Study On The Effect And Mechanism Of Small-molecule Compound QW24 Against Colorectal Cancer

Colorectal cancer is the third most common cancer in morbidity and mortality worldwide.Treatment for patients with cancers of the colon and rectum contains surgery to move,chemotherapy and radiation therapy.However,cancer recurrence is still common among colorectal cancer survivors.Cancer stem cell(CSC),also known as cancer-initiating cell(CIC),is assumed to drive the tumor initiation,development,growth and metastasis formation and is a source of tumor recurrence.Targeting CSC self-renewal has been proposed as a therapeutic strategy and could be an effective approach to control tumor growth.BMI-1,one of the key components of polycomb repressive complex(PRC1)where it functions as an epigenetic chromation modifier targeting many genes,represents the most important regulator closely related to the self-renewal of CSC and maintains the stemness of CSC.BMI-1 also increases proliferation and decreases senescence and apoptosis,hence the recurrence and chemoresistence of cancer.In colorectal cancer,BMI-1 is overexpressed in patients,which links to the lower overall survival.Therefore,targeting the BMI-1 provides the basis for a new therapeutic approach in the treatment of colorectal cancer.In this study,we report the development and characterization of a novel small molecule inhibitor QW24 against BMI-1.QW24 potently down-regulated BMI-1 protein level through autophagy-lysosome protein degradation pathway without affecting the BMI-1 mRNA level.Moreover,QW24 effectively inhibited the proliferation of colorectal cancer cell lines HCT116,HT29,HCT8,HCT15,LS174T and LoVo(IC50,0.5-1?M).In contrast,the IC50 in human normal liver cell L02 is 19.4 ?M and in human adult skin fibroblasts HAF is 7.9 ?M.Notably,QW24 significantly decreased the self-renew ability of colorectal CSCs in stem-like colorectal cancer cell line HCT116,resulting in the abrogation of their proliferation and metastasis.Importantly,treatment of colorectal cancer xenografts with QW24 significantly suppressed the tumor growth in the subcutaneous xenograft model as well as the tumor metastasis in the liver metastasis model without obvious toxicity,and QW24 exerted a better efficiency than the previously reported BMI-1 inhibitor PTC209.In conclusion,our preclinical data shows that QW24 exerted a potent anti-tumor ability by down-regulating BMI-1 protein level and decreasing colorectal CSCs self-renew ability without obvious toxicity,thus suggesting that QW24 could be a potential candidate for the treatment of colorectal cancer.