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

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.

• Authors: Xiangli He, Jiayan Cui, Hui Ma, Naijipu Abuduaini, Ying Huang, Lu Tang, Wanyan Wang, Yuanyuan Zhang, Yang Wang, Weiqiang Lu, Bo Feng, Jin Huang
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 218 Pg. 115868 (Dec 2023) ISSN: 1873-2968 [Electronic] England
• PMID: 37871880 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.

Chemical References

• berberrubine
• Berberine
• Protein Isoforms
• IMPDH2 protein, human
• IMP Dehydrogenase

Topics

• Animals
• Mice
• Humans
• Cell Line
• Berberine (pharmacology, therapeutic use)
• Protein Isoforms
• Colorectal Neoplasms (drug therapy)
• IMP Dehydrogenase