Small Molecule-Induced Differentiation As a Potential Therapy for Liver Cancer

Despite the efficacy demonstrated by immunotherapy recently, liver cancer still remains one of the deadliest cancers, mainly due to heterogeneity of this disease. Continuous exploration of new therapeutics is therefore necessary. Chemical-induced cell differentiation can serve as a promising approach, with its ability to consistently remodel gene expression profile and alter cell fate. Inspired by advances in stem cell and reprogramming field, here it is reported that a small molecule cocktail (SMC) consisted of: SB431542 (TGF beta inhibitor), CHIR99021 (GSK3 beta inhibitor), BIX01294 (H3K9 methyltransferase/G9a inhibitor), and all-trans retinoic acid (ATRA), can induce differentiation of liver cancer cells including cell lines, primary cancer cells, cancer stem cells, and drug resistant cells. Treated cells lose malignant characteristics and regain hepatocyte phenotype instead. When applied in vivo, SMC induces wide range of tissue necrosis or fibrosis within the tumors, while remaining tissues begin to express hepatic nuclear factor 4 alpha (HNF4 alpha), the hepatic nuclear marker. SMC also leads to tumor abrogation in orthotopic xenograft models and life span extension of animals. The powerful differentiation induction of SMC is exerted through modulation of Akt/mTOR/HIF1 alpha signaling and metabolic reprogramming, as well as suppressing Snail and enhancing HNF4 alpha expression. Together, these results highlight that chemical-induced differentiation has the potential to effectively treat liver cancer disregard of heterogeneity.

Automated summary

This article describes a small molecule cocktail (SMC) that can induce differentiation of liver cancer cells and potential treat liver cancer. SMC can remodel gene expression profile and alter cell fate, causing liver cancer cells to lose malignant characteristics and regain hepatocyte phenotype. In vivo experiments showed that SMC induced tissue necrosis or fibrosis within tumors and the expression of hepatic nuclear marker in healthy tissues.