||HEAVY ION IRRADIATION ALONE OR IN COMBINATION WITH CHEMOTHRAPY EFFECTIVELY DISRUPTS PUTATIVE PANCREATIC CANCER STEM CELLS
崔, 星 ,
Vares, Guillaume山田, 滋
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 Meeting