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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 apoptosis. Adult T-cell leukemia–lymphoma-related cell lines were treated with or without AUY922 (12.5 or 25.0 nM [a], or 100 nM [b]) for 48 h, then harvested, stained with annexin V–propidium iodide, and analyzed using flow cytometry. Data shown represent the percentages of apoptotic cells among untreated and AUY922-treated cells.
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fig04: Effects of heat shock protein 90 inhibitor AUY922 on apoptosis. Adult T-cell leukemia–lymphoma-related cell lines were treated with or without AUY922 (12.5 or 25.0 nM [a], or 100 nM [b]) for 48 h, then harvested, stained with annexin V–propidium iodide, and analyzed using flow cytometry. Data shown represent the percentages of apoptotic cells among untreated and AUY922-treated cells.

Mentions: To examine whether induction of apoptosis accounted for the inhibition of proliferation observed in ATL-related cell lines, cells were treated with the control, 12.5 nM AUY922, or 25.0 nM AUY922 for 48 h, or 100 nM AUY922 for 48–72 h, then examined using the annexin V–PI method. Annexin V binds to cells that express phosphatidylserine on the outer layer of the cell membrane, a characteristic finding in those entering apoptosis. AUY922 increased the proportion of cells positive for annexin V in all cell lines in a dose-dependent manner (Fig. 4a). Moreover, 100 nM AUY922 increased the proportion of cells positive for annexin V in all cell lines in a time-dependent manner (Fig. 4b). We carried out additional apoptosis assays using the non-HTLV-1 related T-cell lines Jurkat and Molt4. Those results were similar to the results obtained with ATL-related cell lines (Fig. S1).


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 apoptosis. Adult T-cell leukemia–lymphoma-related cell lines were treated with or without AUY922 (12.5 or 25.0 nM [a], or 100 nM [b]) for 48 h, then harvested, stained with annexin V–propidium iodide, and analyzed using flow cytometry. Data shown represent the percentages of apoptotic cells among untreated and AUY922-treated cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig04: Effects of heat shock protein 90 inhibitor AUY922 on apoptosis. Adult T-cell leukemia–lymphoma-related cell lines were treated with or without AUY922 (12.5 or 25.0 nM [a], or 100 nM [b]) for 48 h, then harvested, stained with annexin V–propidium iodide, and analyzed using flow cytometry. Data shown represent the percentages of apoptotic cells among untreated and AUY922-treated cells.
Mentions: To examine whether induction of apoptosis accounted for the inhibition of proliferation observed in ATL-related cell lines, cells were treated with the control, 12.5 nM AUY922, or 25.0 nM AUY922 for 48 h, or 100 nM AUY922 for 48–72 h, then examined using the annexin V–PI method. Annexin V binds to cells that express phosphatidylserine on the outer layer of the cell membrane, a characteristic finding in those entering apoptosis. AUY922 increased the proportion of cells positive for annexin V in all cell lines in a dose-dependent manner (Fig. 4a). Moreover, 100 nM AUY922 increased the proportion of cells positive for annexin V in all cell lines in a time-dependent manner (Fig. 4b). We carried out additional apoptosis assays using the non-HTLV-1 related T-cell lines Jurkat and Molt4. Those results were similar to the results obtained with ATL-related cell lines (Fig. S1).

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