PO-113 PARP-1 depletion in combination with either high or low LET reduces the metastatic potential in cultured human cells by suppression of its MMP activity

Abstract

IntroductionHadron therapy is producing promising clinical results worldwide. The major advantages are its ability to kill radio-resistant tumour and its anti-metastatic activity. In contrast cells irradiated with gamma rays have been shown to increase the metastatic potential of cancer cells. Poly (ADP-ribose) polymerase-1(PARP-1) inhibitors have been widely used as radiosensitizer and many of them are in clinical trial. The purpose of this study was to investigate the effect of PARP-1 depletion in combination with either Carbon Ion Beam (CIB) or gamma irradiation on metastatic potential of cultured cancerous cells.Material and methodsCancer cells were treated with PARP-1 inhibitor and irradiated with CIB or Gamma. The irradiated cells (0–4Gy) for CIB and (0, 2, 4, 6 and 10 Gy) were tested for cell migratory assay and MMP-2 and MMP-9 activity. Alterations of mRNA expression of the MMP-2, MMP-9 genes and in some of the genes those are involved in cell migration (Cadherin, Fibronectin, Vimentin etc.) were studied.Results and discussionsThe activity of MMP-2 and MMP-9 reduces significantly on CIB exposure, which further diminishes when cells were PARP-1 depleted. On Contrary, MMP- 2 and MMP-9 activity significantly increases when cells were irradiated with gamma, whereas, its activity gets reduced upon PARP-1 depletion on a dose dependant manner. The mRNA expression of the MMP genes and the migratory potential was also found to be down-regulated on a dose dependant manner on CIB irradiated and in PARP-1 depleted CIB irradiated cells. However, MMP expression and migratory ability of the gamma irradiated cells were only found to get reduced only in those which were PARP-1 depleted.ConclusionThus, our study clearly demonstrates that PARP-1 inhibition in combination with either high or low LET can be a promising tool in controlling metastatic cancers.