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

doi:10.4251/wjgo.v15.i2.332

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World Journal of Gastrointestinal Oncology

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World J Gastrointest Oncol. Feb 15, 2023; 15(2): 332-342
Published online Feb 15, 2023. doi: 10.4251/wjgo.v15.i2.332

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

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

Xin-Mo Liu, Shao-You Xia, Song-Yan Li, Xiao-Hui Du, Department of General Surgery, Chinese PLA General Hospital, Beijing 100039, China

Xin-Mo Liu, Shao-You Xia, Song-Yan Li, Xiao-Hui Du, Medical School of Chinese PLA, Beijing 100039, China

Wei Long, Hai-Jun Li, Department of Chemistry, Jacobio Pharmaceuticals, Beijing 102600, China

Gui-Qun Yang, Department of Pharmacology, Jacobio Pharmaceuticals, Beijing 102600, China

Wen Sun, Department of Anesthesiology, the Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300250, China

Author contributions: Liu XM performed experiments and data analysis and wrote the paper; Xia SY performed experiments; Long W and Li H collected data; Yang GQ and Sun W performed the data analysis; Du XH and Li SY designed and revised the manuscript; All authors contributed to the article and approved the submitted version.

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

Institutional animal care and use committee statement: The experimental protocols of animals in this experiment were reviewed, approved and guided by the Jacobio Animal Care and Use Management Committee.

Conflict-of-interest statement: All the authors report having no relevant conflicts of interest for this article.

Data sharing statement: The data used to support the findings of this study are available from the corresponding author upon reasonable request.

ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.

Corresponding author: Xiao-Hui Du, MD, Chief Doctor, Deputy Director, Professor, Department of General Surgery, Chinese PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing 100039, China. duxiaohuiplagh@sina.com

Received: November 20, 2022
Peer-review started: November 20, 2022
First decision: December 14, 2022
Revised: December 21, 2022
Accepted: December 30, 2022
Article in press: December 30, 2022
Published online: February 15, 2023
Processing time: 86 Days and 14.1 Hours

ARTICLE HIGHLIGHTS

Research 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 decrease the function of BET, which is the recognition of acetylated lysine residues, thereby downregulating the expression of MYC.

Research motivation

BET proteins are an important target in solid tumors, hematologic tumors and myelofibrosis. The development of BET small-molecule inhibitors has promising therapeutic value.

Research objectives

The study aimed to investigate the inhibitory effect and mechanism of a BET inhibitor on CRC cells.

Research methods

The effect of the BET inhibitor JAB-8263 on the proliferation of various CRC cell lines was studied by the 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 blot. To predict the anti-tumor effect of JAB-8263 on CRC cells in vivo and to evaluate the safety of the compound, a CRC cell animal tumor model was developed.

Research 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. The SW837 xenograft model was treated with JAB-8263 0.3 mg/kg for 29 d. 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. The average tumor volume was significantly decreased compared to the vehicle control group, P = 0.003.

Research conclusions

BET can 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.

Research perspectives

BET proteins are an important target in solid tumors, hematologic tumors and myelofibrosis. The development of BET small-molecule inhibitors has promising therapeutic value. Our study results are encouraging and will motivate further clinical evolution.