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Salinomycin induces cell cycle arrest and apoptosis and modulates hepatic cytochrome P450 mRNA expression in
Andressa Megumi Niwa1, Simone Cristine Semprebon1, Glaucia Fernanda Rocha D'Epiro1
1Department of General Biology, Center of Biological Sciences, Londrina State University - UEL, Londrina, Brazil.
Abstract:
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.
Insights
Salinomycin (SAL) shows antitumor potential by halting cancer cell growth and inducing apoptosis in liver cancer cells. It also alters drug-metabolizing enzymes, impacting potential chemotherapy interactions.
Area of Science:
- Pharmacology
- Molecular Biology
- Oncology
Background:
- Salinomycin (SAL), an ionophore antibiotic from *Streptomyces albus*, demonstrates antitumor properties against various human cancer cells.
- Hepatocellular carcinoma (HCC) remains a significant health concern, necessitating novel therapeutic strategies.
Purpose of the Study:
- To evaluate the antiproliferative effects of Salinomycin (SAL) on the human hepatocellular carcinoma HepG2/C3a cell line.
- To elucidate the molecular mechanisms underlying SAL's action, including its impact on cell cycle, apoptosis, and gene expression.
Main Methods:
- Investigated SAL's effects on HepG2/C3a cell viability, DNA damage, cell cycle progression, and apoptosis.
- Analyzed relative mRNA expression changes of cell cycle-related genes (e.g., *CDKN1A*, *CCNB1*), apoptosis-related genes (e.g., *BCL-2*), and cytochrome P450 (CYP) genes.
Main Results:
- SAL induced G2/M cell cycle arrest and apoptosis, evidenced by altered expression of cell cycle regulators (*CDKN1A*, *GADD45A*, *CCNB1*, *CCNA2*) and downregulation of antiapoptotic *BCL-2*.
- SAL significantly suppressed the oncogene *CTNNB1* mRNA levels.
- SAL modulated hepatic CYP expression, upregulating *CYP1A* members and *CYP3A5*, while downregulating *CYP3A4*.
Conclusions:
- SAL exhibits significant antiproliferative and pro-apoptotic effects on HepG2/C3a cells through distinct molecular pathways.
- SAL's modulation of CYP enzymes suggests potential drug-drug interactions, which must be considered in combined therapeutic approaches for liver cancer.
- These findings enhance the understanding of SAL's mechanism of action and its therapeutic potential in hepatocellular carcinoma treatment.
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