BET inhibitors combined with chemotherapy synergistically inhibit the growth of NSCLC cells

Abstract

The bromodomain and extra-terminal domain (BET) family proteins are essential epigenetic regulators in lung cancer. However, BET inhibitors have not had the antici- pated therapeutic efficacy. Combined treatment using BET inhibitors along with other drugs had favorable therapeutic effects but the underlying molecular mechanisms remain elusive. The aim of the present study was to investigate the antineoplastic effects and mechanisms of a combination of a BET inhibitor and paclitaxel or cisplatin in non-small cell lung cancer (NSCLC). By using the online Kaplan-Meier plotter, it was revealed that increased mRNA levels of several BET protein-coding genes were associated with poor prognosis in NSCLC. SRB assay results revealed that pharmaceutical or genetic targeting of BET proteins suppressed the growth of NSCLC cells. Inhibition of BET protein expression, in combination with the use of chemotherapeutic drugs such as paclitaxel and cisplatin, further restrained NSCLC cell growth in a synergistic manner. Mechanistically, this combination of suppression of BET expression and chemotherapeutic treat- ment blocked NSCLC cell growth by inhibiting autophagy and promoting apoptosis, which were revealed by both western blot and ELISA results. The present findings revealed a new rationale for using a combination of BET inhibitors with chemotherapy in NSCLC treatment.