Optimize radiochemotherapy in pancreatic cancer: PARP inhibitors a new therapeutic opportunity
Menée sur des lignées cellulaires de cancer du pancréas, cette étude évalue l'efficacité du rucaparib, un inhibiteur de PARP, pour sensibiliser les cellules tumorales à une chimioradiothérapie
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 chemo-radiotherapy treatment in BRCA2 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 BRCA1/2 wild type. Cells were treated with Rucaparib and/or radiotherapy (2-10Gy) 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 antitumor 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 chemo-radiosensitizer in pancreatic cancer models has been hypothesized and demonstrated.
http://www.sciencedirect.com/science/article/pii/S1574789112001007?v=s5 2012