Journal Article Carbon Ion Beam Combined with Cisplatin Effectively Disrupts Triple Negative Breast Cancer Stem-Like Cells In Vitro

Sai, Sei  ,  Vares, Guillaume  ,  Ho Kim, Eun  ,  Karasawa, Kumiko  ,  Bing, Wang  ,  Nenoi, Mitsuru  ,  Horimoto, Yoshiya  ,  al, et

Aims: Although a relatively small proportion of all breast cancer (BC), triple negative (TN) BC is responsible for a relatively large proportion of BC deaths because of its worse clinical outcome. To investigate whether a carbon ion beam alone or in combination with cisplatin has a beneficial effect compared to X-rays, we target triple negative (TN) breast cancer stem-like cells (CSCs). Methods: Human breast CSCs sorted from MDA-MB-231 cells were treated with a carbon ion beam or X-ray irradiation alone or in combination with cisplatin (CDDP), and then colony, spheroid and tumor formation assays, RT-PCR Array analysis, and immunofluorescence γH2AX foci assay were performed.Results: The colony, spheroid formation, and tumorigenicity assays confirmed that CD44+/CD24- and ESA+/CD24- cells have CSC properties in MDA-MB-231 and MDA-MB-453 cells, respectively. The proportion of CSCs was more enriched after CDDP combination with either X-ray or carbon ion beam, however carbon ion beam combined with CDDP significantly suppressed colony and spheroid formation and more significantly inhibited cell cycle progression (sub-G1 arrest) compared to X-ray combined with CDDP or carbon ion beam alone. RT-PCR Array analysis showed that carbon ion beam combined with CDDP significantly induced apoptosis-related Cytochrome c, almost completely eliminated expression of the CSC markers CD44 and ESA, and significantly inhibited angiogenesis, and metastasis-related HIF1α and CD26 compared to carbon ion beam alone, X-ray alone, or X-ray combined with CDDP. The immunofluorescence assay showed that not only the number but also the size of γH2AX foci in CSCs were larger 24 h after carbon ion beam combined with CDDP compared to those of X-ray alone and X-ray combined with CDDP. Conclusions: Carbon ion beam combined with CDDP has superior potential to kill TN breast CSCs with irreparable severe DNA damage and enhanced apoptosis.

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