Hsp90 Inhibitor SNX-2112 Induces AML Cells Differentiation And Apoptosis

Acute myeloid leukemia(AML)was originating from hematopoietic stem / progenitor cells which was a heterogeneous clonal hematologic disorder.The cytotoxic effects induced by using standard therapy damaged the health of patients and inhibited the further development of AML treatment.Hsp90 was expressing high in AML and playing a role in maintaining the stability of cancer proteins in cells,resulting in the finally transform normal cells into malignant leukemia cells.Thus,Hsp90 was a good target for AML treatment.The present study investigated the effect of Hsp90 inhibition on human acute myeloid leukemia(AML)cells using the novel small-molecule inhibitor SNX-2112.First,we examined the effect of SNX-2112 on the proliferation of acute myeloid leukemia cells using CCK8 method;then,the effect of SNX-2112 on the cell cycle and apoptosis of AML cells was analyzed by the flow cytometry and western blot;the expression of CD11 b was analyzed by the flow cytometry,western blot and qRT-PCR,soft agar clone formation and Wright-Giemsa staining were used to investigate the effect of SNX-2112 on the differentiation of AML cells;finally molecular mechanism of SNX-2112 against acute myeloid leukemia was analyzed by western blot and laser scanning confocal microscope.The results showed that,SNX-2112 significantly inhibited the proliferation of AML cells,which was significantly better than 17-AAG,also had low cytotoxicity on human normal cells;and SNX-2112 induced the acute myeloid leukemia cells arrested in G2/M phase and down-regulation the expression of cyclinA;on the other hand,SNX-2112 induced the acute myeloid leukemia cells apoptosis;SNX-2112 induced the differentiation of AML cells,inhibited the expression of C-Myc,and upregulated the expression of transcription factors PU.1 and C/EBP?;mechanism studies showed that SNX-2112 inhibited the expression of Hsp90 client protein(IKK and Akt),and inhibited the activation of downstream signaling pathways.Conclusion: This study demonstrated that SNX-2112 can induce AML cell cycle arrest,apoptosis and differentiation in vitro,had the potential effect on anti-acute myeloid leukemia,the mechanism studies showed that SNX-2112 inhibited the a ctivation of NF-?B signaling pathway,down-regulated the expression of Akt and C-Myc,and activated the expression of differentiation-related transcription factors.This study provided the theoretical basis for the treatment of acute myeloid leukemia with SNX-2112.