PARP1-Inhibition Sensitizes Cervical Cancer Cell Lines for Chemoradiation and Thermoradiation

Cancers

Johannes Crezee¹  Denise Whitton²  Roy Winiarczyk²  NicolaasA. P. Franken²  Marloes IJff²  Celina Honhoff²  GregorG. W. van Bochove²  Hans Rodermond²  ArleneL. Oei²  LukasJ. A. Stalpers² 

[1] Department of Radiation Oncology, Amsterdam University Medical Centers, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands;Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine, Amsterdam University Medical Centers, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands;

关键词: cervical cancer;    LACC;    DSB repair;    PARP1-inhibition;    cisplatin;    radiosensitization;   

DOI  :  10.3390/cancers13092092

来源: DOAJ

【 摘 要 】

Radiotherapy plus cisplatin (chemoradiation) is standard treatment for women with locoregionally advanced cervical cancer. Both radiotherapy and cisplatin induce DNA single and double-strand breaks (SSBs and DSBs). These double-strand breaks can be repaired via two major DNA repair pathways: Classical Non-Homologous End-Joining (cNHEJ) and Homologous Recombination. Besides inducing DNA breaks, cisplatin also disrupts the cNHEJ pathway. Patients contra-indicated for cisplatin are treated with radiotherapy plus hyperthermia (thermoradiation). Hyperthermia inhibits the HR pathway. The aim of our study is to enhance chemoradiation or thermoradiation by adding PARP1-inhibition, which disrupts both the SSB repair and the Alternative NHEJ DSB repair pathway. This was studied in cervical cancer cell lines (SiHa, HeLa, C33A and CaSki) treated with hyperthermia (42 °C) ± ionizing radiation (2–6 Gy) ± cisplatin (0.3–0.5 µM) ± PARP1-inhibitor (olaparib, 4.0–5.0 µM). Clonogenic assays were performed to measure cell reproductive death. DSBs were analyzed by γ-H2AX staining and cell death by live cell imaging. Both chemoradiation and thermoradiation resulted in lower survival fractions and increased unrepaired DSBs when combined with a PARP1-inhibitor. A quadruple modality, including ionizing radiation, hyperthermia, cisplatin and PARP1-i, was not more effective than either triple modality. However, both chemoradiation and thermoradiation benefit significantly from additional treatment with PARP1-i.

【 授权许可】

Unknown