Enhancing synthetic lethality of PARP-inhibitor and cisplatin in BRCA-proficient tumour cells with hyperthermia
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Arlene L. Oei1,2, Caspar M. van Leeuwen2, Vidhula R. Ahire1,2, Hans M. Rodermond1,2, Rosemarie ten Cate1,2, Anneke M. Westermann3, Lukas J.A. Stalpers1,2, Johannes Crezee2, H. Petra Kok2, Przemek M. Krawczyk4, Roland Kanaar5,6, Nicolaas A.P. Franken1,2
1Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine, Academic Medical Center (AMC), Amsterdam, The Netherlands
2Department of Radiotherapy, Academic Medical Center (AMC), Amsterdam, The Netherlands
3Department of Medical Oncology, Academic Medical Center (AMC), Amsterdam, The Netherlands
4Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, The Netherlands
5Department of Molecular Genetics, Cancer Genomics Center Netherlands, Utrecht, The Netherlands
6Department of Radiation Oncology, Erasmus University Rotterdam (EUR), Rotterdam, The Netherlands
Nicolaas A.P. Franken, email: firstname.lastname@example.org
Keywords: PARP1-inhibitor, hyperthermia, synthetic lethality, cDDP
Received: September 24, 2016 Accepted: February 21, 2017 Published: March 06, 2017
Background: Poly-(ADP-ribose)-polymerase1 (PARP1) is involved in repair of DNA single strand breaks. PARP1-inhibitors (PARP1-i) cause an accumulation of DNA double strand breaks, which are generally repaired by homologous recombination (HR). Therefore, cancer cells harboring HR deficiencies are exceptionally sensitive to PARP1-i. For patients with HR-proficient tumors, HR can be temporarily inhibited by hyperthermia, thereby inducing synthetic lethal conditions in every tumor type. Since cisplatin is successfully used combined with hyperthermia (thermochemotherapy), we investigated the effectiveness of combining PARP1-i with thermochemotherapy.
Results: The in vitro data demonstrate a decreased in cell survival after addition of PARP1-i to thermochemotherapy, which can be explained by increased DNA damage induction and less DSB repair. These in vitro findings are in line with in vivo model, in which a decreased tumor growth is observed upon addition of PARP1-i.
Materials and Methods: Survival of three HR-proficient cell lines after cisplatin, hyperthermia and/or PARP1-i was studied. Cell cycle analyses, quantification of γ-H2AX foci and apoptotic assays were performed to understand these survival data. The effects of treatments were further evaluated by monitoring tumor responses in an in vivo rat model.
Conclusions: Our results in HR-proficient cell lines suggest that PARP1-i combined with thermochemotherapy can be a promising clinical approach for all tumors independent of HR status.
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