Abstract
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) in vitro. 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.
Highlights
Malignant mesothelioma (MM) has a long latency period and usually detected at the disease has already reached the advanced stages
Considering the fact that cisplatin (CDDP) is a highly effective chemotherapeutic agent for mesothelioma [19, 20], in the present study, we explored the mechanism through which carbon ion beams kill MM cells when used alone or induce DNA damage and alter the expression of apoptotic and autophagy-related genes when used in combination with cisplatin compared with photon beams
We found that the percentage changes in CD44+/CD26+ cells among H226 cells after irradiation with carbon ion beams, X-ray alone or in combination with CDDP was similar to that observed in MESO1 cells
Summary
Malignant mesothelioma (MM) has a long latency period and usually detected at the disease has already reached the advanced stages. Treatment using charged carbon ion beams is an emerging and promising form of radiotherapy that can target deeply located and radioresistant tumors, because of the high energy released by the “spread out bragg peak www.oncotarget.com (SOBP) [3, 4]. Carbon ion beams have several advantages over conventional radiation, such as low dependence on cell cycle and oxygenation, and they can induce complex DNA damage compared to [5, 6]. In the past two decades, 11,000 cancer patients have been treated by carbon ion radiotherapy using HIMAC (Heavy Ion Medical Accelerator in Chiba), and the outcomes have been encouraging [7, 8]. There are lack of basic biological studies about effects of heavy ion beams on MM cells
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