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

Anne V McNamara, Monica Barclay, Alastair J M Watson, John R Jenkins

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8 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)355-367
Number of pages13
JournalBiochemical Pharmacology
Issue number3
Publication statusPublished - 1 Feb 2012


  • 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

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