Sensitizing thermochemotherapy with a PARP1-inhibitor
| Autor: | Nicolaas A. P. Franken, Lukas J.A. Stalpers, Hans M. Rodermond, Roland Kanaar, Anneke M. Westermann, Przemek M. Krawczyk, Lianne E.M. Vriend, Caspar M. van Leeuwen, Rosemarie ten Cate, H. Petra Kok, Johannes Crezee, Arlene L. Oei |
|---|---|
| Přispěvatelé: | Medical Biology, CCA - Cancer biology and immunology, Radiotherapy, Graduate School, Cell Biology and Histology, Center of Experimental and Molecular Medicine, Oncology, APH - Methodology, Molecular Genetics, Radiation Oncology |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
DNA End-Joining Repair Hot Temperature medicine.medical_treatment RAD51 Apoptosis 0302 clinical medicine PARP1 Cytotoxic T cell Microscopy Confocal Cell Cycle Drug Synergism hyperthermia female genital diseases and pregnancy complications Oncology 030220 oncology & carcinogenesis Toxicity Poly(ADP-ribose) Polymerases medicine.drug Research Paper Hyperthermia inorganic chemicals Cell Survival Antineoplastic Agents Poly(ADP-ribose) Polymerase Inhibitors Time-Lapse Imaging 03 medical and health sciences Cell Line Tumor cDDP medicine Animals Humans neoplasms Cisplatin Dose-Response Relationship Drug business.industry fungi Recombinational DNA Repair medicine.disease PARP1-inhibitor synthetic lethality Rats Radiation therapy 030104 developmental biology Immunology Cancer cell Cancer research business HeLa Cells |
| Zdroj: | Oncotarget Oncotarget, 8(10), 16303-16312. Impact Journals Oncotarget, 8(10), 16303-16312. Impact Journals LLC |
| ISSN: | 1949-2553 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|