Berberine Induces Combined Cell Death in Gastrointestinal Cell Lines.

Content Provider	Europe PMC
Author	Mori, Shiori Fujiwara-Tani, Rina Gyoten, Momoko Nukaga, Shota Sasaki, Rika Ikemoto, Ayaka Ogata, Ruiko Kishi, Shingo Fujii, Kiyomu Kuniyasu, Hiroki
Editor	Azmi, Asfar S.
Copyright Year	2023
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.
Journal	International Journal of Molecular Sciences [Int J Mol Sci]
Volume Number	24
DOI	10.3390/ijms24076588
PubMed Central reference number	PMC10094831
Issue Number	7
PubMed reference number	37047563
e-ISSN	14220067
Language	English
Publisher	Molecular Diversity Preservation International (MDPI)
Publisher Date	2023-04-01
Access Restriction	Open
Subject Keyword	mitochondrial complex autophagy apoptosis ferroptosis ROS
Content Type	Text
Resource Type	Article
Subject	Physical and Theoretical Chemistry Molecular Biology Spectroscopy Catalysis Computer Science Applications Medicine Inorganic Chemistry Organic Chemistry