A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells

Purpose: The anti-apoptotic function of the 70 kDa family of heat shock proteins and their role in Cancer is well documented. Dual targeting of Hsc70 and HSP70 with siRNA induces proteasome-dependent degradation of HSP90 client proteins and extensive tumor specific Apoptosis as well as the potentiation of tumor cell Apoptosis following pharmacological HSP90 inhibition.

Methods: We have previously described the discovery and synthesis of novel adenosine-derived inhibitors of the 70 kDa family of heat shock proteins; the first inhibitors described to target the ATPase binding domain. The in vitro activity of VER-155008 was evaluated in HCT116, HT29, BT474 and MDA-MB-468 carcinoma cell lines. Cell proliferation, cell Apoptosis and Caspase 3/7 activity was determined for VER-155008 in the absence or presence of small molecule HSP90 inhibitors.

Results: VER-155008 inhibited the proliferation of human breast and colon Cancer cell lines with GI(50)s in the range 5.3-14.4 microM, and induced HSP90 client protein degradation in both HCT116 and BT474 cells. As a single agent, VER-155008 induced Caspase-3/7 dependent Apoptosis in BT474 cells and non-caspase dependent cell death in HCT116 cells. VER-155008 potentiated the apoptotic potential of a small molecule HSP90 Inhibitor in HCT116 but not HT29 or MDA-MB-468 cells. In vivo, VER-155008 demonstrated rapid metabolism and clearance, along with tumor levels below the predicted pharmacologically active level.

Conclusion: These data suggest that small molecule inhibitors of Hsc70/HSP70 phenotypically mimic the cellular mode of action of a small molecule HSP90 Inhibitor and can potentiate the apoptotic potential of a small molecule HSP90 Inhibitor in certain cell lines. The factors determining whether or not cells apoptose in response to HSP90 inhibition or the combination of HSP90 plus Hsc70/HSP70 inhibition remain to be determined.