Potent bromodomain and extraterminal domain inhibitor JAB-8263 suppresses MYC expression and exerts anti-tumor activity in colorectal cancer models  

作　　者：Xin-Mo Liu Shao-You Xia Wei Long Hai-Jun Li Gui-Qun Yang Wen Sun Song-Yan Li Xiao-Hui Du 

机构地区：[1]Department of General Surgery,Chinese PLA General Hospital,Beijing 100039,China [2]Medical School of Chinese PLA,Beijing 100039,China [3]Department of Chemistry,Jacobio Pharmaceuticals,Beijing 102600,China [4]Department of Pharmacology,Jacobio Pharmaceuticals,Beijing 102600,China [5]Department of Anesthesiology,the Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine,Tianjin 300250,China

出　　处：《World Journal of Gastrointestinal Oncology》2023年第2期332-342,共11页世界胃肠肿瘤学杂志（英文版）（电子版）

基　　金：Supported by the National Natural Science Foundation of China,No.81871317.

摘　　要：BACKGROUND The overexpression of the MYC gene plays an important role in the occurrence,development and evolution of colorectal cancer(CRC).Bromodomain and extraterminal domain(BET)inhibitors can decrease the function BET by recognizing acetylated lysine residues,thereby downregulating the expression of MYC.AIM To investigate the inhibitory effect and mechanism of a BET inhibitor on CRC cells.METHODS The effect of the BET inhibitor JAB-8263 on the proliferation of various CRC cell lines was studied by CellTiter-Glo method and colony formation assay.The effect of JAB-8263 on the cell cycle and apoptosis of CRC cells was studied by propidium iodide staining and Annexin V/propidium iodide flow assay,respectively.The effect of JAB-8263 on the expression of c-MYC,p21 and p16 in CRC cells was detected by western blotting assay.The anti-tumor effect of JAB-8263 on CRC cells in vivo and evaluation of the safety of the compound was predicted by constructing a CRC cell animal tumor model.RESULTS JAB-8263 dose-dependently suppressed CRC cell proliferation and colony formation in vitro.The MYC signaling pathway was dose-dependently inhibited by JAB-8263 in human CRC cell lines.JAB-8263 dose-dependently induced cell cycle arrest and apoptosis in the MC38 cell line.SW837 xenograft model was treated with JAB-8263(0.3 mg/kg for 29 d),and the average tumor volume was significantly decreased compared to the vehicle control group(P<0.001).The MC38 syngeneic murine model was treated with JAB-8263(0.2 mg/kg for 29 d),and the average tumor volume was significantly decreased compared to the vehicle control group(P=0.003).CONCLUSION BET could be a potential effective drug target for suppressing CRC growth,and the BET inhibitor JAB-8263 can effectively suppress c-MYC expression and exert anti-tumor activity in CRC models.

关 键 词：BROMODOMAIN Bromodomain and extraterminal domain inhibitor Colorectal cancer JAB-8263 MYC p21 

分 类 号：R735.37[医药卫生—肿瘤]