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Heat shock protein 90 inhibitor NVP-AUY922 exerts potent activity against adult T-cell leukemia-lymphoma cells.

Taniguchi H, Hasegawa H, Sasaki D, Ando K, Sawayama Y, Imanishi D, Taguchi J, Imaizumi Y, Hata T, Tsukasaki K, Uno N, Morinaga Y, Yanagihara K, Miyazaki Y - Cancer Sci. (2014)

Bottom Line: AUY922 caused strong upregulation of HSP70, a surrogate marker of HSP90 inhibition, and a dose-dependent decrease in HSP90 client proteins associated with cell survival, proliferation, and cell cycle in the G1 phase, including phospho-Akt, Akt, IKKα, IKKβ, IKKγ, Cdk4, Cdk6, and survivin.In fact, SGI-1776, a pan-PIM kinase inhibitor, successfully inhibited the growth of primary ATL cells as well as ATL-related cell lines.Our findings suggest that AUY922 is an effective therapeutic agent for ATL, and PIM kinases may be a novel therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Department of Hematology, Sasebo City General Hospital, Sasebo, Japan; Atomic Bomb Disease and Hibakusha Medicine Unit, Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.

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Growth inhibition effects of heat shock protein 90 inhibitor 17-AAG. Inhibitory effects of 17-AAG on cell survival of adult T-cell leukemia–lymphoma-related cell lines. Cells were incubated in the presence of various concentrations of 17-AAG for 72 h and in vitro survival was determined using MTS assay. The relative viability of cultured cells is presented as the mean determined from triplicate cultures. A relative viability of 100% was determined based on the total number of cells that survived after 72 h in the absence of 17-AAG. The relative viability of cultured cells was determined from triplicate cultures and is presented as the mean ± SD (bars).
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fig02: Growth inhibition effects of heat shock protein 90 inhibitor 17-AAG. Inhibitory effects of 17-AAG on cell survival of adult T-cell leukemia–lymphoma-related cell lines. Cells were incubated in the presence of various concentrations of 17-AAG for 72 h and in vitro survival was determined using MTS assay. The relative viability of cultured cells is presented as the mean determined from triplicate cultures. A relative viability of 100% was determined based on the total number of cells that survived after 72 h in the absence of 17-AAG. The relative viability of cultured cells was determined from triplicate cultures and is presented as the mean ± SD (bars).

Mentions: First, we analyzed the effects of AUY922 on proliferation of ATL-related cell lines. Incubation with AUY922 at various concentrations (0–100 nM) for 72 h inhibited cellular proliferation in a dose-dependent manner in a range from 0 to 25 nM, while a plateau was reached at concentrations >25 nM, as assessed by an MTS assay (Fig. 1a). The concentrations of AUY922 required to inhibit cellular proliferation of ATL-related cell lines by 50% (IC50) varied from 12.5 to 25.0 nM. Importantly, AUY922 was effective regardless of the presence of wild-type or mutant p53. We also assessed AUY922-induced cellular inhibition of PBMCs obtained from both normal subjects and patients with ATL. Importantly, primary ATL cells were more susceptible to AUY922 than normal PBMCs, and the difference was statistically significant at 25 nM (Fig. 1b). Also, when compared directly with 17-AAG, AUY922 was between 20- and 50-fold more active at inhibiting growth of ATL-related cell lines (Fig. 2).


Heat shock protein 90 inhibitor NVP-AUY922 exerts potent activity against adult T-cell leukemia-lymphoma cells.

Taniguchi H, Hasegawa H, Sasaki D, Ando K, Sawayama Y, Imanishi D, Taguchi J, Imaizumi Y, Hata T, Tsukasaki K, Uno N, Morinaga Y, Yanagihara K, Miyazaki Y - Cancer Sci. (2014)

Growth inhibition effects of heat shock protein 90 inhibitor 17-AAG. Inhibitory effects of 17-AAG on cell survival of adult T-cell leukemia–lymphoma-related cell lines. Cells were incubated in the presence of various concentrations of 17-AAG for 72 h and in vitro survival was determined using MTS assay. The relative viability of cultured cells is presented as the mean determined from triplicate cultures. A relative viability of 100% was determined based on the total number of cells that survived after 72 h in the absence of 17-AAG. The relative viability of cultured cells was determined from triplicate cultures and is presented as the mean ± SD (bars).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317953&req=5

fig02: Growth inhibition effects of heat shock protein 90 inhibitor 17-AAG. Inhibitory effects of 17-AAG on cell survival of adult T-cell leukemia–lymphoma-related cell lines. Cells were incubated in the presence of various concentrations of 17-AAG for 72 h and in vitro survival was determined using MTS assay. The relative viability of cultured cells is presented as the mean determined from triplicate cultures. A relative viability of 100% was determined based on the total number of cells that survived after 72 h in the absence of 17-AAG. The relative viability of cultured cells was determined from triplicate cultures and is presented as the mean ± SD (bars).
Mentions: First, we analyzed the effects of AUY922 on proliferation of ATL-related cell lines. Incubation with AUY922 at various concentrations (0–100 nM) for 72 h inhibited cellular proliferation in a dose-dependent manner in a range from 0 to 25 nM, while a plateau was reached at concentrations >25 nM, as assessed by an MTS assay (Fig. 1a). The concentrations of AUY922 required to inhibit cellular proliferation of ATL-related cell lines by 50% (IC50) varied from 12.5 to 25.0 nM. Importantly, AUY922 was effective regardless of the presence of wild-type or mutant p53. We also assessed AUY922-induced cellular inhibition of PBMCs obtained from both normal subjects and patients with ATL. Importantly, primary ATL cells were more susceptible to AUY922 than normal PBMCs, and the difference was statistically significant at 25 nM (Fig. 1b). Also, when compared directly with 17-AAG, AUY922 was between 20- and 50-fold more active at inhibiting growth of ATL-related cell lines (Fig. 2).

Bottom Line: AUY922 caused strong upregulation of HSP70, a surrogate marker of HSP90 inhibition, and a dose-dependent decrease in HSP90 client proteins associated with cell survival, proliferation, and cell cycle in the G1 phase, including phospho-Akt, Akt, IKKα, IKKβ, IKKγ, Cdk4, Cdk6, and survivin.In fact, SGI-1776, a pan-PIM kinase inhibitor, successfully inhibited the growth of primary ATL cells as well as ATL-related cell lines.Our findings suggest that AUY922 is an effective therapeutic agent for ATL, and PIM kinases may be a novel therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Department of Hematology, Sasebo City General Hospital, Sasebo, Japan; Atomic Bomb Disease and Hibakusha Medicine Unit, Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.

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Related in: MedlinePlus