HEAVY ION IRRADIATION ALONE OR IN COMBINATION WITH CHEMOTHRAPY EFFECTIVELY DISRUPTS PUTATIVE PANCREATIC CANCER STEM CELLS

To examine different effects of carbon ion beam alone or in combination with chemotherapy on putative pancreatic cancer stem cell (CSC) survival and DNA repair in comparison with X-ray, human pancreatic CSCs sorted from PANC1 and PK45 cells were treated with carbon ion beam, X-ray alone or in combination with gemcitabine. We found that the number of colony and spheroid formed from CSCs (CD44+/ESA+) after carbon ion beam was significantly reduced compared to that of X-ray, and it was extremely suppressed when combined with gemcitabine or 5-FU. The relative biological effectiveness (RBE) values for the carbon ion beam relative to X-ray at the D10 levels for CSCs were 2.23-2.66. RT Profiler PCR Array analysis showed that expressions of apoptosis-related genes (Bax, Cytochrome c), autophagy-related genes (LC3, p62), and senescence-related gene p21 were remarkably induced after carbon ion beam combined with gemcitabine compared to carbon ion beam alone or X-ray combined with gemcitabine. Not only the number but also the size of γH2AX foci in CSCs were lager 24 h after carbon ion beam combined with gemcitabine or 5-FU compared to carbon ion beam alone or X-ray combined with gemcitabine. Xenograft tumor control analysis showed that the tumors were not completely controlled even treated with 60 Gy of X-ray, but it was destroyed with 25 Gy of carbon ion beam combined with 50 mg/kg gemcitabine. In conclusion, carbon ion beam combined with gemcitabine or 5-FU has superior potential to kill pancreatic CSCs via unrepairable clustered DSB, and multiple cell death pathways.19th International Association of Pancreatology (IAP) Annual Meetin