Preclinical evaluation of olaparib and metformin combination in BRCA1 wildtype ovarian cancer
Autor: | Ismail Mert, Sajad Ahmad Dar, Jasdeep Chhina, Rouba Ali-Fehmi, Adnan R. Munkarah, Thomas E. Buekers, M. Taylor, Miriana Hijaz, Ramandeep Rattan, Z. Al-Wahab |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Oncology medicine.medical_specialty endocrine system diseases Genes BRCA1 Mice Nude Cell Growth Processes Synthetic lethality AMP-Activated Protein Kinases Carcinoma Ovarian Epithelial Poly(ADP-ribose) Polymerase Inhibitors Piperazines Olaparib Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Animals Humans Neoplasms Glandular and Epithelial Ovarian Neoplasms Cisplatin BRCA1 Protein Cell growth business.industry Obstetrics and Gynecology Cell cycle medicine.disease Xenograft Model Antitumor Assays Metformin female genital diseases and pregnancy complications 030104 developmental biology chemistry 030220 oncology & carcinogenesis Cancer cell Phthalazines Female Drug Screening Assays Antitumor Ovarian cancer business medicine.drug |
Zdroj: | Gynecologic Oncology. 142:323-331 |
ISSN: | 0090-8258 |
Popis: | BRCA mutated ovarian cancers show increased responsiveness to PARP inhibitors. PARP inhibitors target DNA repair and provide a second hit to BRCA mutated tumors, resulting in "synthetic lethality". We investigated a combination of metformin and olaparib to provide "synthetic lethality" in BRCA intact ovarian cancer cells.Ovarian cancer cell lines (UWB1.289, UWB1.289.BRCA, SKOV3, OVCAR5, A2780 and C200) were treated with a combination of metformin and olaparib. Cell viability was assessed by MTT and colony formation assays. Flow cytometry was used to detect cell cycle events. In vivo studies were performed in SKOV3 or A2780 xenografts in nude mice. Animals were treated with single agent, metformin or olaparib or combination. Molecular downstream effects were examined by immunohistochemistry.Compared to single drug treatment, combination of olaparib and metformin resulted in significant reduction of cell proliferation and colony formation (p0.001) in ovarian cancer cells. This treatment was associated with a significant S-phase cell cycle arrest (p0.05). Combination of olaparib and metformin significantly inhibited SKOV3 and A2780 ovarian tumor xenografts which were accompanied with decreased Ki-index (p0.001). Metformin did not affect DNA damage signaling, while olaparib induced adenosine monophosphate activated kinase activation; that was further potentiated with metformin combination in vivo.Combining PARP inhibitors with metformin enhances its anti-proliferative activity in BRCA mutant ovarian cancer cells. Furthermore, the combination showed significant activity in BRCA intact cancer cells in vitro and in vivo. This is a promising treatment regimen for women with epithelial ovarian cancer irrespective of BRCA status. |
Databáze: | OpenAIRE |
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