3-Bromopyruvate modified with cholesterol enhances anti-hepatoma activity by inducing ferroptosis and apoptosis

Abstract

Ferroptosis offers an alternative to traditional apoptotic pathways for cancer therapy. Efficient glycolytic pathways reduce tumor sensitivity to ferroptosis. We hypothesize that inhibiting glycolysis to enhance tumor cell ferroptosis could be a potential strategy for cancer therapy. This study aimed to synthesize a pH-responsive prodrug of 3-bromopyruvate-cholesteryl ester (3-BP-CL) to improve the specific distribution of 3-bromopyruvate (3-BP)—an efficient antitumor alkylating agent capable of selectively inhibitng hexokinase-2 (HK-2) activity—to the tumor, hence increasing its efficacy and reducing toxicity. The results showed that the prodrug could release 3-BP in an acidic environment, thus increasing reactive oxygen species (ROS) production, inhibiting glutathione peroxidase 4 expression, increasing Fe2+ and lipid peroxide levels, and finally inducing ferroptosis in hepatoma cells. In addition, 3-BP-CL increased ROS production by releasing 3-BP, further promoting the apoptosis of hepatoma cells. Cell migration, growth, and in vivo experiments revealed a significantly higher anti-hepatocellular carcinoma effect of 3-BP-CL than 3-BP in mice (P < 0.05). Unlike 3-BP, 3-BP-CL displayed no toxicity to mice. These results suggested that 3-BP-CL was a promising prodrug for hepatoma treatment and acted via ferroptosis and apoptosis pathways.