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Erschienen in: Investigational New Drugs 1/2019

06.06.2018 | PRECLINICAL STUDIES

The poly (ADP-ribose) polymerase inhibitor rucaparib suppresses proliferation and serves as an effective radiosensitizer in cervical cancer

verfasst von: Mei Tang, Qiuli Liu, Leyuan Zhou, Ling Chen, Xueqing Yang, Jinjin Yu, Yuan Wang, Haifeng Qiu

Erschienen in: Investigational New Drugs | Ausgabe 1/2019

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Summary

Objectives Our goal was to investigate the effects of rucaparib on the proliferation of cervical cancer cells and sensitivity to radiotherapy. Methods We used the human cervical cancer cell lines Hela and Siha and evaluated their viability and activity using various methods. Cellular proliferation was assessed by CCK-8 and clonogenic assays after treatment with rucaparib. Cell cycle analysis was performed using propidium iodide staining. Western immunoblotting analysis was used to detect the expression of cyclin D1 and CDK4. Immunofluorescence staining assay was performed to detect the expression of the DNA injury marker ץ-H2AX after treatment with rucaparib and radiotherapy. Animal experiments were also performed to evaluate tumor size after treatment with rucaparib. Immunohistochemistry was performed to analyze the expression of Ki-67. Results Rucaparib suppressed proliferation, induced G2/M phase arrest, and reduced the expression of cyclin D1 and CDK4 in cervical cancer cells. When rucaparib was combined with radiotherapy in cervical cancer cells, clone formation decreased significantly and G2/M phase arrest was accentuated. The expression of the DNA-damage marker ץ-H2AX was increased significantly, and rucaparib suppressed tumor growth in vivo. Conclusions Rucaparib exerts significant anti-proliferative effects and can serve as an effective radiosensitizer in cervical cancer, suggesting its candidacy in cervical cancer treatment and worthiness for further investigation.
Literatur
1.
Zurück zum Zitat Jemal A, Bray F, Center MM et al (2011) Global cancer statistics [J]. CA Cancer J Clin 61(2):69–90CrossRefPubMed Jemal A, Bray F, Center MM et al (2011) Global cancer statistics [J]. CA Cancer J Clin 61(2):69–90CrossRefPubMed
2.
Zurück zum Zitat Chen W, Zheng R, Baade PD et al (2016) Cancer statistics in China, 2015 [J]. CA Cancer J Clin 66(2):115–132CrossRefPubMed Chen W, Zheng R, Baade PD et al (2016) Cancer statistics in China, 2015 [J]. CA Cancer J Clin 66(2):115–132CrossRefPubMed
3.
Zurück zum Zitat Shi JF, Canfell K, Lew JB et al (2011) The burden of cervical cancer in China: synthesis of the evidence [J]. Int J Cancer. 130:641–652CrossRefPubMed Shi JF, Canfell K, Lew JB et al (2011) The burden of cervical cancer in China: synthesis of the evidence [J]. Int J Cancer. 130:641–652CrossRefPubMed
4.
Zurück zum Zitat Barker HE, Paget JT, Khan AA et al (2015) The tumor microenvironment after radiotherapy: mechanisms of resistance and recurrence [J]. Nat Rev Cancer 15(7):409–425CrossRefPubMedPubMedCentral Barker HE, Paget JT, Khan AA et al (2015) The tumor microenvironment after radiotherapy: mechanisms of resistance and recurrence [J]. Nat Rev Cancer 15(7):409–425CrossRefPubMedPubMedCentral
6.
Zurück zum Zitat Anwar M, Aslam HM, Anwar S (2015) PARP inhibitors [J]. Hered Cancer ClinPract 13(1):4CrossRef Anwar M, Aslam HM, Anwar S (2015) PARP inhibitors [J]. Hered Cancer ClinPract 13(1):4CrossRef
