Presentation Cancer Stem Cell-Targeting Radiotherapy by Carbon Ion Beam Alone or in Combination with DNA Damaging Drugs

崔, 星

For the last several decades, cancer stem cells (CSCs) have been identified in many tumor types, including solid tumors such as pancreatic and breast cancer. CSCs have been shown to be resistant to conventional chemotherapy and radiation therapy, and are closely related to metastasis and recurrence. The heavy ion medical accelerator in Chiba (HIMAC) is the world’s leading heavy ion cancer treatment facility, and more than 9000 of patients with various radioresistant cancers were treated by HIMAC, and achieved promising results. Here I try to report our recent new findings on the mechanisms of high radiocurability produced by carbon ion beam alone or in combination with DNA damaging drugs from the point of view of targeting CSCs in vitro and in vivo. Human pancreatic and breast CSCs sorted from various cell lines (PK45, PANC1, MDA MB231, MDA MB453) were treated with carbon ion beam, X-ray irradiation alone or in combination with DNA damaging drugs (gemcitabine: GEM, cisplatin: CDDP), and then colony, spheroid and tumor formation assays, immunofluorescence H2AX foci assay as well as in vivo tumor control analysis were performed. The colony, spheroid formation as well as tumorigenicity assays confirmed that subpopulation of CD44+/ESA+, and CD44+/CD24- cells exactly have CSC properties compared to CD44-/ESA-, CD44-/CD24+ cells 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 GEM or CDDP 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. RT Profiler PCR Array analysis showed that apoptosis- and autophagy-related gene expression was significantly induced after carbon ion beam combined with GEM or CDDP compared to carbon ion alone or X-ray combined with GEM or CDDP in pancreatic and breast cancer cells. Immunofluorescence assay showed that not only the number but also the size of H2AX foci in CSCs were lager 24 h after carbon ion beam combined with GEM or CDDP compared to carbon ion beam and X-ray irradiation alone. Taken together, because the carbon ion beams have a well-defined range with well-localized energy called “spread out bragg peak (SOBP)”, and release enormous energy at the end of their range, carbon ion beams therefore induce more irreparable DNA damage and kill more radioresistant CSCs than photon beams, and combination with a DNA-damaging antitumor drugs further enhances those of actions based on the present data. In addition, xenograft tumors from pancreatic or breast cancer cells were not completely controlled even treated with 60 Gy of X-ray, but it was destroyed with 25 Gy or 15Gy of carbon ion beam combined with 50 mg/kg GEM or 5 mg/kg CDDP, respectively. All together, carbon ion beam has superior potential to kill pancreatic and breast CSCs, produced unrepairable severe DNA damage, and can achieve high curability when combined with DNA damaging drugs at relatively lower doses compared to carbon ion beam alone.

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