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Bryant KG, Chae YC, Martinez RL, et al. A Mitochondrial-targeted purine-based HSP90 antagonist for leukemia therapy. Oncotarget. 2017;8(68):112184-112198doi: 10.18632/oncotarget.23097.
Bryant, K. G., Chae, Y. C., Martinez, R. L., Gordon, J. C., Elokely, K. M., Kossenkov, A. V., Grant, S., Childers, W. E., Abou-Gharbia, M., & Altieri, D. C. (2017). A Mitochondrial-targeted purine-based HSP90 antagonist for leukemia therapy. Oncotarget, 8(68), 112184-112198. https://doi.org/10.18632/oncotarget.23097
Bryant, Kelly G, et al. "A Mitochondrial-targeted purine-based HSP90 antagonist for leukemia therapy." Oncotarget vol. 8,68 (2017): 112184-112198. doi: https://doi.org/10.18632/oncotarget.23097
Bryant KG, Chae YC, Martinez RL, Gordon JC, Elokely KM, Kossenkov AV, Grant S, Childers WE, Abou-Gharbia M, Altieri DC. A Mitochondrial-targeted purine-based HSP90 antagonist for leukemia therapy. Oncotarget. 2017 Dec 11;8(68):112184-112198. doi: 10.18632/oncotarget.23097. eCollection 2017 Dec 22. PMID: 29348817; PMCID: PMC5762502.
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Oncotarget. 2017 Dec 11;8(68):112184-112198. doi: 10.18632/oncotarget.23097. eCollection 2017 Dec 22.

A Mitochondrial-targeted purine-based HSP90 antagonist for leukemia therapy.

Oncotarget

Kelly G Bryant, Young Chan Chae, Rogelio L Martinez, John C Gordon, Khaled M Elokely, Andrew V Kossenkov, Steven Grant, Wayne E Childers, Magid Abou-Gharbia, Dario C Altieri

Affiliations

  1. Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, PA, USA.
  2. Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA.
  3. Moulder Center for Drug Discovery Research, School of Pharmacy, Temple University, Philadelphia, PA, USA.
  4. Department of Pharmaceutical Chemistry, Tanta University, Tanta, Egypt.
  5. Center for System and Computational Biology, The Wistar Institute, Philadelphia, PA, USA.
  6. Department of Medicine and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.

PMID: 29348817 PMCID: PMC5762502 DOI: 10.18632/oncotarget.23097

Abstract

Reprogramming of mitochondrial functions sustains tumor growth and may provide therapeutic opportunities. Here, we targeted the protein folding environment in mitochondria by coupling a purine-based inhibitor of the molecular chaperone Heat Shock Protein-90 (Hsp90), PU-H71 to the mitochondrial-targeting moiety, triphenylphosphonium (TPP). Binding of PU-H71-TPP to ADP-Hsp90, Hsp90 co-chaperone complex or mitochondrial Hsp90 homolog, TRAP1 involved hydrogen bonds, π-π stacking, cation-π contacts and hydrophobic interactions with the surrounding amino acids in the active site. PU-H71-TPP selectively accumulated in mitochondria of tumor cells (17-fold increase in mitochondria/cytosol ratio), whereas unmodified PU-H71 showed minimal mitochondrial localization. Treatment of tumor cells with PU-H71-TPP dissipated mitochondrial membrane potential, inhibited oxidative phosphorylation in sensitive cell types, and reduced ATP production, resulting in apoptosis and tumor cell killing. Unmodified PU-H71 had no effect. Bioinformatics analysis identified a "mitochondrial Hsp90" signature in Acute Myeloid Leukemia (AML), which correlates with worse disease outcome. Accordingly, inhibition of mitochondrial Hsp90s killed primary and cultured AML cells, with minimal effects on normal peripheral blood mononuclear cells. These data demonstrate that directing Hsp90 inhibitors with different chemical scaffolds to mitochondria is feasible and confers improved anticancer activity. A potential "addiction" to mitochondrial Hsp90s may provide a new therapeutic target in AML.

Keywords: Hsp90; acute myeloid leukemia; chaperone; metabolism; mitochondria

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest with the contents of this article.

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