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

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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-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.

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Acknowledgments

Not applicable.

Funding

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).

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Authors and Affiliations

  1. Department of Structural and Functional Biology, Institute of Biology, State University of Campinas (UNICAMP), P.O. Box 6109, Campinas, São Paulo, 13083-865, Brazil

    Raquel Frenedoso da Silva, Letícia Ferreira Alves & Valéria Helena Alves Cagnon

  2. Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Raquel Frenedoso da Silva & Rajesh Agarwal

  3. Chemical, Biological and Agricultural Pluridisciplinary Research Center, State University of Campinas (UNICAMP), São Paulo, Brazil

    Thais Petrochelli Banzato & João Ernesto Carvalho

  4. Faculty of Pharmaceutical Sciences, State University of Campinas (UNICAMP), São Paulo, Brazil

    João Ernesto Carvalho

Authors
  1. Raquel Frenedoso da Silva
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  2. Thais Petrochelli Banzato
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  3. Letícia Ferreira Alves
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  4. João Ernesto Carvalho
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  5. Rajesh Agarwal
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  6. Valéria Helena Alves Cagnon
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Contributions

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.

Corresponding author

Correspondence to Valéria Helena Alves Cagnon.

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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.

Ethical approval

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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Fig. S1

Experimental design: Animals received treatment from 8 to 12 weeks of age and were euthanized at the end of the treatment (TC12 and TN12, respectively) or at 22 weeks of age (TC22(8–12) and TN22(8–12), respectively). Furthermore, groups receiving treatment from 12 to 16 weeks of age were euthanized either at the end of the treatment (TC16 and TN16, respectively) or at 22 weeks of age (TC22(12–16) and TN22(12–16), respectively). Nintedanib was administered in a dose of 10 mg/kg/day, orally. (JPG 2721 kb)

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da Silva, R.F., Banzato, T.P., Alves, L.F. et al. Antiangiogenic therapy with Nintedanib affects hypoxia, angiogenesis and apoptosis in the ventral prostate of TRAMP animals. Cell Tissue Res 379, 407–420 (2020). https://doi.org/10.1007/s00441-019-03091-x

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  • DOI: https://doi.org/10.1007/s00441-019-03091-x

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