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Targeting Mitochondrial Molecular Chaperones as a Potential Therapeutic Target in Leukemia Kelly G. Bryant and Dario C. Altieri Prostate Cancer Discovery and Development Program and Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia PA 19104
Author(s) -
Bryant Kelly G.,
Altieri Dario C.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.942.14
Subject(s) - myeloid leukemia , hsp90 , mitochondrion , cancer research , leukemia , tumor microenvironment , biology , heat shock protein , cancer cell , cell culture , programmed cell death , hsp90 inhibitor , microbiology and biotechnology , apoptosis , cancer , biochemistry , immunology , genetics , tumor cells , gene
Molecular chaperones of the Heat Shock Protein‐90 (HSP90) family play an important role in proper protein folding, protein complex formation, as well as minimizing aggregate formation. The discovery of HSP90 and its ortholog, tumor necrosis factor receptor‐associated protein‐1 (TRAP‐1) abundantly localized to the mitochondria of tumor, but not the majority of normal cells has broadened the field to include a role in cancer progression, and importantly, a therapeutic candidate in many solid tumors. We sought to determine whether targeting the mitochondrial HSP90s with small molecule inhibitors would be effective in leukemia. Fractionation studies of several different types of leukemia cell lines show both TRAP‐1 and HSP90 proteins in the mitochondria, thus providing a target for the mitochondrial targeted HSP90 inhibitor Gamitrinib (GA‐mitochondrial matrix inhibitors). Accordingly, a variety of different leukemia cell lines were treated with Gamitrinib and for each line tested, we found growth inhibition in a dose and cell‐dependent manner. Treatment also induced cell death, PARP cleavage, and caspase activation at lower doses than is required for solid tumors. Treatment with low doses of Gamitrinib did not affect protein levels of the mitochondrial electron transport chains I through V. Additionally there were not significant differences in the levels of lactate produced by these cells, and only a slight decrease in glucose consumption. Metabolic studies also show that treatment leads to a decrease in ATP levels in the leukemia cell lines, as well as a decrease in the oxygen consumption rates of these cells. Utilizing several primary Acute Myeloid Leukemia Patient derived samples, Gamitrinib treatment resulted in a dose‐dependent decrease in viability and increase in apoptosis as determined by FACS analysis for Annexin V/Propidium Iodide, as well as protein markers of cell death. Current ongoing experiments are focused on determining the efficacy of this inhibitor in vivo by utilizing whole body luciferase imaging in MV‐411 GFP/Luciferase xenografts. Taken together, Gamitrinib results in robust cell death in all of the leukemia cells tested, and these studies provide ample evidence that Gamitrinib could be a strong clinical candidate as an alternative HSP90 inhibitor for the treatment of different types of leukemia. Support or Funding Information Wistar Institute T32 Training Grant