Bortezomib-mediated inhibition of steroid receptor coactivator-3 degradation leads to activated Akt.

Abstract

PURPOSE:

To assess the safety of administering bortezomib to patients undergoing a radical prostatectomy, to assess pathologic changes induced by bortezomib in prostate cancer specimen, and to verify alterations by the drug in proteasome protein targets.

EXPERIMENTAL DESIGN:

Bortezomib is a proteasome inhibitor that has shown activity in vitro and in vivo in prostate cancer. We performed a neoadjuvant clinical trial of bortezomib in men with prostate cancer at high risk of recurrence. The primary endpoints were to evaluate safety and biological activity.

RESULTS:

Bortezomib is generally safe in the preoperative setting. Antitumor activity was manifested by tumor cytopathic effect, drops in serum prostate-specific antigen in some patients, and increases in tumor apoptosis. This was associated with cytoplasmic entrapment of nuclear factor-kappaB. We found an unexpected increase in proliferation in treated tissues and in vitro. Bortezomib also increased SRC-3 levels and phosphorylated Akt, both in vitro and in treated prostate cancer tissues. Knockdown of SRC-3 blocked the increase in activated Akt in vitro. Combined treatment with bortezomib and the Akt inhibitor perifosine was more effective than either agent alone in vitro.

CONCLUSION:

These data suggest that combined therapies targeting the proteasome and the Akt pathway may have increased efficacy.

• Authors: Gustavo Ayala, Jun Yan, Rile Li, Yi Ding, Timothy C Thompson, Martha P Mims, Teresa G Hayes, Vivian MacDonnell, R Garret Lynch, Anna Frolov, Brian J Miles, Thomas M Wheeler, J Wade Harper, Ming-Jer Tsai, Michael M Ittmann, Dov Kadmon
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 22 Pg. 7511-8 (Nov 15 2008) ISSN: 1078-0432 [Print] United States
• PMID: 19010869 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Boronic Acids
• NF-kappa B
• Pyrazines
• Trans-Activators
• Phosphorylcholine
• perifosine
• Bortezomib
• Histone Acetyltransferases
• NCOA3 protein, human
• Nuclear Receptor Coactivator 3
• Proto-Oncogene Proteins c-akt
• Prostate-Specific Antigen

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Boronic Acids (therapeutic use)
• Bortezomib
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Enzyme Activation (drug effects)
• Flow Cytometry
• Histone Acetyltransferases (drug effects, metabolism)
• Humans
• Immunohistochemistry
• Male
• Middle Aged
• NF-kappa B (drug effects)
• Neoadjuvant Therapy
• Nuclear Receptor Coactivator 3
• Phosphorylcholine (administration & dosage, analogs & derivatives)
• Prostate-Specific Antigen (blood, drug effects)
• Prostatectomy
• Prostatic Neoplasms (drug therapy, surgery)
• Proto-Oncogene Proteins c-akt (drug effects, metabolism)
• Pyrazines (therapeutic use)
• RNA Interference
• Trans-Activators (drug effects, metabolism)