Efficacy of the novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 in a preclinical model of adrenocortical carcinoma.

Abstract

Adrenocortical cancer is a rare malignancy for which current pharmacological therapies are still insufficient. We tested the effect of a novel PI3 kinase - mammalian target of rapamycin dual inhibitor (NVP-BEZ235) on proliferation of the H295R adrenocortical cancer cell line in vitro and grown as xenografts in immunodeficient mice. NVP-BEZ235 was able to significantly inhibit phosporylation of Akt kinase and S6 ribosomal protein in H295R cells and to significantly reduce their proliferation in vitro and xenograft growth in vivo. The drug also induced activation of Erk phosphorylation, which could be inhibited by simultaneous treatment with the Erk inhibitor FR180204. This latter drug synergized with NVP-BEZ235 in the inhibition of H295R proliferation in vitro. Our data suggest that dual PI3K/mTOR inhibitors may represent a useful pharmacological tool in the therapy of advanced adrenocortical cancer and that simultaneous inhibition of both Erk and PI3K - mTOR pathways may be required to obtain a higher antiproliferative effect in this type of tumor.

• Authors: Mabrouka Doghman, Enzo Lalli
• Journal: Molecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 364 Issue 1-2 Pg. 101-4 (Nov 25 2012) ISSN: 1872-8057 [Electronic] Ireland
• PMID: 22960230 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antibiotics, Antineoplastic
• Antineoplastic Agents
• FR 180204
• Imidazoles
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Pyrazoles
• Pyridazines
• Quinolines
• MTOR protein, human
• Phosphatidylinositol 3-Kinase
• TOR Serine-Threonine Kinases
• Extracellular Signal-Regulated MAP Kinases
• dactolisib
• Sirolimus

Topics

• Adrenal Cortex Neoplasms (drug therapy, metabolism, pathology)
• Adrenocortical Carcinoma (drug therapy, metabolism, pathology)
• Animals
• Antibiotics, Antineoplastic (pharmacology)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Evaluation, Preclinical
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
• Humans
• Imidazoles (pharmacology)
• Mice
• Phosphatidylinositol 3-Kinase (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Pyrazoles (pharmacology)
• Pyridazines (pharmacology)
• Quinolines (pharmacology)
• Signal Transduction (drug effects)
• Sirolimus (pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Treatment Outcome
• Xenograft Model Antitumor Assays