Metabolic activation enhances the cytotoxicity, genotoxicity and mutagenicity of two synthetic alkaloids with selective effects against human tumour cell lines

• Published in: Mutation research Vol. 861-862; p. 503294
• Main Authors: Oliveira, Júlia Teixeira de, Franco, Filipe Nogueira, Tecchio, Kimberly Brito, Gonçalves, Alessandra Mirtes Marques Neves, Barbosa, Camila de Souza, Ribeiro, Rosy Iara Maciel de Azambuja, Viana, Gustavo Henrique Ribeiro, Santos, Vanessa J. da Silva Vieira dos, Santos, Fabio Vieira dos
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2021
• Subjects: Activation, Metabolic; Alkaloids - pharmacology; Antineoplastic Agents - pharmacology; Clastogenesis; Comet Assay; Cytokinesis - drug effects; DNA Damage; Double-Strand breaks; Humans; Micronucleus Tests; Mutagens - pharmacology; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Preclinical; Rat liver S9; Selectivity index; Tumor Cells, Cultured; Double-Strand breaks; Selectivity index; Rat liver S9; Preclinical; Clastogenesis
• ISSN: 1383-5718; 1879-3592; 1873-135X
• DOI: 10.1016/j.mrgentox.2020.503294

•Two synthetic alkaloids were cytotoxic against tumor cell lines.•Alkaloid 3-APA 2 presented high selectivity against breast and ovary cancer cells.•Compounds assessed induced genotoxic and mutagenic effects.•Genotoxicity and mutagenicity were more pronounced in cancer cells.•Metabolic activation enhanced the toxic effects. 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.