Hsp90 inhibitors sensitise human colon cancer cells to topoisomerase I poisons by depletion of key anti-apoptotic and cell cycle checkpoint proteins

McNamara, Anne V, Barclay, Monica, Watson, Alastair J M and Jenkins, John R (2012) Hsp90 inhibitors sensitise human colon cancer cells to topoisomerase I poisons by depletion of key anti-apoptotic and cell cycle checkpoint proteins. Biochemical Pharmacology, 83 (3). pp. 355-367. ISSN 0006-2952

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Abstract

Hsp90 and topoisomerase I are both targets for chemotherapeutic agents. Topoisomerase I poisons are standard clinical treatments, whilst Hsp90 inhibitors are progressing through clinical trials. We have demonstrated that when an Hsp90 inhibitor and topoisomerase I poison are combined they produce a synergistic increase in apoptosis in both p53⁺/⁺ and p53⁻/⁻ HCT116 human colon cancer cells. Lack of p53 is associated with an increase in sensitivity to the combination treatment; p53⁺/⁺ cells treated with the topoisomerase I poison topotecan (TPT) arrest at G2, whereas in p53⁻/⁻ cells the additional presence of the Hsp90 inhibitor geldanamycin (GA) selectively abrogates the G2M checkpoint. More importantly we report that there is a common underlying p53-independent mechanism behind the observed synergistic combined drug effect. We show that concurrent treatment with GA and TPT is able to reverse TPT induced up-regulation of the anti-apoptotic protein Bcl2 in both p53⁺/⁺ and p53⁻/⁻ HCT116 cells. The data suggests that inhibition of Hsp90 mediates down-regulation of Bcl2 following the combination treatment and cause a synergistic increase in apoptosis in both p53⁺/⁺ and p53⁻/⁻ HCT116 cells; p53⁻/⁻ HCT116 cells are more sensitive to the treatment because they also fail to arrest at G2 in the cell cycle.

Item Type: Article
Additional Information: Copyright © 2011 Elsevier Inc. All rights reserved.
Uncontrolled Keywords: apoptosis regulatory proteins,benzoquinones,cell cycle checkpoints,cell cycle proteins,colonic neoplasms,dna topoisomerases, type i,drug therapy, combination,hct116 cells,hsp90 heat-shock proteins,humans,lactams, macrocyclic,topoisomerase i inhibitors
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
University of East Anglia > Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology
Depositing User: Pure Connector
Date Deposited: 07 Jul 2014 14:44
Last Modified: 25 Jul 2018 09:45
URI: https://ueaeprints.uea.ac.uk/id/eprint/48955
DOI: 10.1016/j.bcp.2011.11.017

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