B7 Induces Apoptosis in Colorectal Cancer Cells by Regulating the Expression of Caspase-3 and Inhibits Autophagy

Xinyi Zhang; Fengxi Li; Rong Li; Nan Zhao; Dianfeng Liu; Yuelin Xu; Lei Wang; Dongxu Wang; Ruihong Zhao

doi:10.2147/OTT.S429128

B7 Induces Apoptosis in Colorectal Cancer Cells by Regulating the Expression of Caspase-3 and Inhibits Autophagy

Onco Targets Ther. 2023 Oct 27:16:867-883. doi: 10.2147/OTT.S429128. eCollection 2023.

Authors

Xinyi Zhang¹, Fengxi Li², Rong Li¹, Nan Zhao², Dianfeng Liu¹, Yuelin Xu², Lei Wang², Dongxu Wang¹, Ruihong Zhao³

Affiliations

¹ Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, 130062, People's Republic of China.
² Key Laboratory of Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun, 130023, People's Republic of China.
³ Department of Gastroenterology Endoscopy Center, The First Hospital of Jilin University, Changchun, 130021, People's Republic of China.

Abstract

Purpose: Heterocyclic compounds are organic compounds with heterocyclic structures, which are common in drug molecules. They include pyrazines with diverse functions, including anti-cancer, antimicrobial, antidiabetic, and anticholinergic activities. In this study a new small molecular compound B7 based on tetrazolium substituted pyrazine was synthesized and its effect on the progression of colorectal cancer (CRC) and its potential mechanism were investigated.

Methods: We synthesized a series of tetrazolium-substituted pyrazine compounds by chemoenzymatic method. NCM460 (Human), HCT116 (Human), SW480 (Human) cell lines were selected to analyse the inhibitory effect of B7 on CRC by CCK-8, apoptosis, cell migration and invasion, qPCR, Western blotting, molecular docking, immunofluorescence. Moreover, a CRC xenograft model of mice was used to analyzed the role of B7 in vivo.

Results: Among these compounds, 3-methyl-5je-6-bis (1H-tetrazole-5-yl) pyrazine-2-carboxylic acid (B7) inhibited CRC cell proliferation and induced apoptosis. The expression of Caspase-3 was increased after B7 treatment. In addition, the mitochondria abnormalities was observed in B7 group due to decrease the expression of Beclin-1. In addition, B7 inhibited the migration and invasion in CRC cells. Finally, the results showed that B7 had anti-tumor activity in CRC xenograft model of mice.

Conclusion: In summary, compound B7 was synthesized efficiently using tetrazolium-substituted pyrazine via a chemoenzymatic method. Moreover, B7 have ability to regulate the expression of Caspase-3 which induced apoptosis in CRC cells. In addition, decreased Beclin-1 expression after B7 treatment, indicating inhibited autophagy. This study showed that B7 effectively induced apoptosis and inhibited autophagy in CRC cells.

Keywords: apoptosis; autophagy; colorectal cancer; pyrazines; tetrazoles.

Grants and funding

This work was funded by the Jilin Health Commission Program under Grant 2020J05S, the Fundamental Research Funds for the Central Universities under Grant 2019-JCKT-70 and 2023-JCXK-08, the Jilin Education Department Program under Grant JJKH20200950KJ, the Jilin Scientific and Technological Development Program under Grant 20190103071JH, 202002006JC, 20210101010JC and 20220505033ZP, and the Jilin Development and Reform Commission under Grant 2023C028-6.