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Antiangiogenic activity of the penicillin derivative TAP7f in melanoma

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Abstract

Previously , we demonstrated that the non-antibiotic penicillin derivative TAP7f inhibited melanoma metastasis in vitro and in vivo through the downregulation of β-catenin and integrin αVβ3. As angiogenesis is required for tumor growth and metastasis, we decided to explore the possible antiangiogenic effect of TAP7f. We found that TAP7f inhibited proliferation, migration, tube formation, and actin cytoskeleton organization of human endothelial cells. In a gel plug assay, an in vivo model for angiogenesis, TAP7f also blocked vascular formation induced by fibroblast growth factor 2. Furthermore, when murine B16-F10 melanoma cells pre-treated with TAP7f were injected intradermally in mice, we observed a decrease in the number and thickness of the capillaries surrounding the tumor. Additionally, TAP7f downregulated vascular endothelial growth factor (VEGF) and platelet-derived growth factor-B (PDGF-B) expression in B16-F10 cells and VEGF receptor expression in HMEC-1 endothelial cells. When the antitumor effect of TAP7f was studied in C57BL/6 J mice challenged with B16-F10 melanoma cells, a significant reduction of tumor growth was observed. Furthermore, a decreased expression of VEGF, PDGF-B, and the endothelial cell marker CD34 was observed in tumors from TAP7f-treated mice. Together, our results suggest that the antiangiogenic activity of TAP7f contributes to its antitumor and antimetastatic action and positions this penicillin derivative as an alternative or complementary agent for the treatment of melanoma.

Key messages

• TAP7f inhibits proliferation, migration, tube formation, and actin cytoskeleton organization of endothelial cells.

• TAP7f downregulates VEGF receptor expression in endothelial cells.

• TAP7f downregulates VEGF and PDGF expression in melanoma cells.

• TAP7f inhibits angiogenesis in vivo.

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Data availability

All data supporting the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We are thankful to Dr. Magali Cercato for her help with the histological processing of tissues and Marianela Vence for her help with in vivo assays.

Funding

This work was supported by grants from the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET, PIP 0154: “Propiedades y mecanismo de acción de nuevos agentes antitumorales: péptidos quiméricos del IFN alfa, ftalocianinas de Zn(II) y derivados sintéticos de penicilinas”; PUE-2016: “Contribución al proceso de desarrollo del medicamento. Anti-infecciosos y anti-cancerígenos”), Universidad de Buenos Aires (Programación Científica 2018–2020, UBACYT 20020170100041BA: “Mecanismos de acción in vitro e in vivo de novedosos agentes antitumorales. Implementación de estrategias terapéuticas innovadoras”), and Agencia Nacional de Promoción Científca y Tecnológica (ANPCyT, PICT 2017–1278: “Mecanismo de acción antitumoral de péptidos quiméricos del IFN-α2b y compuestos peptidomiméticos. Efecto del tratamiento combinado con hipertermia magnética”; PICT 2017–2694: “Diseño de nuevas metodologías para la generación de scaffolds cíclicos y heterocíclicos sintética y biológicamente atractivos. Los productos naturales como fuente de inspiración”), Argentina.

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Authors and Affiliations

  1. Laboratorio de Oncología y Transducción de Señales, Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, CONICET, Buenos Aires, Argentina

    Elizabeth Barrionuevo, Leonor P. Roguin & Viviana C. Blank

  2. Facultad de Ciencias Bioquímicas y Farmacéuticas, Instituto de Química Rosario (CONICET-UNR), Universidad Nacional de Rosario, Rosario, Argentina

    Patricia G. Cornier, Carina M. L. Delpiccolo & Ernesto G. Mata

  3. Buenos Aires, 956, C1113AAD, Argentina

    Viviana C. Blank

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Contributions

EB, LPR, and VCB hypothesized, designed the research plan, and performed in vivo experiments. EB performed the required in vitro experiments. PGC, CMLD, and EGM synthesized and purified the TAP7f. EB, LPR, and VCB analyzed the data. VCB compiled the data and wrote the first draft of the manuscript. All authors revised and approved the final manuscript before submission.

Corresponding author

Correspondence to Viviana C. Blank.

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Ethics approval

The in vivo experiments were carried out in accordance with the principles of the Basel Declaration and recommendations of the National Institute of Health (NIH) Guide for the Care and the Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committee (CICUAL) of the School of Pharmacy and Biochemistry, University of Buenos Aires (14–1-2019/ Res No. 217/19).

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Barrionuevo, E., Cornier, P.G., Delpiccolo, C.M.L. et al. Antiangiogenic activity of the penicillin derivative TAP7f in melanoma. J Mol Med 101, 249–263 (2023). https://doi.org/10.1007/s00109-023-02287-7

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