well as JNK and p38 mitogenactivated protein kinase (MAPK)independent apoptosis. OBP801 treatment strongly induced the protein expression levels of thioredoxininteracting protein (TXNIP), and amrubicin treatment increased the levels of intracellular reactive oxygen species (ROS), which suggested that this combination oxidized and dissociated thioredoxin 2 (Trx2) from mitochondrial ASK1 and activated ASK1. Moreover, mouse xenograft experiments using human H520 SQCLC cells revealed that the cotreatment potently suppressed tumor growth in vivo. These results suggested that a combined treatment with OBP801 and amrubicin may have potential as a therapeutic strategy for SQCLC.