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Cancer Chemotherapy and Pharmacology

Published in:

01-05-2008 | Original Article

IPI-504, a novel and soluble HSP-90 inhibitor, blocks the unfolded protein response in multiple myeloma cells

Authors: Jon Patterson, Vito J. Palombella, Christian Fritz, Emmanuel Normant

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2008

Abstract

Background

Inhibitors of heat shock protein (Hsp) 90 induce apoptosis in multiple myeloma (MM) cells, but the molecular mechanisms underlying this cytotoxic outcome are not clear. Here, we investigate the effect of IPI-504, a novel and highly soluble inhibitor of the Hsp90 ATPase activity, on the unfolded protein response (UPR) in MM cells. The UPR is a stress response pathway triggered by sensors located at the endoplasmic reticulum (ER) membrane whose function is to reduce an excessive accumulation of misfolded protein in the ER. During normal development of B-lymphocytes to antibody-producing plasma cells, a partial UPR has been described, where IREα and ATF-6 are stimulated, whereas the third sensor, PERK, is not induced.

Methods

Levels of the activated forms of the three main UPR sensors ATF-6, XBP-1 and PERK/eIF-2 were monitored in two different MM cells lines and one non-MM cell lines under various experimental conditions including incubation with increasing concentration of IPI-504. Also, MM cells were incubated with IPI-504 and several apoptosis markers were monitored.

Results

We show here that a partial UPR is constitutively activated in plasma cell-derived MM cells and that IPI-504 can potently inhibit this pathway. IPI-504 achieves this by inactivating the transcription factors XBP1 and ATF6. In addition, IPI-504 also blocks the tunicamycin-induced phosphorylation of eIF2 by PERK. Dose-response and time course experiments reveal that IPI-504’s inhibitory effect on the UPR parallels its cytotoxic and pro-apoptotic effects on MM cells.

Conclusion

The results presented here suggest that the IPI-504-induced apoptosis might be, in part, mediated by the inhibition of the partial UPR. Other malignancies that rely on intact and efficient UPR to survive could be considered as new indications for Hsp90 inhibitors.

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Title: IPI-504, a novel and soluble HSP-90 inhibitor, blocks the unfolded protein response in multiple myeloma cells
Authors: Jon Patterson
Vito J. Palombella
Christian Fritz
Emmanuel Normant
Publication date: 01-05-2008
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 6/2008
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-007-0546-0

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Abstract

Background

Methods

Results

Conclusion

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