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


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

SUBMITTER: Ayala G 

PROVIDER: S-EPMC2820291 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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

Ayala Gustavo G   Yan Jun J   Li Rile R   Ding Yi Y   Thompson Timothy C TC   Mims Martha P MP   Hayes Teresa G TG   MacDonnell Vivian V   Lynch R Garret RG   Frolov Anna A   Miles Brian J BJ   Wheeler Thomas M TM   Harper J Wade JW   Tsai Ming-Jer MJ   Ittmann Michael M MM   Kadmon Dov D  

Clinical cancer research : an official journal of the American Association for Cancer Research 20081101 22


<h4>Purpose</h4>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.<h4>Experimental design</h4>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 recurrenc  ...[more]

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