8.
Zurück zum Zitat Underhill C, Toulmonde M, Bonnefoi H (2011) A review of PARP inhibitors:from bench to bedside [J]. Ann Oncol 22(2):268–279CrossRefPubMed Underhill C, Toulmonde M, Bonnefoi H (2011) A review of PARP inhibitors:from bench to bedside [J]. Ann Oncol 22(2):268–279CrossRefPubMed
9.
Zurück zum Zitat Ceccaldi R, Rondinelli B (2016) D’ Andrea AD. Repair pathway choices and consequences at the double-strand break [J]. Trends Cell Biol 26(1):52–64CrossRefPubMed Ceccaldi R, Rondinelli B (2016) D’ Andrea AD. Repair pathway choices and consequences at the double-strand break [J]. Trends Cell Biol 26(1):52–64CrossRefPubMed
11.
12.
Zurück zum Zitat Hong JH, Tsal CS, Lai CH (2004) et a1. Recurrent squamous cell carcinoma of cervix after definitive radiotherapy [J]. Int J Radiat Oncol Biol Phys 60(1):249–257CrossRefPubMed Hong JH, Tsal CS, Lai CH (2004) et a1. Recurrent squamous cell carcinoma of cervix after definitive radiotherapy [J]. Int J Radiat Oncol Biol Phys 60(1):249–257CrossRefPubMed
13.
Zurück zum Zitat Chambon P, Weill JD, Mandel P (1963) Nicotinamide mononucleotide activation of new DNA-dependent polyadenylicacid synthesizing nuclear enzyme [J]. Biochem Biophys Res Commun 11:39–43CrossRefPubMed Chambon P, Weill JD, Mandel P (1963) Nicotinamide mononucleotide activation of new DNA-dependent polyadenylicacid synthesizing nuclear enzyme [J]. Biochem Biophys Res Commun 11:39–43CrossRefPubMed
14.
Zurück zum Zitat Nirmal S, Amteshwar SJ (2010) Poly(ADP-ribose) polymerase-1(PARP-1) and its therapeutic implications [J]. Vascul Pharmacol 53(3-4):77–78CrossRef Nirmal S, Amteshwar SJ (2010) Poly(ADP-ribose) polymerase-1(PARP-1) and its therapeutic implications [J]. Vascul Pharmacol 53(3-4):77–78CrossRef
15.
Zurück zum Zitat Plummer ER (2006) Inhibition of poly(ADP-ribose) polymerase in cancer [J]. Curr Opin Pharmacol 6(4):364–368CrossRefPubMed Plummer ER (2006) Inhibition of poly(ADP-ribose) polymerase in cancer [J]. Curr Opin Pharmacol 6(4):364–368CrossRefPubMed
16.
Zurück zum Zitat Powell C, Mikropoulos C, Kaye SB et al (2010) Pre-clinical and clinical evaluation of PARP inhibitors as tumor-specific radiosensitisers [J]. Cancer Treat Rev 36(7):566–575CrossRefPubMed Powell C, Mikropoulos C, Kaye SB et al (2010) Pre-clinical and clinical evaluation of PARP inhibitors as tumor-specific radiosensitisers [J]. Cancer Treat Rev 36(7):566–575CrossRefPubMed
17.
Zurück zum Zitat Peralta LA, Rodriguez MI, Linares JL et al (2009) PARP inhibitors: new partners in the therapy of cancer and inflammatory diseases [J]. Free Radic Biol Med 47(1):13–26CrossRef Peralta LA, Rodriguez MI, Linares JL et al (2009) PARP inhibitors: new partners in the therapy of cancer and inflammatory diseases [J]. Free Radic Biol Med 47(1):13–26CrossRef
18.
Zurück zum Zitat Chalmers AJ (2009) The potential role and application of PARP inhibitors in cancer treatment [J]. Br Med Bull 89:23–40CrossRefPubMed Chalmers AJ (2009) The potential role and application of PARP inhibitors in cancer treatment [J]. Br Med Bull 89:23–40CrossRefPubMed
19.
20.
Zurück zum Zitat Cepeda V, Fuertes MA, Castilla J et al (2006) Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors in cancer chemotherapy [J]. Recent Pat Anticancer Drug Discov 1(1):39–53CrossRefPubMed Cepeda V, Fuertes MA, Castilla J et al (2006) Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors in cancer chemotherapy [J]. Recent Pat Anticancer Drug Discov 1(1):39–53CrossRefPubMed
