Cytoprotection of human cells from thermal injury by pretreatment with geldanamcyin and derivatives

• Published in: The FASEB journal Vol. 21; no. 6; p. A1346
• Main Authors: Bowman, Phillip D., Schuschereba, Steven T., Walker, Kerfoot P., Bynum, James A.
• Format: Journal Article
• Language: English
• Published: The Federation of American Societies for Experimental Biology 2007
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.21.6.A1346-b

The purpose of this research was to provide a practical means of cytoprotection of human cells by preinducing the heat shock response. Benzoquinoid ansamycin antibiotics are inhibitors of hsp90 ATPase and inducers of heat shock protein70 (hsp70). Here we investigated doses and regimens of geldanamcyin and 17‐allylamino‐17‐demethoxygeldanamycin (17‐AAG) for cytoprotection of human cells against thermal injury. At appropriate doses (0.1–1 μg/ml) and treatment times (6 hours), they provided cytoprotection as effective as pretreatment with a sublethal dose of heat (55°C, 2 s) against a lethal thermal insult (55°C, 7–9 s). Treated cultures recovered and could be passaged to produce new cultures while untreated cells underwent apoptosis. This protection was observed in three different human cell lines: human umbilical vein endothelial cells (HUVEC), retinal pigment epithelium, and HeLa cells, and therefore seems to be a general ability of these compounds. Gene expression analysis with whole genome microarrays of HUVEC indicated limited alterations in gene expression by 17‐AAG, affecting heat shock genes and network analysis gave no indication of induction of cytopathological effects. Genes for hsp27 (5.4), hsp40 (3.7), hsp70 (29.8), hsp90 (3.6), and GRP78 (9.0) were highly upregulated by 17AAG. These compounds may provide a means of utilizing the heat shock response to protect against subsequent injury.