GSK3 inhibitor suppresses cell growth and metabolic process in FLT3-ITD leukemia cells

Abstract

Glycogen Synthase Kinase-3 (GSK-3) was recently implicated in the dysregulated biology of acute myeloid leukemia (AML). Low concentrations of GSK-3 inhibitors, SB216763 and BIO, suppressed the proliferation of AML cells with FLT3-ITD as early as 24 h after treatment. BIO was used in subsequent assays since it exhibited higher inhibitory effects than SB216763. BIO induced G1 cell cycle arrest by regulating the expression of cyclin D2 and p21 in MV4-11 cells, and promoted apoptosis by regulating the cleaved-caspase3 and AKT signaling pathways. In vivo assays demonstrated that BIO suppressed tumor growth, while metabolomics assay showed that BIO reduced the levels of ATP and pyruvate in MV4-11 cells suggesting that it inhibited glycolysis. BIO markedly suppressed cell growth and induced apoptosis of AML cells with FLT3-ITD by partially inhibiting glycolysis, suggesting that BIO may be a promising therapeutic candidate for AML.