Targeting Foxm1 Improves Cytotoxicity of Paclitaxel and Cisplatinum in Platinum-Resistant Ovarian Cancer
| Autor: | Yi Chen, Gina L. Westhoff, Nelson N.H. Teng |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Oncology medicine.medical_specialty Paclitaxel Carcinoma Ovarian Epithelial Thiostrepton 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols medicine Humans Molecular Targeted Therapy Neoplasms Glandular and Epithelial RNA Messenger Platinum Cisplatin Ovarian Neoplasms Cell growth business.industry Forkhead Box Protein M1 Obstetrics and Gynecology Ascites Drug Synergism medicine.disease 030104 developmental biology chemistry Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer cell Cancer research FOXM1 Female Ovarian cancer business Ex vivo medicine.drug Signal Transduction |
| Zdroj: | International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 27(5) |
| ISSN: | 1525-1438 |
| Popis: | Objective Aberrantly activated FOXM1 (forkhead box protein M1) leading to uncontrolled cell proliferation and dysregulation of FOXM1 transcription network occurs in 84% of ovarian cancer cases. It was demonstrated that thiostrepton, a thiazole antibiotic, decreases FOXM1 expression. We aimed to determine if targeting the FOXM1 pathway with thiostrepton could improve the efficacy of paclitaxel and cisplatin in human ovarian cancer ascites cells ex vivo. Methods Human ovarian cancer cell lines and patients’ ascites cells were treated with paclitaxel, cisplatin, and thiostrepton or a combination for 48 hours, and cytotoxicity was assessed. Drug combination effects were determined by calculating the combination index values using the Chou and Talalay method. Quantitative reverse transcriptase–polymerase chain reaction was performed to determine changes in FOXM1 expression and its downstream targets. Results Ovarian cancer cell lines and the patients’ ascites cancer cells had an overexpression of FOXM1 expression levels. Targeting FOXM1 with thiostrepton decreased FOXM1 mRNA expression and its downstream targets such as CCNB1 and CDC25B, leading to cell death in both cell lines and patients’ ascites cancer cells. Furthermore, addition of thiostrepton to paclitaxel and cisplatin showed synergistic effects in chemoresistant ovarian cancer patients’ ascites cells ex vivo. Conclusion Targeting FOXM1 may lead to novel therapeutics for chemoresistant epithelial ovarian cancer. |
| Databáze: | OpenAIRE |
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