Bruceine a exerts antitumor effect against colon cancer by accumulating ROS and suppressing PI3K/Akt pathway

Chaozheng Zhang; Yuening Cao; Yi Zuo; Hongbin Cheng; Changqun Liu; Xila Xia; Bo Ren; Yun Deng; Maolin Wang; Jun Lu

doi:10.3389/fphar.2023.1149478

Bruceine a exerts antitumor effect against colon cancer by accumulating ROS and suppressing PI3K/Akt pathway

Front Pharmacol. 2023 Mar 28:14:1149478. doi: 10.3389/fphar.2023.1149478. eCollection 2023.

Authors

Chaozheng Zhang¹, Yuening Cao¹, Yi Zuo¹, Hongbin Cheng^{1

2}, Changqun Liu¹, Xila Xia¹, Bo Ren¹, Yun Deng¹, Maolin Wang^{3

4}, Jun Lu¹

Affiliations

¹ State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
² Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
³ Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
⁴ Department of Physiology, School of Basic Medical Sciences, Shenzhen University, Shenzhen, China.

Abstract

Bruceine A (BA), a quassic ester from bruceine javanica, regulates diverse intracellular signal transduction pathways and manifests a variety of biological activities, however, its pharmacological mechanism in treating colon cancer (CC) is unclear. In this study, we investigated the anticancer effects of BA on CC cells and the underlying mechanisms. The network pharmacology research indicated that Akt1 and Jun and PI3K/Akt pathways are the predominant targets and critical signaling pathways, respectively, for BA treatment of CC. Meanwhile, molecular docking results implied that BA could conjugate to pivotal proteins in the PI3K/Akt pathway. BA remarkably suppressed the proliferation of CC cells HCT116 and CT26 with 48-h IC50 of 26.12 and 229.26 nM, respectively, and the expression of p-PI3K/p-Akt was restrained by BA at the molecular level as verified by Western blot assay. Further mechanistic studies revealed BA impacted cell cycle-related proteins by regulating the expression of P27 (a protein bridging the PI3K/Akt signaling pathway with cycle-related proteins), arresting the cell cycle in the G2 phase, inhibiting the proliferation of HCT116 and CT26, and facilitated the apoptosis in CC cells by activating the mitochondria-associated apoptosis protein Bax and accumulating reactive oxygen species, in addition to BA apparently inhibited the migration of CC cells. Taken together, our results demonstrated that BA might be a promising chemotherapy drug in the treatment of CC.

Keywords: Bruceine A (BA); PI3K/AKT; apoptosis; colon cancer; molecular dock; network pharmacology.

Grants and funding

This study was supported by the National Natural Science Foundation of China (No. 82273812), the National Interdisciplinary Innovation Team of Traditional Chinese Medicine (No. ZYYCXTD-D-202209), the Sichuan Outstanding Youth Fund Project (No. 23NSFJQ0099), Xinglin Scholar Research Promotion Project of Chengdu University of Traditional Chinese Medicine (No. BJRC2020002), the “Thousand Talents Program” of Sichuan Province, the Health Commission of Sichuan Province (No. 21PJ106), Shenzhen Commission of Science and Innovation programs (JCYJ20200109105613463).