Selenite promotes all- trans retinoic acid-induced maturation of acute promyelocytic leukemia cells

// Sougat Misra 1 , Arun Kumar Selvam 1 , Marita Wallenberg 1 , Aditya Ambati 2,3 , Andras Matolcsy 4 , Isabelle Magalhaes 5 , Gilbert Lauter 6 and Mikael Bjornstedt 1 1 Department of Laboratory Medicine, Division of Pathology F46, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden 2 Therapeutic Immunology Unit, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden 3 Centre for Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital, Stockholm, Sweden 4 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Faculty of Medicine, Budapest, Ullői ut, Hungary 5 Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden 6 Department of Biosciences and Nutrition, NOVUM, Karolinska Institutet, Huddinge, Sweden Correspondence to: Sougat Misra, email: // Mikael Bjornstedt, email: // Keywords : acute myeloid leukemia, selenite, all-trans retinoic acid, differentiation, PML/RARA Received : August 04, 2016 Accepted : September 29, 2016 Published : October 08, 2016 Abstract Selective targeting of the PML/RARα oncoprotein demonstrates a successful molecular targeted therapy in acute promyelocytic leukemia (APL) with a typical t(15:17) chromosomal translocation. The zinc-thiolate coordination is critical for structural stability of zinc finger proteins, including the PML moiety of PML/RARα. Based on the known interaction of redox-active selenium compounds with thiolate ligands of zinc, we herein have investigated the abrogatory effects of selenite alone or in combination with all- trans retinoic acid on PML/RARα and the possible effects on differentiation in these cells. At pharmacological concentrations, selenite inhibited the proliferation and survival of APL originated NB4 cells. In combination with ATRA, it potentiated the differentiation of NB4 cells without any differentiating effects of its own as a single agent. Concordant with our hypothesis, PML/RARα oncoprotein expression was completely abrogated by selenite. Increased expression of RAR, PU.1 and FOXO3A transcription factors in the combined treatment suggested the plausible basis for increased differentiation in these cells. We show that selenite at clinically achievable dose targets PML/RARα oncoprotein for degradation and potentiates differentiation of promyelocytic leukemic cells in combination with ATRA. The present investigation reveals the hitherto unknown potential of selenite in targeted abrogation of PML/RARα in APL cells with prospective therapeutic value.