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
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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