Antiangiogenic therapy with Nintedanib affects hypoxia, angiogenesis and apoptosis in the ventral prostate of TRAMP animals

Author(s)

da Silva, Raquel Frenedoso ^{[1, 2]} ; Banzato, Thais Petrochelli ^[3] ; Alves, Leticia Ferreira ^[1] ; Carvalho, Joao Ernesto ^{[3, 4]} ; Agarwal, Rajesh ^[2] ; Cagnon, Valeria Helena Alves ^[1]

Affiliation

^[1] State Univ Campinas UNICAMP, Inst Biol, Dept Struct & Funct Biol, POB 6109, BR-13083865 Sao Paulo - Brazil

^[2] Univ Colorado, Skaggs Sch Pharm, Dept Pharmaceut Sci, Anschutz Med Campus, Aurora, CO - USA

^[3] State Univ Campinas UNICAMP, Chem Biol & Agr Pluridisciplinary Res Ctr, Sao Paulo - Brazil

^[4] State Univ Campinas UNICAMP, Fac Pharmaceut Sci, Sao Paulo - Brazil

• Document type: Journal article
• Source: Cell and Tissue Research; v. 379, n. 2, p. 407-420, FEB 2020.
• Web of Science Citations: 0

Abstract

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-1 alpha 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. (AU)

• FAPESP's process: 13/26677-7 - Prostate tissue response after treatment with Nintedanibe in transgenic mice for adenocarcinoma (TRAMP) at different stages of tumor development
• Grantee: Raquel Frenedoso da Silva
• Support Opportunities: Scholarships in Brazil - Doctorate