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Enrichment for Chemoresistant Ovarian Cancer Stem Cells from Human Cell Lines
Published on: September 10, 2014
Small Molecules Identified from a Quantitative Drug Combinational Screen Resensitize Cisplatin's Response in
Ni Sima1, Wei Sun2, Kirill Gorshkov2
1Department of Gynecologic Oncology, Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Abstract:
Drug resistance to chemotherapy occurs in many ovarian cancer patients resulting in failure of treatment. Exploration of drug resistance mechanisms and identification of new therapeutics that overcome the drug resistance can improve patient prognosis. Following a quantitative combination screen of 6060 approved drugs and bioactive compounds in a cisplatin-resistant A2780-cis ovarian cancer cell line, 38 active compounds with IC50s under 1 μM suppressed the growth of cisplatin-resistant ovarian cancer cells. Among these confirmed compounds, CUDC-101, OSU-03012, oligomycin A, VE-821, or Torin2 in a combination with cisplatin restored cisplatin's apoptotic response in the A2780-cis cells, while SR-3306, GSK-923295, SNX-5422, AT-13387, and PF-05212384 directly suppressed the growth of A2780-cis cells. One of the mechanisms for overcoming cisplatin resistance in these cells is mediated by the inhibition of epidermal growth factor receptor (EGFR), though not all the EGFR inhibitors are equally active. The increased levels of total EGFR and phosphorylated-EGFR (p-EGFR) in the A2780-cis cells were reduced after the combined treatment of cisplatin with EGFR inhibitors. In addition, a knockdown of EGFR mRNA reduced cisplatin resistance in the A2780-cis cells. Therefore, the top active compounds identified in this work can be studied further as potential treatments for cisplatin-resistant ovarian cancer. The quantitative combinational screening approach is a useful method for identifying effective compounds and drug combinations against drug-resistant cancer cells.
Insights
Researchers screened 6060 compounds to find new ovarian cancer treatments. Several compounds, including EGFR inhibitors, showed promise in overcoming cisplatin resistance by restoring apoptosis and suppressing tumor growth.
Area of Science:
- Oncology
- Pharmacology
- Drug Discovery
Background:
- Chemotherapy resistance is a major challenge in ovarian cancer treatment.
- Identifying novel therapeutic strategies is crucial for improving patient outcomes.
Purpose of the Study:
- To identify compounds that can overcome cisplatin resistance in ovarian cancer.
- To explore mechanisms underlying drug resistance and potential therapeutic interventions.
Main Methods:
- Quantitative combination screening of 6060 approved drugs and bioactive compounds.
- Utilized a cisplatin-resistant A2780-cis ovarian cancer cell line.
- Assessed compound efficacy through IC50 measurements, apoptosis assays, and gene knockdown experiments.
Main Results:
- 38 compounds suppressed cisplatin-resistant ovarian cancer cell growth.
- Several compounds, including CUDC-101 and OSU-03012, restored cisplatin's apoptotic response.
- Epidermal growth factor receptor (EGFR) inhibition was identified as a key mechanism for overcoming cisplatin resistance.
Conclusions:
- The study identified promising compounds for treating cisplatin-resistant ovarian cancer.
- Combination therapies involving EGFR inhibitors and cisplatin warrant further investigation.
- Quantitative combination screening is an effective approach for discovering drugs against resistant cancers.
