Optimize radiochemotherapy in pancreatic cancer: PARP inhibitors a new therapeutic opportunity

Letizia Porcelli, Anna E. Quatrale, Paola Mantuano, Maria G. Leo, Nicola Silvestris, Jean F. Rolland, Enza Carioggia, Marco Lioce, Angelo Paradiso, Amalia Azzariti

Research output: Contribution to journalArticlepeer-review

Abstract

Cancer cells may use PARP enzymes and Homologous Recombination to repair single and double strand breaks caused by genotoxic insults. In this study, the PARP-1 inhibitor Rucaparib was utilized to increase the sensitivity to chemoradiotherapy treatment in BRCA-2-deficient and -proficient pancreatic cancer cells. We used the pancreatic cancer cell lines, Capan-1 with mutated BRCA-2 and Panc-1, AsPC-1 and MiaPaCa-2 with BRCA-1/2 wild type. Cells were treated with Rucaparib and/or radiotherapy (4-10 Gy) plus Gemcitabine then the capability to proliferate was evaluated by colony formation, cell counting and MTT assays. Flow cytometry, immunocytochemistry and western blotting were utilized to assess cell response to Rucaparib plus irradiation. The antitumour effectiveness of combining the PARP-1 inhibitor before, together and after radiotherapy evidenced the first as the optimal schedule in blocking cell growth. Pre-exposure to Rucaparib increased the cytotoxicity of Gemcitabine plus radiotherapy by heavily inducing the accumulation of cells in G2/M phase, impairing mitosis and finally inducing apoptosis and authophagy. The upregulation of p-Akt and downregulation of p53 were evidenced in MiaPaCa-2 which displayed replication stress features. For the first time, the rationale of using a PARP inhibitor as chemoradiosensitizer in pancreatic cancer models has been hypothesized and demonstrated.

Original languageEnglish
Pages (from-to)308-322
Number of pages15
JournalMolecular Oncology
Volume7
Issue number3
DOIs
Publication statusPublished - Jun 2013

Keywords

  • Chemoradiotherapy
  • Gemcitabine
  • Pancreatic cancer
  • PARP inhibitor
  • Rucaparib

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Medicine

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