R115777 (Zarnestra®)/zoledronic acid (Zometa®) cooperation on inhibition of prostate cancer proliferation is paralleled by Erk/Akt inactivation and reduced Bcl-2 and bad phosphorylation

Michele Caraglia, Monica Marra, Carlo Leonetti, Giuseppina Meo, Anna Maria D'Alessandro, Alfonso Baldi, Daniele Santini, Giuseppe Tonini, Raffaello Bertieri, Gabriella Zupi, Alfredo Budillon, Alberto Abbruzzese

Research output: Contribution to journalArticle

Abstract

Zoledronic acid (ZOL) has proved activity in bone metastases from prostate cancer through inhibition of mevalonate pathway and of prenylation of intracellular proteins. We have reported that ZOL synergizes with R115777 farnesyltransferase inhibitor (FTI, Zarnestra) in inducing apoptosis and growth inhibition on epidermoid cancer cells. Here, we have studied the effects of the combination of these agents in prostate adenocarcinoma models and, specifically, on androgen-independent (PC3 and DU145) and -dependent (LNCaP) prostate cancer cell lines. We have found that ZOL and R115777 were synergistic in inducing both growth inhibition and apoptosis in prostate adenocarcinoma cells. These effects were paralleled by disruption of Ras→Erk and Akt survival pathways, consequent decreased phosphorylation of both mitochondrial bcl-2 and bad proteins, and caspase activation, Finally, ZOL/R115777 combination induced cooperative effects also in vivo on tumor growth inhibition of prostate cancer xenografts in nude mice with a significant survival increase. These effects were paralleled by enhanced apoptosis and inactivation of both Erk and Akt. In conclusions, the combination between ZOL and FTI leads to enhanced anti-tumor activity in human prostate adenocarcinoma cells likely through a more efficacious inhibition of ras-dependent survival pathways and consequent bcl-related proteins-dependent apoptosis.

Original languageEnglish
Pages (from-to)533-543
Number of pages11
JournalJournal of Cellular Physiology
Volume211
Issue number2
DOIs
Publication statusPublished - May 2007

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Fingerprint Dive into the research topics of 'R115777 (Zarnestra®)/zoledronic acid (Zometa®) cooperation on inhibition of prostate cancer proliferation is paralleled by Erk/Akt inactivation and reduced Bcl-2 and bad phosphorylation'. Together they form a unique fingerprint.

  • Cite this