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Research article - Peer-reviewed, 2019

Evaluation of Angiogenesis Process after Metformin and LY294002 Treatment in Mammary Tumor

Moschetta, Marina G.; Leonel, Camila; Maschio-Signorini, Larissa B.; Borin, Thaiz F.; Gelaleti, Gabriela B.; Jardim-Perassi, Bruna V.; Ferreira, Livia C.; Sonehara, Nathalia M.; Carvalho, Livia G. S.; Hellmen, Eva; de Campos Zuccari, Debora A. P.


Background: The angiogenesis process is regulated by many factors, such as Hypoxia-Inducible Factor-1 (HIF-1) and Vascular Endothelial Growth Factor (VEGF). Metformin has demonstrated its ability to inhibit cell growth and the LY294002 is the major inhibitor of PI3K/AKT/mTOR pathway that has antiangiogenic properties.Methods: Canine mammary tumor cell lines CMT-U229 and CF41 were treated with metformin and LY294002. Cell viability, protein and gene expression of VEGF and HIF-1 were determined in vitro. For the in vivo study, CF41 cells were inoculated in female athymic nude mice treated with either metformin or LY294002. The microvessel density by immunohistochemistry for CD31 as well as the gene and protein expression of HIF-1 and VEGF were evaluated.Results: The treatment with metformin and LY294002 was able to reduce the cellular viability after 24 hours. The protein and gene expression of HIF-1 and VEGF decreased after treatment with metformin and LY294002. In the in vivo study, there was a decrease in tumor size, protein and gene expression of HIF-1 and VEGFA, in addition to the decreasing of CD31 expression after all treatments.Conclusion: Our results demonstrate the effectiveness of metformin and LY294002 in controlling the angiogenesis process in mammary tumors by VEGF and HIF-1, the most important angiogenic markers.


Angiogenesis; canine mammary tumors; hypoxia; hypoxia-inducible factor-1 alpha; mammary tumors; metformin; vascular endothelial growth factor

Published in

Anti-Cancer Agents in Medicinal Chemistry
2019, volume: 19, number: 5, pages: 655-666

Authors' information

Moschetta, Marina G.
Universidade de Sao Paulo
Leonel, Camila
Universidade de Sao Paulo
Maschio-Signorini, Larissa B.
Universidade de Sao Paulo
Borin, Thaiz F.
Augusta University
Gelaleti, Gabriela B.
Universidade de Sao Paulo
Jardim-Perassi, Bruna V.
H Lee Moffitt Cancer Center and Research Institute
Ferreira, Livia C.
Universidade de Sao Paulo
Sonehara, Nathalia M.
Universidade de Sao Paulo
Carvalho, Livia G. S.
Universidade de Sao Paulo
Swedish University of Agricultural Sciences, Department of Anatomy, Physiology and Biochemistry (AFB)
de Campos Zuccari, Debora A. P.
Universidade de Sao Paulo

Sustainable Development Goals

SDG3 Good health and well-being

UKÄ Subject classification

Medicinal Chemistry

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