Tetrandrine enhances antitumor effects of the histone deacetylase inhibitor MS-275 in human cancer in a Bax- and p53-dependent manner

Abstract

MS-275 (Entinostat), is an oral histone deacetylase (HDAC) inhibitor with a high specificity for class 1 HDACs. As single agent, MS-275 exerts only modest antitumor activity against most solid malignancies. The use of MS-275 in combination with other anticancer agents is currently being evaluated to determine whether this approach can achieve superior therapeutic efficacy. Tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the root of a Chinese medicinal herb, is safe and exhibits low toxicity, showing great potential to enhance chemotherapeutic efficacy. In the present study, we investigated the synergistic antitumor effects of MS-275 in combination with tetrandrine. Based on the results of in vitro experiments, the application of MS-275 in combination with tetrandrine induced selective apoptotic death in various cancer cells but spared normal cells. Mechanistically, the combination treatment induced a dramatic accumulation of reactive oxygen species (ROS), and a pretreatment with the ROS scavenger N-acetyl-L-cysteine (NAC) significantly prevented the cellular apoptosis induced by MS-275/tetrandrine. Moreover, molecular assays indicated that Bax and p53 were the key regulators of MS-275/tetrandrine induced apoptosis. The results of the in vivo studies were consistent with the results of the in vitro studies. Based on our findings, tetrandrine enhanced the antitumor effects of MS-275 in a Bax- and p53-dependent manner. The combination of MS-275 and tetrandrine may represent a novel and promising therapeutic strategy for cancer.