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Evaluation of the anti-cervical cancer effect of a prodrug :CBZ-AAN-DOX with hypoxic cell culture and tumor-bearing zebrafish models.
Chen, Hong-Ce; Rui, Wen; You, Si-Yuan; Liu, Xia-Wan; Huang, Jun; Chen, Hong-Yuan.
Afiliação
  • Chen HC; Department of Pathogenic Biology and Immunology, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, Guangzhou, 510632, Guangdong Province, PR China.
  • Rui W; Centre for Novel Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong Province, PR China; Guangdong Engineering & Technology Research Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong Prov
  • You SY; Department of Pathogenic Biology and Immunology, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, Guangzhou, 510632, Guangdong Province, PR China.
  • Liu XW; Department of Pathogenic Biology and Immunology, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, Guangzhou, 510632, Guangdong Province, PR China.
  • Huang J; Key Laboratory of Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences; Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Guangdong Province, PR China.
  • Chen HY; Department of Pathogenic Biology and Immunology, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, Guangzhou, 510632, Guangdong Province, PR China; Guangdong Engineering & Technology Research Center of Topical Precise Drug Delivery System, Guangdong Pharmaceuti
Exp Cell Res ; 391(1): 111980, 2020 06 01.
Article em En | MEDLINE | ID: mdl-32229193
ABSTRACT

BACKGROUND:

Prodrugs are medications or compounds that, after administration, can be converted into pharmacologically active drugs through metabolism. Unlike conventional drugs, prodrugs have reduced adverse or unintended effects, which could become critical limitations in treatments such as chemotherapy. Previously through computer-aided drug design and chemical synthesis, we have obtained and examined a prodrug N-benzyloxycarbonyl-Ala-Asn-Doxorubicin (CBZ-AAN-DOX). CBZ-AAN-DOX is essentially Doxorubicin that is chemically-modified with tripeptides to target Legumain, a highly expressed protein in cancer cells and is involved in tumor metastasis and tumor microvessel formation. The difficulty to test the safety and efficacy of the prodrug (including the pharmacodynamic parameters of CBZ-AAN-DOX on metastasis and invasion of tumors, as well as cardiac and vascular toxicity) primarily comes from the lack of appropriate experimental models.

METHODS:

Human cervical cancer cell lines CaSki under hypoxic conditions were used to evaluate the cell viability by CCK-8 assay after the prodrug treatment. Western blotting method was performed for Legumain protein determination in the cell culture. Wound healing and transwell invasion assays were performed to determine the effects of the prodrug on tumor metastasis and invasion, respectively. Zebrafish models were constructed for toxicity and angiogenesis visual analysis after in vivo treatment with the prodrug.

RESULTS:

The CCK-8 results showed that CBZ-AAN-DOX exhibits an IC50 of 28.7 µM in 48 h on CaSki cells that had a lower cell inhibition rate than DOX 80.3 µM for 24 h. Legumain expression was significantly increased in a time-dependent manner in 48 h under hypoxia conditions. The results also showed that 13.9 µM of the prodrug significantly inhibited the migration and invasion of cells and the effects were significantly stronger than that of 41.8 µM of DOX under hypoxia conditions after 48 h. The effects of 160 µM of the prodrug on the survival rate of zebrafish after 72 h and heart-toxicity showed no obvious abnormalities. Cell metastasis and angiogenesis were also inhibited in tumor-bearing zebrafish model.

CONCLUSION:

The findings in this study demonstrated that CBZ-AAN-DOX is a promising chemotherapy candidate with low toxicity and high efficiency for cervical cancer. Remarkably, the hypoxic culture model together with the zebrafish model serve as a good system for the evaluation of the toxicity, targeting and impact of the prodrug on tumor invasion and metastasis.
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Texto completo: 1 Coleções: 01-internacional Contexto em Saúde: 6_ODS3_enfermedades_notrasmisibles Base de dados: MEDLINE Assunto principal: Oligopeptídeos / Cisteína Endopeptidases / Pró-Fármacos / Doxorrubicina / Regulação Neoplásica da Expressão Gênica / Neoplasias do Colo do Útero / Antibióticos Antineoplásicos / Neovascularização Patológica Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Exp Cell Res Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Contexto em Saúde: 6_ODS3_enfermedades_notrasmisibles Base de dados: MEDLINE Assunto principal: Oligopeptídeos / Cisteína Endopeptidases / Pró-Fármacos / Doxorrubicina / Regulação Neoplásica da Expressão Gênica / Neoplasias do Colo do Útero / Antibióticos Antineoplásicos / Neovascularização Patológica Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Exp Cell Res Ano de publicação: 2020 Tipo de documento: Article