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

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.

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