Preclinical evaluation of olaparib and metformin combination in BRCA1 wildtype ovarian cancer.
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 (p<0.001) in ovarian cancer cells. This treatment was associated with a significant S-phase cell cycle arrest (p<0.05). Combination of olaparib and metformin significantly inhibited SKOV3 and A2780 ovarian tumor xenografts which were accompanied with decreased Ki-index (p<0.001). 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.
Department of Women's Health, Henry Ford Hospital, 1 Ford Place, Detroit, MI, USA. Electronic address: mhijaz1@hfhs.org.
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Hijaz
Department of Women's Health, Henry Ford Hospital, 1 Ford Place, Detroit, MI, USA. Electronic address: jchhina1@hfhs.orGg.
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Chhina
Department of Obstetrics and Gynecology, Wayne State University, 42 W Warren Ave, Detroit, MI, USA. Electronic address: imert@med.wayne.edu.
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Mert
Department of Obstetrics and Gynecology, Wayne State University, 42 W Warren Ave, Detroit, MI, USA. Electronic address: mtaylor@med.wayne.edu.
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Taylor
Department of Women's Health, Henry Ford Hospital, 1 Ford Place, Detroit, MI, USA. Electronic address: darsajad990@gmail.com.
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Dar
Department of Obstetrics and Gynecology, Wayne State University, 42 W Warren Ave, Detroit, MI, USA. Electronic address: zalwahab@med.wayne.edu.
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Al-Wahab
Department of Pathology, Harper University Hospital, 3990 John R, Detroit, MI, USA. Electronic address: rali@med.wayne.edu.
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Ali-Fehmi
Department of Women's Health, Henry Ford Hospital, 1 Ford Place, Detroit, MI, USA. Electronic address: tbueker1@hfhs.org.
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Buekers
Department of Women's Health, Henry Ford Hospital, 1 Ford Place, Detroit, MI, USA; Josephine Ford Cancer Institute, Henry Ford Hospital, 2799 W. Grand Blvd, Detroit, MI, USA. Electronic address: amunkar1@hfhs.org.
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Munkarah
Department of Women's Health, Henry Ford Hospital, 1 Ford Place, Detroit, MI, USA; Josephine Ford Cancer Institute, Henry Ford Hospital, 2799 W. Grand Blvd, Detroit, MI, USA. Electronic address: rrattan1@hfhs.org.
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Rattan
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000235:genetics*; D000077216:Carcinoma, Ovarian Epithelial; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D004354:Drug Screening Assays, Antitumor; D005260:Female; D019398:Genes, BRCA1; D006801:Humans; D008687:Metformin / Q000008:administration & dosage / Q000009:adverse effects; D051379:Mice; D008819:Mice, Nude; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010793:Phthalazines / Q000008:administration & dosage / Q000009:adverse effects; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D023041:Xenograft Model Antitumor Assays
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D002945:Cisplatin; C531550:olaparib
AMPK; Metformin; Olaparib; Ovarian cancer