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

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.

Epigallocatechin-3-gallate promotes all-trans retinoic acid-induced maturation of acute promyelocytic leukemia cells via PTEN

“…PMA was added at a final concentration of 200 ng/ml to the cells (3x10 5 cells/well). Immediately, 10 µl of CCK-8 was added to each well, with each experimental group paired with three parallel control groups, and the cells were incubated for 1 h (37˚C, 5% CO 2 ) prior to measuring the absorbance at 412 nm (31).…”

The Regulation of Pathways of Inflammation and Resolution in Immune Cells and Cancer Stem Cells by Selenium

“…An early clinical study reported a decrease in total leukocyte counts, immature leukocytes, and spleen size upon oral administration of selenium cystine (diseleno - dialanine) in patients with both CML and AML (Weisberger & Suhrland, 1956). Since then several in vitro studies have demonstrated the anti-leukemic properties of sodium selenite in leukemia cell lines (Jiang Xr, 1992; Liao, Bian, Xie & Peng, 2017; Misra et al, 2016). Sodium selenite supplementation was effective in decreasing circulating leukemia cells in murine Friend erythroleukemia (FV) as well as murine CML models (Gandhi et al, 2014).…”

2-NDC from dithiocarbamates improves ATRA efficiency and ROS-induced apoptosis via downregulation of Bcl2 and Survivin in human acute promyelocytic NB4 cells

“…4 This protein has been considered to have a critical role in APL pathogenesis, while blocking apoptosis and maturation of promyelocytes. 5 Although it has been mostly confirmed that all-trans retinoic acid (ATRA) induces complete remission in near 90% of APL patients, about half of the patients treated with ATRA may develop the ATRA-related syndrome. 2,6 So, there is still intense interest in new chemicals and strategies with therapeutic potential for APL.…”