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

Abstract

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.

• Authors: Andrew J Massey, Douglas S Williamson, Helen Browne, James B Murray, Pawel Dokurno, Terry Shaw, Alba T Macias, Zoe Daniels, Stephanie Geoffroy, Melanie Dopson, Paul Lavan, Natalia Matassova, Geraint L Francis, Christopher J Graham, Rachel Parsons, Yikang Wang, Antony Padfield, Mike Comer, Martin J Drysdale, Mike Wood
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 66 Issue 3 Pg. 535-45 (Aug 2010) ISSN: 1432-0843 [Electronic] Germany
• PMID: 20012863 (Publication Type: Journal Article)

Chemical References

• HSC70 Heat-Shock Proteins
• HSP70 Heat-Shock Proteins
• HSP90 Heat-Shock Proteins
• Purine Nucleosides
• VER 155008
• Caspase 3
• Caspase 7

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, pathology)
• Caspase 3 (metabolism)
• Caspase 7 (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Colonic Neoplasms (drug therapy, pathology)
• Drug Delivery Systems
• Drug Synergism
• Female
• HSC70 Heat-Shock Proteins (antagonists & inhibitors)
• HSP70 Heat-Shock Proteins (antagonists & inhibitors)
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Humans
• Purine Nucleosides (pharmacokinetics, pharmacology)