title: Hsp90 inhibitors sensitise human colon cancer cells to topoisomerase I poisons by depletion of key anti-apoptotic and cell cycle checkpoint proteins.
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.
authors.affiliation: The University of Liverpool, Institute of Translational Medicine, Department of Gastroenterology, The Henry Wellcome Laboratory, Crown Street, Liverpool L69 3GE, UK.
authors.forename: Anne V
authors.initials: AV
authors.lastname: McNamara
authors.forename: Monica
authors.initials: M
authors.lastname: Barclay
authors.forename: Alastair J M
authors.initials: AJ
authors.lastname: Watson
authors.forename: John R
authors.initials: JR
authors.lastname: Jenkins
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D016227:Benzoquinones / Q000008:administration & dosage; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004359:Drug Therapy, Combination; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage
chemical_list: D051017:Apoptosis Regulatory Proteins; D016227:Benzoquinones; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D059004:Topoisomerase I Inhibitors; C112765:tanespimycin; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human