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Cyclosporin A suppresses cisplatin-induced oncogene expression in human cancer cells
1Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA 91010.
Abstract:
Most cancer chemotherapeutic agents are designed to damage DNA directly or indirectly. One mechanism of cellular resistance to these agents is enhanced DNA repair. Human ovarian carcinoma cells resistant to cisplatin (A2780DDP) respond to cisplatin treatment with a 3-6-fold increase in gene expression for oncogenes, DNA repair enzymes and enzymes necessary for the synthesis of thymidine. Cyclosporin A has been shown to reverse drug resistance, but its mechanism of action is unclear. In this study, weekly exposures of A2780DDP cells to cyclosporin A resulted in the evolution of a revertant cell line A2780DDP/CSA that was sensitive to cisplatin again and suppressed the induction of genes necessary for the repair of drug-induced DNA damage.
Insights
Cyclosporin A reverses cisplatin resistance in ovarian cancer cells by suppressing DNA repair gene induction. This finding offers a potential strategy to enhance chemotherapy effectiveness against drug-resistant cancers.
Area of Science:
- Molecular Biology
- Cancer Research
- Pharmacology
Background:
- Chemotherapeutic agents often target DNA, and enhanced DNA repair is a key mechanism of cellular resistance.
- Cisplatin-resistant human ovarian carcinoma cells (A2780DDP) exhibit increased gene expression for oncogenes and DNA repair enzymes upon treatment.
- Cyclosporin A is known to reverse drug resistance, but its precise mechanism remains elusive.
Purpose of the Study:
- To investigate the mechanism by which Cyclosporin A (CSA) reverses cisplatin resistance in ovarian cancer cells.
- To determine the effect of CSA on the induction of genes involved in DNA repair pathways in resistant cells.
Main Methods:
- A2780DDP cells, resistant to cisplatin, were exposed weekly to Cyclosporin A.
- A revertant cell line (A2780DDP/CSA) that regained sensitivity to cisplatin was generated.
- Gene expression analysis was performed to assess changes in oncogenes and DNA repair enzymes.
Main Results:
- Weekly exposure to Cyclosporin A led to the development of a cisplatin-sensitive cell line (A2780DDP/CSA).
- The revertant cell line (A2780DDP/CSA) showed suppressed induction of genes essential for repairing drug-induced DNA damage.
- This suggests Cyclosporin A interferes with the cellular response mechanisms that confer cisplatin resistance.
Conclusions:
- Cyclosporin A can re-sensitize cisplatin-resistant ovarian cancer cells to chemotherapy.
- The mechanism involves the suppression of gene induction required for DNA repair.
- This study highlights a potential therapeutic strategy for overcoming chemoresistance in ovarian cancer.