Roque Diaz1, Paul A Nguewa1,2, Miriam Redrado1, Irene Manrique1, Alfonso Calvo1,3. 1. Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. 2. Department of Microbiology and Parasitology, Instituto de Salud Tropical, University of Navarra, Pamplona, Spain. 3. Department of Histology and Pathology, University of Navarra, Pamplona, Spain.
Abstract
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 < 0.001 with respect to controls). Depletion of Hif-1α levels in vitro and a decrease in FMISO uptake in vivo showed that Sunitinib inhibits tumor hypoxia. When combined with radiotherapy, this drug enhanced cell death in vitro and in vivo, and significantly decreased CD-31, PDGFRβ, Hif-1α, Id1, and PCNA protein levels (whereas apoptosis was increased) in tumors as compared to controls or single-therapy treated mice. Moreover, Sunitinib reduced the number of ALDH + cancer stem-like cells and sensitized these cells to radiation-mediated loss of clonogenicity. DISCUSION: Our results support the use of Sunitinib in prostate cancer and shows that both hypoxia and cancer stem cells are involved in the effect elicited by this drug. Combination of Sunitinib with radiotherapy warrants further consideration to reduce prostate cancer burden.
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 < 0.001 with respect to controls). Depletion of Hif-1α levels in vitro and a decrease in FMISO uptake in vivo showed that Sunitinib inhibits tumor hypoxia. When combined with radiotherapy, this drug enhanced cell death in vitro and in vivo, and significantly decreased CD-31, PDGFRβ, Hif-1α, Id1, and PCNA protein levels (whereas apoptosis was increased) in tumors as compared to controls or single-therapy treated mice. Moreover, Sunitinib reduced the number of ALDH + cancer stem-like cells and sensitized these cells to radiation-mediated loss of clonogenicity. DISCUSION: Our results support the use of Sunitinib in prostate cancer and shows that both hypoxia and cancer stem cells are involved in the effect elicited by this drug. Combination of Sunitinib with radiotherapy warrants further consideration to reduce prostate cancer burden.
Authors: Larisa Venkova; Alexander Aliper; Maria Suntsova; Roman Kholodenko; Denis Shepelin; Nicolas Borisov; Galina Malakhova; Raif Vasilov; Sergey Roumiantsev; Alex Zhavoronkov; Anton Buzdin Journal: Oncotarget Date: 2015-09-29
Authors: Laura Guarnaccia; Stefania Elena Navone; Elena Trombetta; Chiara Cordiglieri; Alessandro Cherubini; Francesco Maria Crisà; Paolo Rampini; Monica Miozzo; Laura Fontana; Manuela Caroli; Marco Locatelli; Laura Riboni; Rolando Campanella; Giovanni Marfia Journal: Sci Rep Date: 2018-06-08 Impact factor: 4.379
Authors: Andrés Vacas; Celia Fernández-Rubio; Miriam Algarabel; José Peña-Guerrero; Esther Larrea; Fabio Rocha Formiga; Alfonso T García-Sosa; Paul A Nguewa Journal: Biomolecules Date: 2019-11-11