VITAMIN D ANALOGUE EB1089 SENSITIZES HUMAN TRANSFORMED CELL LINES TO GAMMA RADIATIONS BY INDUCING LETHAL AUTOPHAGY AND APOPTOSIS

Introduction: The gold standard for unresectable solid tumours and advanced forms of leukemia is represented by chemo-radiation. However, therapeutic options are limited and patients undergo systemic cytotoxicity. Vitamin D insufficiency is a widespread problem and its low serum levels are linked to higher cancer incidence. Previous studies showed a strong correlation between serum concentration of vitamin D and time of first treatment in chronic lymphocytic leukemia (CLL). Other studies demonstrated that vitamin D and its ipocalcemic analogue EB1089 are able to bypass radio-resistance in breast and lung cancer cell lines by activating cytostatic/cytotoxic forms of autophagy. However, only few data are available on the intracellular and molecular effects of vitamin D in osteosarcoma (OS) and CLL-derived cells and on its association with gamma-radiation in sensitizing these cancer types. Objectives: We studied the antiproliferative effects of an active form of vitamin D, the analogue EB1089, in two cells lines U2Os and HG3 derived from a human OS and a CLL, respectively, and its efficacy after treatment with gamma-radiations in terms of cytotoxicity, autophagic and apoptotic effects. Results: EB1089, used at physiological concentration (100 ng/ml), is able to bypass gamma-radiations resistance in U2Os and HG3 cell lines by activating cytotoxic autophagy and apoptosis. The co-treatment resulted highly synergic in terms of combination index (C.I. <1) inducing 85% of cell death at higher doses of radiation after 24h of co-treatment. Conclusions: The results obtained will be discussed at the light of the cytostatic/cytotoxic function of autophagy mediated by vitamin D and involving MAPK/ERK and AMPK pathways in enhancing the therapeutic response to gamma-radiations.