Affiliation:
1. Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan
Abstract
Berberine (BBR) is a plant alkaloid that has various biological activities. The effects of BBR on gastrointestinal cancer (GIC) have also been investigated and anti-tumor effects such as induction of cell death have been reported. However, the mechanism of BBR-induced cell death has not been fully elucidated. To this end, we investigated the effects of BBR using three GIC cell lines. Our analyses revealed that BBR inhibited cell proliferation, invasion, sphere formation, and anticancer drug resistance in all of the cell lines. BBR also induced an increase in mitochondrial superoxide, lipid peroxide and Fe2+ levels, decreased mitochondrial membrane potential and respiration, decreased glutathione peroxidase 4 expression and glutathione and induced Parkin/PINK1-associated mitophagy. BBR, as well as rotenone, inhibited mitochondrial complex I and enhanced complex II, which were associated with autophagy, reactive oxidative species production, and cell death. Inhibition of complex II by malonate abrogated these changes. BBR-induced cell death was partially rescued by ferrostatin-1, deferoxamine, Z-VAD-FMK, and ATG5 knockdown. Furthermore, oral administration of BBR significantly reduced tumor weight and ascites in a syngeneic mouse peritoneal metastasis model using CT26 GIC cells. These findings suggest that BBR induced a combined type of cell death via complex I inhibition and autophagy. The marked anti-tumor and anti-stemness effects are expected to be useful as a new cell death-inducing agent for the treatment of GIC.
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Reference58 articles.
1. Wakao, F. (2021). Cancer Statistics in Japan 2021, Foundation for Promotion of Cancer Research.
2. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012;Ferlay;Int. J. Cancer,2015
3. Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States;Rahib;Cancer Res.,2014
4. Japanese Association of Clinical Cancer Centers (2022, October 25). Survival Studies in Japanese Association of Clinical Cancer Centers, Available online: https://www.zengankyo.ncc.go.jp/etc/seizonritsu/seizonritsu2013.html.
5. Shabbir, U., Rubab, M., Daliri, E.B., Chelliah, R., Javed, A., and Oh, D.H. (2021). Curcumin, Quercetin, Catechins and Metabolic Diseases: The Role of Gut Microbiota. Nutrients, 13.
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