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Budina-Kolomets A , Balaburski GM , Bondar A , Beeharry N , Yen T , Murphy ME
Comparison of the activity of three different HSP70 inhibitors on apoptosis, cell cycle arrest, autophagy inhibition, and HSP90 inhibition
Cancer Biol Ther. 2014 Feb;15(2) :194-9
PMID: 24100579    PMCID: PMC3928135    URL: https://www.ncbi.nlm.nih.gov/pubmed/24100579
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The chaperone HSP70 promotes the survival of cells exposed to many different types of stresses, and is also potently anti-apoptotic. The major stress-induced form of this protein, HSP70-1, is overexpressed in a number of human cancers, yet is negligibly expressed in normal cells. Silencing of the gene encoding HSP70-1 (HSPA1A) is cytotoxic to transformed but not normal cells. Therefore, HSP70 is considered to be a promising cancer drug target, and there has been active interest in the identification and characterization of HSP70 inhibitors for cancer therapy. Because HSP70 behaves in a relatively non-specific manner in the control of protein folding, to date there are no reliably-identified "clients" of this protein, nor is there consensus as to what the phenotypic effects of HSP70 inhibitors are on a cancer cell. Here for the first time we compare three recently-identified HSP70 inhibitors, PES-Cl, MKT-077, and Ver-155008, for their ability to impact some of the known and reported functions of this chaperone; specifically, the ability to inhibit autophagy, to influence the level of HSP90 client proteins, to induce cell cycle arrest, and to inhibit the enzymatic activity of the anaphase-promoting complex/cyclosome (APC/C). We report that all three of these compounds can inhibit autophagy and cause reduced levels of HSP90 client proteins; however, only PES-Cl can inhibit the APC/C and induce G 2/M arrest. Possible reasons for these differences, and the implications for the further development of these prototype compounds as anti-cancer agents, are discussed.
Budina-Kolomets, Anna Balaburski, Gregor M Bondar, Anastasia Beeharry, Neil Yen, Tim Murphy, Maureen E eng P01 CA114046/CA/NCI NIH HHS/ P30 CA010815/CA/NCI NIH HHS/ R01 CA139319/CA/NCI NIH HHS/ Comparative Study Research Support, N.I.H., Extramural Cancer Biol Ther. 2014 Feb;15(2):194-9. doi: 10.4161/cbt.26720. Epub 2013 Nov 1.