Aberrant DNA damage response pathways may predict the outcome of platinum chemotherapy in ovarian cancer

Dimitra T Stefanou; Aristotelis Bamias; Hara Episkopou; Soterios A Kyrtopoulos; Maria Likka; Theodore Kalampokas; Stylianos Photiou; Nikos Gavalas; Petros P Sfikakis; Meletios A Dimopoulos; Vassilis L Souliotis

doi:10.1371/journal.pone.0117654

Aberrant DNA damage response pathways may predict the outcome of platinum chemotherapy in ovarian cancer

PLoS One. 2015 Feb 6;10(2):e0117654. doi: 10.1371/journal.pone.0117654. eCollection 2015.

Affiliations

¹ Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece; Department of Clinical Therapeutics, Athens University Medical School, 11528 Athens, Greece.
² Department of Clinical Therapeutics, Athens University Medical School, 11528 Athens, Greece.
³ Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece; Genetic and Epigenetic Alterations of Genomes, de Duve Institute, Catholic University of Louvain, Brussels, 1200, Belgium.
⁴ Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece.
⁵ Second Department of Obstetrics & Gynaecology, Athens University Medical School, 11528 Athens, Greece.
⁶ First Department of Propedeutic Medicine, Athens University Medical School, 11527 Athens, Greece.

Abstract

Ovarian carcinoma (OC) is the most lethal gynecological malignancy. Despite the advances in the treatment of OC with combinatorial regimens, including surgery and platinum-based chemotherapy, patients generally exhibit poor prognosis due to high chemotherapy resistance. Herein, we tested the hypothesis that DNA damage response (DDR) pathways are involved in resistance of OC patients to platinum chemotherapy. Selected DDR signals were evaluated in two human ovarian carcinoma cell lines, one sensitive (A2780) and one resistant (A2780/C30) to platinum treatment as well as in peripheral blood mononuclear cells (PBMCs) from OC patients, sensitive (n = 7) or resistant (n = 4) to subsequent chemotherapy. PBMCs from healthy volunteers (n = 9) were studied in parallel. DNA damage was evaluated by immunofluorescence γH2AX staining and comet assay. Higher levels of intrinsic DNA damage were found in A2780 than in A2780/C30 cells. Moreover, the intrinsic DNA damage levels were significantly higher in OC patients relative to healthy volunteers, as well as in platinum-sensitive patients relative to platinum-resistant ones (all P<0.05). Following carboplatin treatment, A2780 cells showed lower DNA repair efficiency than A2780/C30 cells. Also, following carboplatin treatment of PBMCs ex vivo, the DNA repair efficiency was significantly higher in healthy volunteers than in platinum-resistant patients and lowest in platinum-sensitive ones (t1/2 for loss of γH2AX foci: 2.7±0.5h, 8.8±1.9h and 15.4±3.2h, respectively; using comet assay, t1/2 of platinum-induced damage repair: 4.8±1.4h, 12.9±1.9h and 21.4±2.6h, respectively; all P<0.03). Additionally, the carboplatin-induced apoptosis rate was higher in A2780 than in A2780/C30 cells. In PBMCs, apoptosis rates were inversely correlated with DNA repair efficiencies of these cells, being significantly higher in platinum-sensitive than in platinum-resistant patients and lowest in healthy volunteers (all P<0.05). We conclude that perturbations of DNA repair pathways as measured in PBMCs from OC patients correlate with the drug sensitivity of these cells and reflect the individualized response to platinum-based chemotherapy.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Antineoplastic Agents / administration & dosage*
Apoptosis / drug effects*
Carboplatin / administration & dosage*
Cell Line, Tumor
DNA Damage*
DNA Repair / drug effects
Disease-Free Survival
Drug Resistance, Neoplasm / drug effects*
Female
Follow-Up Studies
Humans
Middle Aged
Ovarian Neoplasms* / drug therapy
Ovarian Neoplasms* / genetics
Ovarian Neoplasms* / metabolism
Ovarian Neoplasms* / mortality
Platinum / administration & dosage
Survival Rate

Substances

Antineoplastic Agents
Platinum
Carboplatin

Grants and funding

This work was supported in part by the Athens University Medical School grant ELKE 097, and by the ECNIS (Environmental Cancer, Nutrition and Individual Susceptibility) Network of Excellence of the European Union (contract no. 513943). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.