Targeting Cancer Stem Cells Using Carbon Ion Beam in Combination with DNA Damaging Drugs

In this study, we try to explore the new molecular mechanisms of high radiocurability produced by carbon ion beam in combination with DNA damaging drugs (gemcitabine, 5-FU, cisplatin) in vitro and in vivo. The colony, spheroid formation as well as tumorigenicity assays confirmed that subpopulation of CD44+/ESA+, and CD44+/CD24- cells exactly have cancer stem cell (CSC) properties in pancreatic and breast cancer cells. CSCs were more highly enriched after X-ray irradiation compared to carbon ion beam alone, and in combination with gemcitabine, 5-FU or cisplatin extremely enhanced CSC proportion either by X-ray or carbon ion beam. The relative biological effectiveness (RBE) values for the carbon ion beam relative to X-ray at the D10 levels for CSCs were 2.1-2.4. The data showed that apoptosis- and autophagy-related gene expression was significantly induced after carbon ion beam combined with gemcitabine, 5-FU or cisplatin in pancreatic and breast cancer cells. We found that not only the number but also the size of H2AX foci in CSCs were lager 24 h after carbon ion beam combined with gemcitabine, 5-FU or cisplatin compared to carbon ion beam and X-ray irradiation alone. In vivo study showed that 25 Gy of carbon ion beam combined with 50 mg/kg gemcitabine or 5mg/kg cisplatin effectively destroyed pancreatic and breast xenograft tumors. Taken together, carbon ion beam can achieve high curability when combined with DNA damaging drugs at relatively lower doses compared to carbon ion beam alone.56th Annual Conference of the Particle Therapy Co-operative Group (PTCOG56