Treatment with alternating electric fields at an intermediate frequency (100–300 kHz), referred to as tumor treating fields (TTF) therapy, inhibits cancer cell proliferation. In the present study, we demonstrated that TTF application suppressed the metastatic potential of U87 and U373 glioblastoma cell lines via the NF-kB, MAPK and PI3K/AKT signaling pathways. Wound-healing and transwell assays showed that TTF suppressed cell migration and invasion compared with controls. Soft agar and three-dimensional culture assays showed that TTF inhibited both anchorage-dependent (cell proliferation) and anchorage-independent (colony formation) GBM cell growth. TTF dysregulated epithelial-to-mesenchymal transition-related genes, such as vimentin and E-cadherin, which partially accounted for TTF inhibition of cell migration and invasion. We further demonstrated that TTF application suppressed angiogenesis by downregulating VEGF, HIF1α and matrix metalloproteinases 2 and 9. TTF also inhibited NF-kB transcriptional activity. Collectively, our findings show that TTF represents a promising novel anti-invasion and anti-angiogenesis therapeutic strategy for use in GBM patients.

Material and methods Cell cultureRenal cell carcinoma cell lines (Caki-1, Caki-2, ACHN, SN12C, SN12PM6, RENCA) were purchased from Korean Cell

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Alternating electric fields at an intermediate frequency (100~300 kHz), referred to as tumour-treating fields (TTF), are believed to interrupt the process of mitosis via apoptosis and to act as an inhibitor of cell proliferation. Although the existence of an antimitotic effect of TTF is widely known, the proposed apoptotic mechanism of TTF on cell function and the efficacy of TTF are controversial issues among medical experts. To resolve these controversial issues, a better understanding of the underlying molecular mechanisms of TTF on cell function and the differences between the effects of TTF alone and in combination with other treatment techniques is essential. Here, we report experimental evidence of TTF-induced apoptosis and the synergistic antimitotic effect of TTF in combination with ionizing radiation (IR). For these experiments, two human Glioblastoma multiforme (GBM) cells (U373 and U87) were treated either with TTF alone or with TTF followed by ionizing radiation (IR). Cell apoptosis, DNA damage, and mitotic abnormalities were quantified after the application of TTF, and their percentages were markedly increased when TTF was combined with IR. Our experimental results also suggested that TTF combined with IR synergistically suppressed both cell migration and invasion, based on the inhibition of MMP-9 and vimentin.

AimsAlthough 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 (CDDP) has a beneficial effect compared to X-rays, we target triple negative (TN) breast cancer stem-like cells (CSCs).MethodsHuman breast CSCs sorted from MDA-MB-231 and MDA-MB-453 cells were treated with a carbon ion beam or X-ray irradiation alone or in combination with CDDP, and then colony, spheroid and tumor formation assays, RT-PCR Array analysis, and immunofluorescence γH2AX foci assay were performed.ResultsThe 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.ConclusionsCarbon ion beam combined with CDDP has superior potential to kill TN breast CSCs with irreparable severe DNA damage and enhanced apoptosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0429-7) contains supplementary material, which is available to authorized users.