The Effects And Mechanism Of Hsp90 Inhibitors、SAHA And QC In Acute Leukemia

Ikaros is a critical transcription factor in the regulation of hematopoiesis and it can function as either a tumor suppressor or a tumor enhancer in different tumors,but its function in AML is obscure.Here we found that pharmacologic inhibition of Hsp90 with STA-9090 or shRNA mediated knockdown of Hsp90 results in the reduction of Ikaros protein in acute myeloid leukemia(AML)cells which is mediated by E3 ubiquitin ligase named C terminal Hsc70 interacting protein(CHIP).Furthermore,knockdown of Ikaros effectively inhibits proliferation of leukemia cells in vitro and in vivo.Collectively,our findings here indicate the interplay between HSP90 and CHIP regulates the activities of Ikaros which provides basis for a novel strategy for AML treatment through targeting HSP90/Ikaros/CHIP axis.Acute lymphocytic leukemia is one kind of hematological malignancies which is more likely to be seen in children and adolescents.Although the survival rate of childhood ALL is approaching 90%,in adults,the cure rate is low and the prognosis is poor.Therefore,it is urgent to find new treatment options.Our present study shows that an antimalarial drug named QC plus histone acetylation enzyme inhibitor vorinostat(SAHA)effectively inhibits the proliferation of leukemia cells in vitro and it also significantly induces apoptosis,which is mediated by the dysfunction of mitochondria.Furthermore,using a xenograft mouse model,we demonstrate that QC plus SAHA significantly reduces cell proliferation and induces cell death in vivo.