Antiangiogenic therapy with Nintedanib affects hypoxia, angiogenesis and apoptosis in the ventral prostate of TRAMP animals
The antiangiogenic therapy for prostate cancer with Nintedanib, a potent inhibitor of important growth factor receptors, has been proven to delay tumor progression and arrest tumor growth; thus, the aim herein is to evaluate Nintedanib effects on tumor cells, besides angiogenesis and apoptosis processes, metalloproteinases and hypoxia factor in an animal model. Nintedanib promoted growth inhibition and cell death in a dose-dependent manner, showing no tumor selectivity. Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) were treated with Nintedanib (10 mg/kg/day) in different stages of tumor development and the ventral prostate was examined for protein levels by means of immunohistochemistry and Western blotting and apoptosis evaluation. In vitro antiproliferative activity of Nintedanib was also assessed in nine human tumor cell lines. Early Nintedanib treatment has shown decreased levels of FGF-2, VEGFR-1, MMP-9 and HIF-1α and a significantly increased apoptosis of epithelial cells. Furthermore, late Nintedanib treatment decreased FGF-2, VEGFR-1 and FGFR-3 levels. Importantly, even after treatment discontinuation, treated animals displayed a significant decrease in VEGFR-1 as well as MMP-9. Although Nintedanib treatment in late stages of tumor growth has shown some good results, it is noteworthy that the drug presents the best tissue response when administered in the early stages of disease development. Nintedanib treatment has shown to be a promising approach for prostate cancer therapy, especially in the early stages of the disease, interfering in different carcinogenesis progression pathways.
KeywordsAngiogenesis Prostate cancer Growth factors Tumor cells Nintedanib
Study design, collection, analyses and interpretation of data and writing of manuscript: Raquel Frenedoso da Silva and Valéria Helena Alves Cagnon. Collection and analyses of data: Thais Petrochelli Banzato and Letícia Ferreira Alves. Analyses and interpretation of data: Rajesh Agarwal and João Ernesto Carvalho.
This work was supported by a grant from the São Paulo Research Foundation (FAPESP 2013/26677-7) and in part by the NCI R01 grant CA195708 (to RA).
Compliance with ethical standards
Conflict of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
The Ethics Committee on Animal Use (CEUA-UNICAMP) approved this study under protocol number 3285-1, carried out in agreement with the Ethical Principles for Animal Research established by the Brazilian College for Animal Experimentation (COBEA).
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