Sensitizing thermochemotherapy with a PARP1-inhibitor
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Arlene L. Oei1,2,*, Lianne E.M. Vriend3,*, Caspar M. van Leeuwen2, Hans M. Rodermond1,2, Rosemarie ten Cate1,2, Anneke M. Westermann4, Lukas J.A. Stalpers1,2, Johannes Crezee2, Roland Kanaar5,6, H. Petra Kok2, Przemek M. Krawczyk3, Nicolaas A.P. Franken1,2
1Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands
2Department of Radiotherapy, Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands
3Department of Cell Biology and Histology, Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands
4Department of Medical Oncology, Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands
5Department of Molecular Genetics, Cancer Genomics Center Netherlands, The Netherlands
6Department of Radiation Oncology, Erasmus University Rotterdam (EUR), 3000 DR Rotterdam, The Netherlands
*These authors equally contributed to this work
Nicolaas A.P. Franken, email: email@example.com
Keywords: PARP1-inhibitor, hyperthermia, synthetic lethality, cDDP, RAD51
Received: June 01, 2016 Accepted: July 29, 2016 Published: August 19, 2016
Cis-diamminedichloroplatinum(II) (cisplatin, cDDP) is an effective chemotherapeutic agent that induces DNA double strand breaks (DSBs), primarily in replicating cells. Generally, such DSBs can be repaired by the classical or backup non-homologous end joining (c-NHEJ/b-NHEJ) or homologous recombination (HR). Therefore, inhibiting these pathways in cancer cells should enhance the efficiency of cDDP treatments. Indeed, inhibition of HR by hyperthermia (HT) sensitizes cancer cells to cDDP and in the Netherlands this combination is a standard treatment option for recurrent cervical cancer after previous radiotherapy. Additionally, cDDP has been demonstrated to disrupt c-NHEJ, which likely further increases the treatment efficacy. However, if one of these pathways is blocked, DSB repair functions can be sustained by the Poly-(ADP-ribose)-polymerase1 (PARP1)-dependent b-NHEJ. Therefore, disabling b-NHEJ should, in principle, further inhibit the repair of cDDP-induced DNA lesions and enhance the toxicity of thermochemotherapy. To explore this hypothesis, we treated a panel of cancer cell lines with HT, cDDP and a PARP1-i and measured various end-point relevant in cancer treatment. Our results demonstrate that PARP1-i does not considerably increase the efficacy of HT combined with standard, commonly used cDDP concentrations. However, in the presence of a PARP1-i, ten-fold lower concentration of cDDP can be used to induce similar cytotoxic effects. PARP1 inhibition may thus permit a substantial lowering of cDDP concentrations without diminishing treatment efficacy, potentially reducing systemic side effects.
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