Sunitinib reduces tumor hypoxia and angiogenesis, and radiosensitizes prostate cancer stem-like cells

INTRODUCTION The need for new treatments for advanced prostate cancer has fostered the experimental use of targeted therapies. Sunitinib is a multi‐tyrosine kinase inhibitor that mainly targets membrane‐bound receptors of cells within the tumor microenvironment, such as endothelial cells and pericyt...

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Bibliographic Details
Published in:The Prostate 2015-08, Vol.75 (11), p.1137-1149
Main Authors: Diaz, Roque, Nguewa, Paul A., Redrado, Miriam, Manrique, Irene, Calvo, Alfonso
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
cancer stem cells
Cell Hypoxia - drug effects
Cell Line, Tumor
Cell Proliferation - drug effects
Humans
hypoxia
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Indoles - pharmacology
Male
Mice
Neoplastic Stem Cells - metabolism
Neoplastic Stem Cells - pathology
Neovascularization, Pathologic - drug therapy
Neovascularization, Pathologic - etiology
Prostate - metabolism
Prostate - pathology
prostate cancer
Prostatic Neoplasms - drug therapy
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
Prostatic Neoplasms - physiopathology
Pyrroles - pharmacology
Sunitinib
Treatment Outcome
Xenograft Model Antitumor Assays
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Summary:INTRODUCTION The need for new treatments for advanced prostate cancer has fostered the experimental use of targeted therapies. Sunitinib is a multi‐tyrosine kinase inhibitor that mainly targets membrane‐bound receptors of cells within the tumor microenvironment, such as endothelial cells and pericytes. However, recent studies suggest a direct effect on tumor cells. In the present study, we have evaluated both direct and indirect effects of Sunitinib in prostate cancer and how this drug regulates hypoxia, using in vitro and in vivo models. METHODS We have used both in vitro (PC‐3, DU145, and LNCaP cells) and in vivo (PC‐3 xenografts) models to study the effect of Sunitinib in prostate cancer. Analysis of hypoxia based on HIF‐1α expression and FMISO uptake was conducted. ALDH activity was used to analyze cancer stem cells (CSC). RESULTS Sunitinib strongly reduced proliferation of PC‐3 and DU‐145 cells in a dose dependent manner, and decreased levels of p‐Akt, p‐Erk1/2, and Id‐1, compared to untreated cells. A 3‐fold reduction in tumor growth was also observed (P 
ISSN:0270-4137
1097-0045
DOI:10.1002/pros.22980