Geldanamycin-induced cytotoxicity in human colon-cancer cell lines: evidence against the involvement of c-Src or DT-diaphorase

Cancer Chemotherapy and Pharmacology
V G BruntonP Workman

Abstract

We investigated two of the major proposed modes of action of the benzoquinoid ansamycin geldanamycin using a pair of human colon-carcinoma cell lines, BE and HT29. One potential mechanism of action in colorectal cancer is the inhibition of c-Src kinase activity, since this proto-oncogene is hyperexpressed in human large-bowel tumours. Our results show that despite the 9-fold higher level of c-Src kinase activity found in HT29 cells, there was only a 1.4-fold difference in cytotoxicity as compared with BE cells, the latter being the most sensitive. Moreover, even at concentrations of geldanamycin that resulted in cell kill of 80% or more after a 24-h period of exposure, there was no effect on c-Src kinase activity in HT29 cells, although c-Src protein was depleted at supralethal levels of exposure. We also investigated the metabolism of the quinone moiety of geldanamycin by DT-diaphorase, an enzyme that activates certain quinone antibiotics such as mitomycin C and is hyperexpressed in colorectal cancer cells. Geldanamycin was shown to be a substrate for DT-diaphorase present in HT29 cells. However, the lack of a major differential in cytotoxicity between HT29 and BE cells indicates that this is unlikely to be pharmacologically s...Continue Reading

Citations

Mar 17, 2004·Biochimica Et Biophysica Acta·Amere Subbarao SreedharPéter Csermely
Mar 20, 2004·Pharmacology & Therapeutics·Amere Subbarao Sreedhar, Peter Csermely
Jul 28, 2006·Cold Spring Harbor Symposia on Quantitative Biology·P Workman
Jan 5, 2002·Expert Opinion on Biological Therapy·Alison Maloney, Paul Workman
Mar 10, 2010·Free Radical Biology & Medicine·Yuval SamuniJames B Mitchell
Sep 20, 2005·British Journal of Pharmacology·Csaba SõtiPéter Ferdinandy
Feb 8, 2006·Analytical Biochemistry·R HowesM J Drysdale

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