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Highly selective HSP90 inhibitor, pimitespib, demonstrates its potent growth suppressive activity to adult T-cell leukemia in preclinical models (HuT102).

ABSTRACT: Adult T-cell leukaemia-lymphoma (ATL) is a highly chemoresistant malignancy of peripheral T lymphocytes caused by human T-lymphotropic virus type I (HTLV-1). ATL cells constitutively activate anti-apoptotic signals through nuclear factor kappaB (NF-κB)-mediated gene expression. The molecular chaperon heat shock protein 90 (HSP90) plays a crucial role on NF-κB-mediated anti-apoptotic activity in ATL cells and HSP90 inhibitors, such as 17-DMAG and NVP-AUY922, have demonstrated their anti-ATL activities. A novel class of orally active inhibitors of cytosolic HSP90α and β, pimitespib, demonstrated its highly selective anti-ATL cell effects both ex-vivo and in vivo preclinical models. Ten ATL-related cell lines achieved their IC50 below 0.5µM dose of TAS-116 while CD4 lymphocytes derived from healthy donors were less harmed than ATL cells. TAS-116 efficiently induces Tax-degradation and IκB-α accumulation to Tax-positive cell-lines. DNA microarray profiling followed by a variety of pathway analysis revealed that TAS-116 down-regulated NF-κB activating pathways in Tax-positive cells and cell cycle promoting pathways in Tax-negative cells and induces anti-ATL effect. Oral administration of TAS-116 to ATL-cell xenograft model mice also demonstrated the growth inhibitory effects against tumor cells. Consequently, TAS-116, one of the most evolved HSP90 inhibitor, may become a promising option against ATL therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE168554 | GEO | 2022/02/18

REPOSITORIES: GEO

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Project description:Background. Heat shock protein 90 (Hsp90) is essential for the stability and the function of many client proteins, such as ERB2, C-RAF, CDK4, HIF-1 aplha and AKT. Recent reports demonstrated that inhibition of Hsp90 modulates multiple functions required for survival of human cancer, such as myeloma (Mitsiades et al, Blood:107, 1092, 2006), however, the precise mechanism of anti-cancer effect of Hsp90 inhibition is still uncertain. Aim. The aim of this study is evaluate the effect of Hsp90 inhibition, and to identify molecular pathways responsible for anti-proliferative effect on ATL cells. Method. For Hsp90 inhibition, Geldanamycin derivates, 17AAG (17-allylamino -17-demethoxygeldanamycin) and 17DMAG (17-(dimethylaminoethylamino) 17-demethoxygeldanamycin) were used in this study. Interleukin 2-independent ATL cell lines (MT-2 and MT-4) and an interleukin 2-dependent ATL cell line (TaY) were incubated, with or without Hsp90 inhibitors. Fresh ATL cells obtained from patients were also used after obtaining informed consent. Cell numbers at 48 h after incubation with or without Hsp90 inhibitors were assessed with the Cell Counting Kit-8 assay (Dojindo Molecular Technologies, Gaithersburg, MD, USA). For detection of apoptosis, we used Annexin V-biotin apoptosis detection kit (Calbiochem, La Jolla, CA, USA). Gene expression analysis was done using a DNA microarray (NCBI Gene expression omnibus; GPL 2531) and statistical analysis was done by a GeneSifter (VizXlabs, Seattle, WA, USA). Results. We found cell death induced by Hsp90 inhibitors in all the 3 ATL cell lines as well as patient specimens. Inhibitory concentration (IC50) of 17AAG in 3 ATL cell lines was 300 to 700 nM, and that of 17DMAG was 150 to 200 nM. Fresh ATL cells obtained from patients were more sensitive for either 17AAG or 17DMAG. Gene expression analysis of ATL cells revealed that up-regulation of HSPA1A encoding Hsp70, and genes related to cell cycle arrest (i.e. CDKN1A). Genes regulating cell proliferation or anti-apoptosis (i.e. MYC, BCL2 and Cyclin C), genes related to cytokine or chemokine (i.e. IL9, CCL 17, and CCL27), and notably, genes involved in Wnt/-catenin signaling pathway (i.e.TCF7L2 and TCF4), were remarkably repressed. Inhibition of AKT at the protein level was also evident, suggesting the possibility that AKT may down-regulates -catenin/ TCF7L2 pathways in response to Hsp90 inhibitors in ATL cells. Conclusion. Our results have provided new insights into the complex molecular pharmacology of Hsp90 inhibitors, and suggest that Hsp90 inhibitors might be beneficial as anti-proliferative agent in treating ATL patients. Six samples treated with Hsp90 inhibitors (17-AAG or 17-DMAG) were analyzed in biological duplicate.

Project description:Background. Heat shock protein 90 (Hsp90) is essential for the stability and the function of many client proteins, such as ERB2, C-RAF, CDK4, HIF-1 aplha and AKT. Recent reports demonstrated that inhibition of Hsp90 modulates multiple functions required for survival of human cancer, such as myeloma (Mitsiades et al, Blood:107, 1092, 2006), however, the precise mechanism of anti-cancer effect of Hsp90 inhibition is still uncertain. Aim. The aim of this study is evaluate the effect of Hsp90 inhibition, and to identify molecular pathways responsible for anti-proliferative effect on ATL cells. Method. For Hsp90 inhibition, Geldanamycin derivates, 17AAG (17-allylamino -17-demethoxygeldanamycin) and 17DMAG (17-(dimethylaminoethylamino) 17-demethoxygeldanamycin) were used in this study. Interleukin 2-independent ATL cell lines (MT-2 and MT-4) and an interleukin 2-dependent ATL cell line (TaY) were incubated, with or without Hsp90 inhibitors. Fresh ATL cells obtained from patients were also used after obtaining informed consent. Cell numbers at 48 h after incubation with or without Hsp90 inhibitors were assessed with the Cell Counting Kit-8 assay (Dojindo Molecular Technologies, Gaithersburg, MD, USA). For detection of apoptosis, we used Annexin V-biotin apoptosis detection kit (Calbiochem, La Jolla, CA, USA). Gene expression analysis was done using a DNA microarray (NCBI Gene expression omnibus; GPL 2531) and statistical analysis was done by a GeneSifter (VizXlabs, Seattle, WA, USA). Results. We found cell death induced by Hsp90 inhibitors in all the 3 ATL cell lines as well as patient specimens. Inhibitory concentration (IC50) of 17AAG in 3 ATL cell lines was 300 to 700 nM, and that of 17DMAG was 150 to 200 nM. Fresh ATL cells obtained from patients were more sensitive for either 17AAG or 17DMAG. Gene expression analysis of ATL cells revealed that up-regulation of HSPA1A encoding Hsp70, and genes related to cell cycle arrest (i.e. CDKN1A). Genes regulating cell proliferation or anti-apoptosis (i.e. MYC, BCL2 and Cyclin C), genes related to cytokine or chemokine (i.e. IL9, CCL 17, and CCL27), and notably, genes involved in Wnt/beta-catenin signaling pathway (i.e.TCF7L2 and TCF4), were remarkably repressed. Inhibition of AKT at the protein level was also evident, suggesting the possibility that AKT may down-regulates beta-catenin/ TCF7L2 pathways in response to Hsp90 inhibitors in ATL cells. Conclusion. Our results have provided new insights into the complex molecular pharmacology of Hsp90 inhibitors, and suggest that Hsp90 inhibitors might be beneficial as anti-proliferative agent in treating ATL patients.