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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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Effects of heat shock protein 90 inhibitor AUY922 on cell cycle. Adult T-cell leukemia–lymphoma-related cell lines were incubated in the absence (−) or presence of AUY922 (12.5 or 25.0 nM) for 48 h and stained with propidium iodide, then DNA content was assayed using flow cytometry. The percentage of cells in various phases of the cell cycle was determined.
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fig03: Effects of heat shock protein 90 inhibitor AUY922 on cell cycle. Adult T-cell leukemia–lymphoma-related cell lines were incubated in the absence (−) or presence of AUY922 (12.5 or 25.0 nM) for 48 h and stained with propidium iodide, then DNA content was assayed using flow cytometry. The percentage of cells in various phases of the cell cycle was determined.

Mentions: Next, we examined the effect of AUY922 on cell cycle progression in the tested cell lines. Cells were incubated with the control, AUY922 at 12.5 nM, or AUY922 at 25.0 nM for 48 h, then cell cycle distribution was analyzed using flow cytometry. Faint increases of G1 and G2–M cell populations were seen in KK1 and KOB, and SO4 cells, at 12.5 nM AUY922, respectively. In all of the tested cell lines, the sub-G1 cell population increased in a dose-dependent manner, indicating apoptotic cell death (Fig. 3).


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)

Effects of heat shock protein 90 inhibitor AUY922 on cell cycle. Adult T-cell leukemia–lymphoma-related cell lines were incubated in the absence (−) or presence of AUY922 (12.5 or 25.0 nM) for 48 h and stained with propidium iodide, then DNA content was assayed using flow cytometry. The percentage of cells in various phases of the cell cycle was determined.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig03: Effects of heat shock protein 90 inhibitor AUY922 on cell cycle. Adult T-cell leukemia–lymphoma-related cell lines were incubated in the absence (−) or presence of AUY922 (12.5 or 25.0 nM) for 48 h and stained with propidium iodide, then DNA content was assayed using flow cytometry. The percentage of cells in various phases of the cell cycle was determined.
Mentions: Next, we examined the effect of AUY922 on cell cycle progression in the tested cell lines. Cells were incubated with the control, AUY922 at 12.5 nM, or AUY922 at 25.0 nM for 48 h, then cell cycle distribution was analyzed using flow cytometry. Faint increases of G1 and G2–M cell populations were seen in KK1 and KOB, and SO4 cells, at 12.5 nM AUY922, respectively. In all of the tested cell lines, the sub-G1 cell population increased in a dose-dependent manner, indicating apoptotic cell death (Fig. 3).

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.

Show MeSH
Related in: MedlinePlus