H1, a derivative of tetrandrine, enhances the efficacy of 5-FU in Bel7402/5-FU cells via suppressing STAT3/MCL-1 and inducing PUMA

Abstract

Currently, 5-fluorouracil (5-FU) resistance became a major obstacle to its clinical use for patients with hepatocellular carcinoma (HCC). It's urgent to develop a novel strategy for enhancing the therapeutic efficacy of 5-FU. Herein, we found that H1 (a derivative of Tetrandrine) exerted a potent anti-MDR effect on growth of 5-FU resistant HCC cells (Bel7402/5FU). The resistant fold (RF) of 5-FU is over 160-fold, while the RF of H1 is only 4.8-fold in Bel7402/5-FU cells. Further studies demonstrated that blockage of STAT3/MCL-1 signaling and induction of PUMA is responsible to anti-MDR activity of H1. Moreover, combination of H1 and 5-FU (Ratio = 1:2) could synergistically induce apoptosis of Bel7402/5-FU cells. Co-treatment of H1 enhances the suppression of p-STAT3 and MCL-1, and significantly increases PUMA expression. Finally, the combination of H1 and 5-FU results in an increase of cleaved PARP. Taken together, H1 effectively improve the cytotoxic effect of 5-FU against Bel7402/5-FU cells via blocking STAT3/MCL-1 pathway and inducing PUMA. Our findings suggested that combination 5-FU with anti-MDR agents might present a novel strategy to enhance the therapeutic efficacy of 5-FU in resistant HCC.

Keywords: 5-FU; Drug resistance; Hepatocellular carcinoma; MCL-1; PUMA; STAT3.