Rosiglitazone ameliorates senescence and promotes apoptosis in ovarian cancer induced by olaparib

• Published in: Cancer chemotherapy and pharmacology Vol. 85; no. 2; pp. 273 - 284
• Main Authors: Wang, Zehua, Gao, Jianwen, Ohno, Yuko, Liu, Haiou, Xu, Congjian
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.02.2020; Springer Nature B.V
• Subjects: Animal models; Animals; Anticancer properties; Antitumor agents; Apoptosis; Apoptosis - drug effects; Cancer; Cancer Research; Cell cycle; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cellular Senescence - drug effects; Cholecystokinin; Cyclin D1; Cyclin D1 - metabolism; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Female; Flow cytometry; Galactosidase; GTP-binding protein; Humans; In vivo methods and tests; Inflammation; Medicine; Medicine & Public Health; Mice; Mice, Nude; Oncology; Original Article; Ovarian cancer; Ovarian Neoplasms - chemically induced; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; p16 Protein; p18 Protein; p53 Protein; Pharmacology/Toxicology; Phenotypes; Phosphors; Phthalazines - pharmacology; Piperazines - pharmacology; Polyimide resins; Polymerase chain reaction; Proteins; Retina; Retinoblastoma; Retinoblastoma protein; Rosiglitazone; Rosiglitazone - pharmacology; Senescence; Staining; Synergistic effect; Tumor Suppressor Protein p53 - metabolism; Xenografts; Xenotransplantation; β-Galactosidase; Rosiglitazone; Senescence; Olaparib; Ovarian cancer
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-019-04025-8

Objective Senescence mechanisms are vital to resistance to long-term olaparib maintenance treatment. Recently, peroxisome proliferator-activated receptor-γ agonists (e.g., rosiglitazone) have been reported to ameliorate the senescence-like phenotype by modulating inflammatory mediator production. This study examined synergistic effects on the anti-tumor activity of rosiglitazone combined with olaparib in ovarian cancer treatment. Methods A2780 and SKOV3 mouse subcutaneous xenograft models were established for observing anti-tumor effects in living organisms and were randomly split into combination (both olaparib and rosiglitazone), rosiglitazone (10 mg/kg), olaparib (10 mg/kg), control (solvent) groups that received treatment once every 2 or 3 days ( n  = 6 per group). Cell counting kit-8 (CCK-8) assays were used to test the influences of rosiglitazone and olaparib on cell proliferation. PI and Annexin-V-FITC staining was used with flow cytometry to assess the cell cycle distribution and cell apoptosis. Senescence-associated β-galactosidase (SA-β-Gal) staining was used to observe cellular senescence. We performed quantitative real-time polymerase chain reaction assays to study the senescence-related secretory phenotype (SASP). Results Olaparib and rosiglitazone were observed to synergistically retard subcutaneous ovarian cancer growth in vivo, and synergistically suppress ovarian cancer cell proliferation in vitro. Compared with olaparib alone, the percentage of positive cells expressed SA-β-gal and SASP were significantly decreased in the treatment of combination of olaparib and rosiglitazone. Furthermore, olaparib plus rosiglitazone increased the percentage of apoptosis in ovarian cancer cell compared with olaparib alone. In A2780 cells, it showed lower expression of P53, phospho-p53 (Ser15), P21, and P18 protein in combination treatment compared with olaparib alone. While, in SKOV3 cells, it showed lower expression of phosphor-retinoblastoma protein (Rb) (Ser807/811), and higher expression of cyclin D1, P21, and P16 protein in combination treatment compared with olaparib alone. Conclusions Rosiglitazone combined with olaparib can help manage ovarian cancer by ameliorating olaparib-induced senescence and improving anti-tumor effects.