APG-1252 combined with Cabozantinib inhibits hepatocellular carcinoma through MEK/ERK and CREB/Bcl-xl pathways

Abstract Background and Purpose Liver cancer is the fourth leading cause of cancer-related death worldwide, and hepatocellular carcinoma (HCC) is the most common primary liver cancer. APG-1252 is a small molecule inhibitor of Bcl-2/Bcl-xl, and the anti-tumor effect of APG-1252 in HCC, or its anti-tumor effects in combination with cabozantinib, has not been researched. Experimental Approach: TCGA database analysis was used to analysis the gene expression levels of Bcl-2 and Bcl-xl in HCC tissues. Western Blot was used to detect the proteins’ expression level. And the inhibitory effects of APG-1252 and Cabozantinib on the proliferation of HCC cell lines was detected by CCK-8. The effect on the migration and invasion of HCC cells was verified by Transwell assay. Huh7 xenograft model in nude mice was used to detect the combined effect in vivo. Key Results: We found that APG-1252 monotherapy could inhibit the proliferation and migration of HCC cells and promote apoptosis of HCC cells. APG-1252 combined with Cabozantinib could inhibit the proliferation, migration and invasion of HCC cells and promote the apoptosis of hepatocellular carcinoma cells and exerted synergistic effect in vivo. The combination could significantly downregulate MEK/ERK phosphorylation levels. Besides, the treatment of Cabozantinib could cause the protein level of phosphorylation CREB and BCL-XL increased, while combined with APG-1252 could impair this effect. Conclusion and Implications: Our data suggest that APG-1252 in combination with Cabozantinib can provide more effective treatment strategies for HCC patients and deserve further clinical investigation.