Format

Send to

Choose Destination
Oncotarget. 2017 Mar 7;8(10):16303-16312. doi: 10.18632/oncotarget.11422.

Sensitizing thermochemotherapy with a PARP1-inhibitor.

Author information

1
Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands.
2
Department of Radiotherapy, Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands.
3
Department of Cell Biology and Histology, Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands.
4
Department of Medical Oncology, Academic Medical Center (AMC), 1100 DE, Amsterdam, The Netherlands.
5
Department of Molecular Genetics, Cancer Genomics Center Netherlands, The Netherlands.
6
Department of Radiation Oncology, Erasmus University Rotterdam (EUR), 3000 DR Rotterdam, The Netherlands.

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.

KEYWORDS:

PARP1-inhibitor; RAD51; cDDP; hyperthermia; synthetic lethality

PMID:
27557507
PMCID:
PMC5369964
DOI:
10.18632/oncotarget.11422
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center