Abstract
Simple SummaryFive-year survival rates from patients with locally advanced cervical cancer (LACC) are between 40% and 60%. These patients are usually treated with chemoradiation or radiotherapy in combination with hyperthermia (thermoradiation). The aim of our study was to enhance chemoradiation or thermoradiation by adding PARP1-inhibition to these conventional therapies. To study this, different cervical cancer cell lines were used to measure cell reproductive death and analyze DNA double strand breaks and cell death. By looking into the surviving fractions and DNA double strand breaks, our results suggest that PARP1-i sensitizes cervical cancer cells for the conventional therapies. The results of the live cell imaging suggest that effects are solely additive.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.
Highlights
When comparing triple modality PARP1-i, 2 Gy and cDDP to standard treatment cDDP, together with 2 Gy, there was a significant reduction in SiHa and HeLa cells
Our research shows that addition of PARP1-i to either ionizing radiation (IR) + cDDP or IR + HT has a significant effect on clonogenicity
The amount of dying and dead cells is increased when PARP1-i is given in combination with both standard treatments
Summary
Cervical cancer is the fourth most common malignant disease in women worldwide [1,2]. In low-income countries, many women suffer from cervical cancer creativecommons.org/licenses/by/ 4.0/). Because of insufficient infrastructure, lack of screening and a lack of trained personnel [3]. 85% of worldwide deaths from cervical cancer are found in the underdeveloped countries [2,4]. Stages IA1 up until IIA are considered to be the lower stages and are usually treated by surgery only. Stages IIB up until IVA are known as the locally advanced cervical cancer (LACC) stages. Most patients with LACC are treated with radiotherapy in combination with chemotherapy (chemoradiation), mostly with cisplatin (cDDP).
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