21.
Zurück zum Zitat Fauzee NJ, Pan J, Wang YL (2010) PARP and PARG Inhibitors-New Therapeutic Targets in Cancer Treatment [J]. Pathol Oncol Res 16(4):469–478CrossRefPubMed Fauzee NJ, Pan J, Wang YL (2010) PARP and PARG Inhibitors-New Therapeutic Targets in Cancer Treatment [J]. Pathol Oncol Res 16(4):469–478CrossRefPubMed
22.
Zurück zum Zitat Bryant HE, Schultz N, Thomas HD et al (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase [J]. Nature 434(7035):913–917CrossRefPubMed Bryant HE, Schultz N, Thomas HD et al (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase [J]. Nature 434(7035):913–917CrossRefPubMed
23.
Zurück zum Zitat Gien LT, Mackay HJ (2009) The Emerging Role of PARP Inhibitors in the Treatment of Epithelial Ovarian Cancer [J]. Journal of Oncology 2010(1687-8450):151750PubMedPubMedCentral Gien LT, Mackay HJ (2009) The Emerging Role of PARP Inhibitors in the Treatment of Epithelial Ovarian Cancer [J]. Journal of Oncology 2010(1687-8450):151750PubMedPubMedCentral
24.
25.
Zurück zum Zitat Farmer H, Mc Cabe N, Lord CJ et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy [J]. Nature 434(7035):917–921CrossRefPubMed Farmer H, Mc Cabe N, Lord CJ et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy [J]. Nature 434(7035):917–921CrossRefPubMed
26.
Zurück zum Zitat Tentori L, Lacal PM, Muzi A et al (2007) Poly(ADP-ribose) polymerase(PARP) inhibition or PARP-1 gene deletion reduces angiogenesis [J]. Eur J Cancer 43(14):2124–2133CrossRefPubMed Tentori L, Lacal PM, Muzi A et al (2007) Poly(ADP-ribose) polymerase(PARP) inhibition or PARP-1 gene deletion reduces angiogenesis [J]. Eur J Cancer 43(14):2124–2133CrossRefPubMed
27.
Zurück zum Zitat Tan DS, Rothermundt C, Thomas K et al (2008) “BRCAness” syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1and BRCA2 mutations [J]. J Clin Oncol 26(34):5530–5536CrossRefPubMed Tan DS, Rothermundt C, Thomas K et al (2008) “BRCAness” syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1and BRCA2 mutations [J]. J Clin Oncol 26(34):5530–5536CrossRefPubMed
28.
Zurück zum Zitat Fong PC, Boss DS, Yap TA et al (2009) Inhibition of poly(ADP-ribose)polymerase in tumors from BRCA mutation carriers [J]. N Engl J Med 361(2):123–134CrossRefPubMed Fong PC, Boss DS, Yap TA et al (2009) Inhibition of poly(ADP-ribose)polymerase in tumors from BRCA mutation carriers [J]. N Engl J Med 361(2):123–134CrossRefPubMed
29.
Zurück zum Zitat Drew Y, Plummer R (2009) PARP inhibitors in cancer therapy: two modes of attack on the cancer cell widening the clinical applications [J]. Drug Resist Updat 12(6):153–156CrossRefPubMed Drew Y, Plummer R (2009) PARP inhibitors in cancer therapy: two modes of attack on the cancer cell widening the clinical applications [J]. Drug Resist Updat 12(6):153–156CrossRefPubMed
Metadaten
Titel
The poly (ADP-ribose) polymerase inhibitor rucaparib suppresses proliferation and serves as an effective radiosensitizer in cervical cancer
verfasst von
Mei Tang
Qiuli Liu
Leyuan Zhou
Ling Chen
Xueqing Yang
Jinjin Yu
Yuan Wang
Haifeng Qiu
Publikationsdatum
06.06.2018
Verlag
Springer US
Erschienen in
Investigational New Drugs / Ausgabe 1/2019
Print ISSN: 0167-6997
Elektronische ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-018-0616-7

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