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01.08.2010 | Original Article

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

verfasst von: 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

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 3/2010

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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 GI₅₀s in the range 5.3–14.4 μM, 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.

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Titel: A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells
verfasst von: 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
Publikationsdatum: 01.08.2010
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 3/2010
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-009-1194-3

Springer Medizin

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