Abstract
Abstract Purpose: Mounting evidence suggests that tumor treatment fields (TTF) are an effective and non-invasive treatment for Glioblastoma (GBM), non-small lung cancer (NSCLCs) and pancreatic cancer. TTF is known to inhibit microtubule spindle formation, leading to mitotic arrest and ultimately cell death. Relatively few studies explore the biological effects of TTF on cells and the mechanism of action of tumor control remains unclear. Therefore, in this study we investigated the mechanism of TTF-induced cell death in NSCLC and explored the potential conditional lethality of combining radiation and TTF. Methods: All studies were conducted in vitro using a panel of NSCLC cell lines and TTF was generated using the Inovitro system developed by Novocure (Haifa, Israel). Experiments assessing the effects of TTF on cell proliferation, cell viability, cell cycle distribution, and clonogenic survival when combined with radiation were conducted to assess the potential effectiveness of TTF in the treatment of NSCLC. Results: Optimized TTF (frequency) was applied to a panel of NSCLC cell lines displaying different genetic characteristics (H1299, H1650, and A549) and resulted in a significant reduction in cell proliferation irregardless of genotype. Trypan blue exclusion determined that 96 hours of TTF the percentage of cell death was significantly elevated in H1650 and H1299, but not in A549 cells indicating that TTF may be slowing, rather than killing cells. Furthermore, cell cycle analysis revealed a dramatic shift in cell cycle distribution in the first 24-48 hours in some cell lines, a phenotype that was reversed by 96 hours, indicating that the cell population may be adapting to TTF. To determine if the observed shift in cell cycle distribution effected radiation sensitivity, clonogenic survival assays were performed on cells irradiated with an acute dose of 2 Gy γ-rays followed by 48 and 72 hours of TTF. TTF significantly enhanced the effect of radiation exposure after both time points examined, however TTF enhancement of radiation induced cell killing in A549 and H1650 after 48 hours of TTF (SF2 = 0.41, 0.16) was greater than that observed after 72 hours of TTF (SF2 = 0.55, 0.38) indicating that the adaptive response of cells to TTF observed in cell cycle analysis may be effecting cellular radiosensitivity. Conclusions: These results indicate that TTF dramatically slows cell proliferation and significantly enhances radiation-induced cell killing of NSCLC cells. The mechanisms of cell death and molecular responses to TTF are now under investigation. Citation Format: Kalayarasan Srinivasan, Brock Sishc, Debabrata Saha, Michael D. Story. Tumor treatment fields slow cell proliferation and enhance radiosensitivity in a model of non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3296. doi:10.1158/1538-7445.AM2015-3296
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