Coumarin derivative 7-isopentenyloxycoumarin induces in vivo antitumor activity by inhibit angiogenesis via CCL2 chemoki
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ORIGINAL ARTICLE
Coumarin derivative 7-isopentenyloxycoumarin induces in vivo antitumor activity by inhibit angiogenesis via CCL2 chemokine decrease Ryldene Marques Duarte da Cruz 1 & Tatianne Mota Batista 1 & Tatyanna Kelvia Gomes de Sousa 1 & Vivianne Mendes Mangueira 1 & Jephesson Alex Floriano dos Santos 1 & Renata Albuquerque de Abrantes 1 & Rafael Carlos Ferreira 1 & Fagner Carvalho Leite 1 & Monalisa Taveira Brito 1 & Leônia Maria Batista 1,2 & Robson Cavalcante Veras 2 & Giciane Carvalho Vieira 3 & Francisco Jaime Bezerra Mendonca Jr 4 & Rodrigo Santos Aquino de Araújo 4 & Marianna Vieira Sobral 1,2 Received: 10 October 2019 / Accepted: 24 April 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Cancer is one of the most urgent problems in medicine. In recent years, cancer is the second leading cause of death globally. In search for more effective and less toxic treatment against cancer, natural products are used as prototypes in the synthesis of new anticancer drugs. The aim of this study was to investigate the in vivo toxicity and the mechanism of antitumor action of 7isopentenyloxycoumarin (UMB-07), a coumarin derivative with antitumor activity. The toxicity was evaluated in vitro (hemolysis assay), and in vivo (micronucleus and acute toxicity assays). Ehrlich ascites carcinoma model was used to evaluate in vivo antitumor activity of UMB-07 (12.5, 25, or 50 mg/kg, intraperitoneally, i.p.), after 9 days of treatment, as well as toxicity. UMB07 (2000 μg/mL) induced only 0.8% of hemolysis in peripheral blood erythrocytes of mice. On acute toxicity assay, LD50 (50% lethal dose) was estimated at around 1000 mg/kg (i.p.), and no micronucleated erythrocytes were recorded after UMB-07 (300 mg/kg, i.p.) treatment. UMB-07 (25 and 50 mg/kg) reduced tumor volume and total viable cancer cells. In the mechanism action investigation, no changes were observed on the cell cycle analysis; however, UMB-07 reduced peritumoral microvessels density and CCL2 chemokine levels. In addition, UMB-07 showed weak toxicity on biochemical, hematological, and histological parameters after 9 days of antitumor treatment. The current findings suggest that UMB-07 has low toxicity and exerts antitumor effect by inhibit angiogenesis via CCL2 chemokine decrease. Keywords Cancer chemotherapy . Coumarin derivative . Angiogenesis . CCL2 . Toxicity
Introduction
* Marianna Vieira Sobral [email protected] 1
Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos, Universidade Federal da Paraíba, João Pessoa, Paraíba 58051-970, Brazil
2
Departamento de Ciências Farmacêuticas, Universidade Federal da Paraíba, João Pessoa, Paraíba 58051-970, Brazil
3
Departamento de Morfologia, Universidade Federal da Paraíba, João Pessoa, Paraíba 58051-970, Brazil
4
Departmento de Ciências Biológicas, Universidade Estadual da Paraíba, João Pessoa, Paraíba 58071-160, Brazil
Cancer is a disease characterized by the exacerbated growth of malignant cells with potential to induce metastasis (Hanahan and Weinberg 2011).
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