Markers of oxidative-nitrosative stress induced by artesunate are followed by clastogenic and aneugenic effects and apoptosis in human lymphocytes.

Autor: Mota TC; Laboratory of Human Cytogenetic and Genetic Toxicology, Institute of Biological Sciences, Federal University of Pará (UFPA), Belém-, Pará, Brazil., Garcia TB; Laboratory of Human Cytogenetic and Genetic Toxicology, Institute of Biological Sciences, Federal University of Pará (UFPA), Belém-, Pará, Brazil., Bonfim LT; Laboratory of Human Cytogenetic and Genetic Toxicology, Institute of Biological Sciences, Federal University of Pará (UFPA), Belém-, Pará, Brazil., Portilho AJS; Laboratory of Human Cytogenetic and Genetic Toxicology, Institute of Biological Sciences, Federal University of Pará (UFPA), Belém-, Pará, Brazil., Pinto CA; Laboratory of Human Cytogenetic and Genetic Toxicology, Institute of Biological Sciences, Federal University of Pará (UFPA), Belém-, Pará, Brazil., Burbano RMR; Laboratory of Human Cytogenetic and Genetic Toxicology, Institute of Biological Sciences, Federal University of Pará (UFPA), Belém-, Pará, Brazil., de Oliveira Bahia M; Laboratory of Human Cytogenetic and Genetic Toxicology, Institute of Biological Sciences, Federal University of Pará (UFPA), Belém-, Pará, Brazil.
Jazyk: angličtina
Zdroj: Journal of applied toxicology : JAT [J Appl Toxicol] 2019 Oct; Vol. 39 (10), pp. 1405-1412. Date of Electronic Publication: 2019 Jul 05.
DOI: 10.1002/jat.3826
Abstrakt: Artesunate (ARS) is a semi-synthetic derivative of artemisinin, used as an outstanding antimalarial drug, which also displays antitumor, anti-inflammatory and immunosuppressive effects. In spite of the numerous reports showing the antitumor activity of ARS, the particular mechanisms associated with its cytotoxicity and genotoxicity in non-neoplastic human cells remain unclear. Here we aimed to verify the specific chromosome damages and the changes in markers of oxidative-nitrosative stress and apoptosis triggered by ARS exposure in human peripheral blood lymphocytes. Cultures were incubated in the presence of ARS and the number of binucleated cells was determined. To discriminate between micronuclei (MN) containing a whole chromosome or an acentric chromosome, the MN test was employed in combination with the fluorescence in situ hybridization assay. Alterations in the levels of superoxide anion (O 2 - ) and nitric oxide (NO) were measured by the nitroblue tetrazolium and Griess assay, respectively. Changes in the expression of the apoptotic markers were assessed by immunocytochemistry. We found that ARS induced a significant formation of both centromere-positive MN (C + MN) and centromere-negative MN (C - MN). These alterations were accompanied by an increase in both cellular levels of O 2 - and total NO production, and a remarkable enhancement in the expression of the apoptotic markers cytochrome c and caspases 8 and 9. Together these findings reveal that ARS induces changes in the oxidative-nitrosative status of human lymphocytes, which are followed by apoptosis and clastogenic and aneugenic effects.
(© 2019 John Wiley & Sons, Ltd.)
Databáze: MEDLINE
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