Sanguinarine as a Potent and Specific Inhibitor of Protein Phosphatase 2C in Vitro and Induces Apoptosis via Phosphorylation of p38 in HL60 Cells

Abstract

Sanguinarine, a plant alkaloid, was identified as a potent and specific protein phosphatase (PP) 2C inhibitor. It inhibited PP2C competitively with respect to α-casein (Ki=0.68 μM) and showed selectivity for PP2C as compared with PP1, PP2A, and PP2B in vitro. In vivo, sanguinarine showed cytotoxicity toward human promyelocytic leukemia cell line HL60, with an IC₅₀ value of 0.37 μM, and induced apoptosis though a caspase-3/7-dependent mechanism involving the phosphorylation of p38, a PP2Cα substrate. The apoptosis activity induced by sanguinarine was partially inhibited by a p38 inhibitor, SB203580, and was involved in the phospho-p38 protein in HL60 cells.