Effects of carbon ion beam alone or in combination with cisplatin on malignant mesothelioma cells in vitro

Malignant mesothelioma (MM) is extremely aggressive and a typical refractory cancer. In this study we investigated how effective on killing MM cells by carbon ion beam alone or in combination with cisplatin (CDDP) . Carbon ion beam (at the center of SOBP with 50 keV/µm of average LET) dose-independently suppressed MM cells MESO-1 and H226 cell viability and in combination with CDDP (25 μM) significantly enhanced its action. Relative biological effectiveness (RBE) values at 73 keV/μm and 13 keV/μm portion of carbon ion beam was estimated as 2.82-2.93 and 1.19-1.22 at D10 level relative to X-ray, respectively by using colony formation assay. Quantitative real time PCR analysis showed that expression of apoptosis-related BAX and autophagy-related Beclin1 and ATG7 was significantly enhanced by carbon ion beam alone or in combination with CDDP. Apoptosis analysis showed that caspase 3/7 activity and the percentage of apoptotic cells was dose-dependently increased after carbon ion beam and it was further increased when combined with CDDP. Spheroid formation ability of cancer stem like CD44+/CD26+ cells was significantly inhibited by carbon ion beam combined with CDDP. Besides, carbon ion beam combined with cisplatin significantly inhibited cell cycle progression (sub-G1 arrest) and induced more large number of γH2AX foci. In conclusion, carbon ion beam combined with CDDP has superior potential to kill MM cells including CSCs with enhanced apoptosis