title: Sensitizing thermochemotherapy with a PARP1-inhibitor.
abstract: 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.
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands.|Department of Radiotherapy, Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands.
authors.forename: Arlene L
authors.initials: AL
authors.lastname: Oei
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands.
authors.forename: Lianne E M
authors.initials: LE
authors.lastname: Vriend
authors.affiliation: Department of Radiotherapy, Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands.
authors.forename: Caspar M
authors.initials: CM
authors.lastname: van Leeuwen
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands.|Department of Radiotherapy, Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands.
authors.forename: Hans M
authors.initials: HM
authors.lastname: Rodermond
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands.|Department of Radiotherapy, Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Ten Cate
authors.affiliation: Department of Medical Oncology, Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands.
authors.forename: Anneke M
authors.initials: AM
authors.lastname: Westermann
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands.|Department of Radiotherapy, Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands.
authors.forename: Lukas J A
authors.initials: LJ
authors.lastname: Stalpers
authors.affiliation: Department of Radiotherapy, Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands.
authors.forename: Johannes
authors.initials: J
authors.lastname: Crezee
authors.affiliation: Department of Molecular Genetics, Cancer Genomics Center Netherlands, The Netherlands.|Department of Radiation Oncology, Erasmus University Rotterdam (EUR), 3000 DR Rotterdam, The Netherlands.
authors.forename: Roland
authors.initials: R
authors.lastname: Kanaar
authors.affiliation: Department of Radiotherapy, Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands.
authors.forename: H Petra
authors.initials: HP
authors.lastname: Kok
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands.
authors.forename: Przemek M
authors.initials: PM
authors.lastname: Krawczyk
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands.|Department of Radiotherapy, Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands.
authors.forename: Nicolaas A P
authors.initials: NA
authors.lastname: Franken
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D059766:DNA End-Joining Repair / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006367:HeLa Cells; D006358:Hot Temperature; D006801:Humans; D018613:Microscopy, Confocal; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D059767:Recombinational DNA Repair / Q000187:drug effects; D059008:Time-Lapse Imaging / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D002945:Cisplatin
keywords: PARP1-inhibitor; RAD51; cDDP; hyperthermia; synthetic lethality