Abstract 3539: Vitamin D/EB 1089 mediated radio-sensitization of lung cancer cells and head and neck cancer cells

Abstract

Abstract Lung cancer is a principal factor contributing to cancer-related mortality in the United States. Patients with lung cancer generally have a poor prognosis and resection is often not possible. Our previous work has demonstrated that Vitamin D and its analog, EB1089 (EB), enhance radio sensitivity of H460 and A549 non-small cell lung cancer (NSCLC) cells (Sharma et al; A novel cytostatic form of autophagy in sensitization of non-small cell lung cancer cells to radiation by vitamin D and the vitamin D analog, EB 1089. Autophagy; 2014;10(12):2346-61). In this study, we have extended these findings of Vitamin D/EB 1089 induced radio-sensitization in multiple tumor cell lines such as Lewis Lung mouse non-small cell lung cancer cells (LLC), head and neck cancer cells (HN30) and a primary cell line established from a lung tumor obtained from a cancer patient. All cell lines were treated with multiple doses of radiation in the range of 2-6 Gy and EB1089 was used at concentration of 100nM. Sensitivity was determined based on viable cell number and clonogenic survival. We observed enhanced radiation sensitivity of LLC and HN30 cells with the combination treatment of radiation and EB1089. However, as reported previously by our laboratory (Sharma et al., 2014; Autophagy), sensitization was dependent on the presence of functional p53 and was not evident in HN6 head and neck tumor cells that are mutant in p53. These data suggest that Vitamin D or a Vitamin D analog could be used to enhance radiation sensitivity of various malignancies but only where the tumors express wild type p53. Furthermore, we were able to demonstrate sensitization in a primary cell line established from lung tumor tissues utilizing conditioned medium from stromal cells treated with EB1089. These data suggest that stromal re-programming of cancer cells could influence radiation sensitivity. In studies to define the signaling pathways associated with radiation sensitization, we also observed inactivation by EB 1089 of the NF-kB pathway that was activated by radiation alone in H460 and H1299 NSCLC cells. Silencing of AMPK attenuated radiation sensitization by EB 1089. Sensitization was accompanied by enhanced secretion of the autophagy/senescence related marker, HMGB1. Taken together, these studies indicate that Vitamin and/or its analogs enhance radiosensitivity by cellular pathways involving NF-kB and AMPK and that HMGB1 may be secreted to activate an immune response to the combination treatment. Citation Format: Theresa Thekkudan, Khushboo Sharma, Tareq Saleh, David Gewirtz. Vitamin D/EB 1089 mediated radio-sensitization of lung cancer cells and head and neck cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3539.