Inducing Cell Death In MCF-7 Cells With Hsp-70 Inhibitors And Geldanamycin
White, Nicholas A.
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Heat shock proteins (HSPs) are a class of chaperones that assist other proteins in assuming their proper three-dimensional shape and, therefore, function. Currently, a lot of research is being directed toward Hsp90 and the inhibitor geldanamycin (GA), which is undergoing clinical trials as an anti-tumor agent (1-3). However, the chaperone Hsp70 has received much less attention. Thus, we tested two promising Hsp70 inhibitors in a cellular model, utilizing MCF-7 cells derived from a breast cancer tumor and combination drug treatments containing GA. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) assays revealed that the small compound SW25 had the most synergistic activity with GA, increasing cytotoxicity by as much as 15% for some concentrations of GA. To determine whether an interaction with Akt/PKB could be involved in the mechanism of action for SW25, given that both Hsp90 and Hsp70 are involved in the Akt/PKB pathway, a Western blot was performed with a-Aktl antibodies (2, 4-7). Treating with SW25 and GA decreased levels of Aktl as compared to treating with GA alone. Thus, it appears that SW25 may help induce apoptosis in MCF-7 cells by increasing interference with Aktl. These exciting preliminary experiments suggest that it may be possible to use combination treatments involving Hsp70 and Hsp90 inhibitors to more effectively combat cancerous tumors. Further research in this area may lead to more effective anti-tumor treatments and a greater understanding of the role Hsp70 plays in the Akt pathway.