Zehua Wang1,2, Jianwen Gao3,4, Yuko Ohno3, Haiou Liu5,6, Congjian Xu7,8,9. 1. Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China. 2. Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China. 3. Department of Health Science, Graduate School of Medical, Osaka University, 1-7 Yamadaoka, Suita, Osaka, 565-0871, Japan. 4. Major of Biotechnological Pharmaceutics, Shanghai Pharmaceutical School, Shanghai, 200135, China. 5. Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China. liuhaiou@fudan.edu.cn. 6. Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China. liuhaiou@fudan.edu.cn. 7. Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China. xucongjian@fudan.edu.cn. 8. Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China. xucongjian@fudan.edu.cn. 9. Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, 200032, China. xucongjian@fudan.edu.cn.
Abstract
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.
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.
Authors: Chi-Hwa Wu; Jan van Riggelen; Alper Yetil; Alice C Fan; Pavan Bachireddy; Dean W Felsher Journal: Proc Natl Acad Sci U S A Date: 2007-07-30 Impact factor: 11.205