17-(dimethylaminoethylamino)-17-demethoxygeldanamycin and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

B-lineage acute lymphoblastic leukemia (B-ALL) is most common in children. We had reported heat shock protein 90 (Hsp90) over-expressed in high risk B-ALL children. 17-DMAG is a water soluble Hsp90 inhibitor, which was proved to be effective for advanced solid tumors and hematological malignancy. However, there is little research on its application in newly diagnosed B-ALL. And the detailed mechanism is seldom discussed.. Primary blast cells from 24 newly diagnosed B-ALL pediatric patients and two B-ALL cell lines were used in this study. Cell viability was measured by MTS assay. Apoptosis was evaluated by flow cytometry after annexin V-PI double staining. Protein expression was detected by immunoblotting analysis and immunofluorescence imaging. Cyto-ID autophagy detection assay was performed to show the autophagosomes and LysoTracker labeling to show the lysosomes. Gene knockdown was performed by RNA interference, and mRNA expression was measured by RT-qPCR.. We showed 17-DMAG induced apoptosis in newly diagnosed B-ALL blasts and cell lines effectively. 17-DMAG induced heat shock cognate protein 70 (Hsc70) expression significantly. High expressed Hsc70 inhibited cathepsin D post-transcriptionally to impede the autophagic flux, which lead to the cell death.. Our work added new information towards understanding the molecular pharmacology of 17-DMAG, and suggested the newly diagnosed B-ALL pediatric patients might be benefited from 17-DMAG. Furthermore, we proved Hsc70 participated in the mechanism of cell death 17-DMAG leading in B-ALL.

Topics: Apoptosis; Autophagy; Benzoquinones; Cathepsin D; Cell Line, Tumor; Cell Proliferation; Child; Child, Preschool; Female; HSC70 Heat-Shock Proteins; Humans; Infant; Lactams, Macrocyclic; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; RNA Processing, Post-Transcriptional

Topics: Antineoplastic Agents; Benzoquinones; Cell Survival; Child; Dose-Response Relationship, Drug; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Molecular Targeted Therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Signal Transduction

To explore the effect of heat shock protein 90(HSP90) inhibitor 17-DMAG, an inhibitor specific for heat shock protein 90, on the proliferation and apoptosis of acute lymphocytic leukemia cell lines Jurkat.. Jurkat cells were collected, then were treated with 17-DMAG. The expression of HSP90 was examined by semi-quantitative RT-PCR analysis, the effect of 17-DMAG on cell proliferation were detected by using WST, and cell apoptosis were detected by using flow cytometry with Annexin V/PI double stenining.. 17-DMAG can inhibit the Jurkat cell proliferation and induce the Jurkat cell apoptosis.

Topics: Apoptosis; Benzoquinones; Cell Line; Cell Proliferation; HSP90 Heat-Shock Proteins; Humans; Jurkat Cells; Lactams, Macrocyclic; Precursor Cell Lymphoblastic Leukemia-Lymphoma