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

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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 through 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.