Tools
Tools
McNamara, Anne V, Barclay, Monica, Watson, Alastair J M 
ORCID: https://orcid.org/0000-0003-3326-0426 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
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,sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being |
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School |
| UEA Research Groups: | Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology |
| Depositing User: | Pure Connector |
| Date Deposited: | 07 Jul 2014 13:44 |
| Last Modified: | 21 Aug 2023 00:25 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/48955 |
| DOI: | 10.1016/j.bcp.2011.11.017 |
Actions (login required)
 |
View Item |