Salinomycin induces cell cycle arrest and apoptosis and modulates hepatic cytochrome P450 mRNA expression in HepG2/C3a cells

Salinomycin (SAL) is a monocarboxylic polyether ionophore antibiotic isolated from Streptomyces albus. It exhibits an effective antitumor potential against numerous human cancer cells. This study aimed to assess the antiproliferative effects of SAL in human hepatocellular carcinoma HepG2/C3a cell li...

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Bibliographic Details
Published in:Toxicology mechanisms and methods 2022-06, Vol.32 (5), p.341-351
Main Authors: Niwa, Andressa Megumi, Semprebon, Simone Cristine, D'Epiro, Glaucia Fernanda Rocha, Marques, Lilian Areal, Zanetti, Thalita Alves, Mantovani, Mário Sérgio
Format: Article
Language:English
Subjects:
Apoptosis
Cell Cycle
Cell Cycle Checkpoints
Cell Line, Tumor
Cell Proliferation
cyclins
CYP3A4
Cytochrome P-450 Enzyme System - genetics
GADD45A
growth arrest
Hep G2 Cells
Humans
liver cancer
Liver Neoplasms - metabolism
Pyrans
RNA, Messenger - genetics
RNA, Messenger - metabolism
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Summary:Salinomycin (SAL) is a monocarboxylic polyether ionophore antibiotic isolated from Streptomyces albus. It exhibits an effective antitumor potential against numerous human cancer cells. This study aimed to assess the antiproliferative effects of SAL in human hepatocellular carcinoma HepG2/C3a cell line. We investigated the effects of SAL on cell growth, DNA damage induction, cell cycle changes and apoptosis; and relative changes in expression of cell cycle-related, apoptosis-related, and CYP450 genes. SAL induced cell cycle arrest in the G2/M phase, upregulation of CDKN1A and GADD45A and downregulation of cyclin genes including CCNB1 and CCNA2. SAL effectively suppressed mRNA levels of CTNNB1 gene, an important oncogene that promotes tumorigenesis. The decrease of HepG2/C3A cells' survival can also be due to downregulation of antiapoptotic BCL-2 expression, thus promoting the induction of apoptosis by SAL. This study also demonstrated the ability of SAL in modulating hepatic cytochrome P450 (CYP) mRNA expression, such that SAL caused the upregulation of CYP1A members and CYP3A5; and downregulation of CYP3A4. Taken together, these data contribute to the understanding of the mechanism of action of SAL, highlighting that metabolizing enzymes modulated by SAL can interfere with chemotherapy treatment and it must be considered in associated treatments.
ISSN:1537-6516
1537-6524
DOI:10.1080/15376516.2021.2008570