O-GlcNAc Transferase Inhibitor Synergistically Enhances Doxorubicin-Induced Apoptosis in HepG2 Cells.

Abstract

Simple SummaryWe found that the combination treatment of doxorubicin (DOX) and O-GlcNAc transferase (OGT) inhibitor OSMI-1 has synergic therapeutic efficacy in the treatment of liver cancer. Our data show that DOX displayed cytotoxicity via the activation of p53 and the inflammatory NF-κB signaling pathway, while OSMI-1 evoked the ER stress response and inhibited NF-κB signaling. Therefore, DOX in combination with the OSMI-1 group showed a 20-fold reduction of tumor formation, whereas the DOX alone group reduced by 1.8-fold compared with control in a HepG2 cell xenograft model.The combination of chemotherapy with chemosensitizing agents is a common approach to enhance anticancer activity while reducing the dose-dependent adverse side effects of cancer treatment. Herein, we investigated doxorubicin (DOX) and O-GlcNAc transferase (OGT) inhibitor OSMI-1 combination treatment, which significantly enhanced apoptosis in hepatocellular carcinoma cells (HepG2) as a result of synergistic drug action in disparate stress signaling pathways. Treatment with a low dose of DOX or a suboptimal dose of OSMI-1 alone did not induce apoptotic cell death in HepG2 cells. However, the combination of DOX with OSMI-1 in HepG2 cells synergistically increased apoptotic cell death through the activation of both the p53 and mitochondrial Bcl2 pathways compared to DOX alone. We also demonstrated that the combination of DOX and OSMI-1 stimulated cell death, dramatically reducing cell proliferation and tumor growth in vivo using a HepG2 xenograft mouse model. These findings indicate that OSMI-1 acts as a potential chemosensitizer by enhancing DOX-induced cell death. This study provides insight into a possible mechanism of chemotherapy resistance, identifies potential novel drug targets, and suggests that OGT inhibition could be utilized in clinical applications to treat hepatocellular carcinoma as well as other cancer types.