Metabolic activation enhances the cytotoxicity, genotoxicity and mutagenicity of two synthetic alkaloids with selective effects against human tumour cell lines
| Autor: | Filipe Nogueira Franco, Camila de Souza Barbosa, Vanessa J. S. V. Santos, Rosy Iara Maciel de Azambuja Ribeiro, Kimberly Brito Tecchio, Fábio Vieira dos Santos, Gustavo Henrique Ribeiro Viana, Júlia Teixeira de Oliveira, Alessandra Mirtes Marques Neves Gonçalves |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Health Toxicology and Mutagenesis Antineoplastic Agents 010501 environmental sciences medicine.disease_cause 01 natural sciences Activation Metabolic 03 medical and health sciences Alkaloids Neoplasms Tumor Cells Cultured Genetics medicine Humans MTT assay Cytotoxicity Clonogenic assay Cytokinesis 0105 earth and related environmental sciences chemistry.chemical_classification Micronucleus Tests 030104 developmental biology Enzyme chemistry S9 fraction Cell culture Micronucleus test Cancer research Comet Assay Genotoxicity DNA Damage Mutagens |
| Zdroj: | Mutation Research/Genetic Toxicology and Environmental Mutagenesis. :503294 |
| ISSN: | 1383-5718 |
| DOI: | 10.1016/j.mrgentox.2020.503294 |
| Popis: | The pharmacological potential of drugs must be evaluated to establish their potential therapeutic benefits and side effects. This evaluation includes assessment of the effects of hepatic enzymes that catalyse their metabolic activation. Previously, our research group synthesized and characterized a set of synthetic 3-alkyl pyridine alkaloid (3-APA) analogues that cause in vitro cytotoxic, genotoxic, and mutagenic effects in various human cancer cell lines. The present study aimed to evaluate these activities with the two most promising synthetic 3-APAs (3-APA 1 and 3-APA 2) against cell lines derived from breast cancer (MDA-MB-231), ovarian cancer (TOV-21 G) and lung fibroblasts (WI-26-VA4) with and without metabolic activation (S9 fraction). The cytotoxicity of the compounds was evaluated employing MTT and clonogenic assays. In addition, comet assays, γH2AX immunocytochemistry labelling assays and cytokinesis-block micronucleus tests were carried out to evaluate the potential of these compounds to induce chromosomal damage. The results obtained in the MTT assay showed that compound 3-APA 2 exhibited high selectivity index (SI) values (ranging between 21.0 and 92.6). In addition, the cytotoxicity of the compounds was clearly enhanced by metabolic activation. Moreover, both compounds were genotoxic and induced double-strand breaks in DNA and chromosomal lesions with and without S9. The cancer cell lines tested showed higher genotoxic sensitivity to the compounds than did the non-tumour cell line used as a reference. The genotoxic and mutagenic effects of the compounds were potentiated in experiments with metabolic activation. The data obtained in this study indicate that compound 3-APA 2 is more active against the human cancer cell lines tested, both with and without metabolic activation, and can therefore be considered a candidate drug to treat human ovarian and breast cancer. |
| Databáze: | OpenAIRE |
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