Combination of carbon ion beam and gemcitabine causes irreparable DNA damage and death of radioresistant pancreatic cancer stem-like cells in vitro and in vivo
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Sei Sai1, Toshifumi Wakai2, Guillaume Vares3, Shigeru Yamada4, Takehiko Kamijo5, Tadashi Kamada4 and Toshiyuki Shirai1
1 Medical Physics Research Program, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan
2 Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
3 Radiation Risk Reduction Research Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, Japan
4 Research Center Hospital for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan
5 Research Institute for Clinical Oncology, Saitama Cancer Center, Ina, Saitama, Japan
Sei Sai, email:
Keywords: carbon-ion beam, pancreatic cancer stem cell, gemcitabine, DNA repair
Received: October 21, 2014 Accepted: February 15, 2015 Published: March 14, 2015
We try to elucidate whether a carbon ion beam alone or in combination with gemcitabine has advantages over X-ray in targeting putative pancreatic cancer stem-like cells (CSCs) in vitro and in vivo. Colony, spheroid formation and tumorigenicity assays confirmed that CD44+/ESA+ cells sorted from PANC1 and PK45 cells have more CSC properties than CD44-/ESA- cells. The number of colonies and spheroids formed from CSCs after carbon ion beam irradiation was significantly reduced compared to after X-ray irradiation, and they were extremely highly suppressed when carbon ion beam combined with gemcitabine. 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. Expressions of multiple cell death-related genes were remarkably highly induced, and large numbers of γH2AX foci in CSCs were formed after carbon ion beam combined with gemcitabine. The highly expressed CSC markers were significantly inhibited after 30 Gy of carbon ion beam and almost lost after 25 Gy carbon ion beam combined with 50 mg/kg gemcitabine. In conclusion, a carbon ion beam combined with gemcitabine has superior potential to kill pancreatic CSCs via irreparable clustered DSB compared to a carbon ion alone or X-rays combined with gemcitabine.
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