Berberrubine is a novel and selective IMPDH2 inhibitor that impairs the growth of colorectal cancer

Xiangli He; Jiayan Cui; Hui Ma; Naijipu Abuduaini; Ying Huang; Lu Tang; Wanyan Wang; Yuanyuan Zhang; Yang Wang; Weiqiang Lu; Bo Feng; Jin Huang

doi:10.1016/j.bcp.2023.115868

Berberrubine is a novel and selective IMPDH2 inhibitor that impairs the growth of colorectal cancer

Biochem Pharmacol. 2023 Dec:218:115868. doi: 10.1016/j.bcp.2023.115868. Epub 2023 Oct 21.

Authors

Xiangli He¹, Jiayan Cui¹, Hui Ma¹, Naijipu Abuduaini², Ying Huang³, Lu Tang¹, Wanyan Wang¹, Yuanyuan Zhang¹, Yang Wang⁴, Weiqiang Lu⁵, Bo Feng⁶, Jin Huang⁷

Affiliations

¹ Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
² Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Drug Inspection Technology, Guangdong Institute For Drug Control, 766 Shenzhou Road, Guangzhou 510663, China.
⁴ Department of Urology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.
⁵ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China. Electronic address: wqlu@bio.ecnu.edu.cn.
⁶ Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: fb11427@rjh.com.cn.
⁷ Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai, China. Electronic address: huangjin@ecust.edu.cn.

PMID: 37871880
DOI: 10.1016/j.bcp.2023.115868

Abstract

Inosine monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting reaction in the de novo synthesis pathway of guanine nucleotides that is highly required for cancer cell outgrowth. Herein, we found that IMPDH isoform 2 (IMPDH2) is highly expressed in colorectal cancer (CRC) and is correlated with poor patient prognosis. Via structure-based virtual screening, we identified berberrubine, a critical ingredient of the medical plant Coptis chinensis, as a novel, selective, and competitive inhibitor of IMPDH2, which demonstrated over 15-fold selectivity to IMPDH2 than IMPDH1. Besides, we also confirmed the interaction between berberrubine and IMPDH2. Of note, berberrubine treatment significantly impairs the growth of human CRC cells in a dose-dependent manner, which can be rescued by supplementing with guanosine. Furthermore, oral administration of berberrubine remarkably reduced tumor volume and weight in a human cell line-derived xenograft model. Importantly, the anti-cancer activity of berberrubine was also confirmed by using the azoxymethane (AOM) / dextran sulfate sodium (DSS)-induced spontaneous CRC mouse model. Taken together, our study highlights that berberrubine acts as a novel IMPDH2 inhibitor, suppressing the growth of CRC in vitro and in vivo, providing a fresh perspective for its potential application in the treatment of CRC.

Keywords: Berberrubine; Colorectal cancer; IMPDH2; Natural products.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Berberine* / pharmacology
Berberine* / therapeutic use
Cell Line
Colorectal Neoplasms* / drug therapy
Humans
IMP Dehydrogenase
Mice
Protein Isoforms

Substances

berberrubine
Berberine
Protein Isoforms
IMPDH2 protein, human
IMP Dehydrogenase