Antitumor effects of citrinin in an animal model of Sarcoma 180 via cytogenetic mechanisms


José Williams Gomes de Oliveira Filho, Teresinha de Jesus Aguiar dos Santos Andrade, Rosália Maria Tôrres de Lima, Antonielly Campinho dos Reis, Aneela Hameed, José Victor de Oliveira Santos, Muhammad Inam Afzal, Ag-Anne Pereira Melo de Menezes, Marcus Vinícius Oliveira Barros de Alencar, Dulce Helena Siqueira Silva, Ana Carolina Soares Dias, José Roberto de Oliveira Ferreira, Muhammad Torequl Islam, Paulo Michel Pinheiro Ferreira, Bahare Salehi, Muhammad Qamar, Muhammad Umer, Muhammad Imran, Javad Sharifi-Rad, Natália Martins, João Marcelo de Castro e Sousa, Ana Amélia de Carvalho Melo Cavalcante

Abstract


Citrinin (CIT) is a cytotoxic, hepatotoxic, nephrotoxic and cardiotoxic metabolite obtained from Penicillium citrinum, that has been increasingly searched as an anticancer drug candidate. In this study, we assessed the antitumor effects of citrinin, using cytogenetic biomarkers for genotoxicity in Sarcoma 180 (S-180) ascitic fluid cells of mice. Citrinin, extracted from P. citrinum acetonitrile extract, was characterized by LC-MS. Cytotoxic assessment was done through using comet (alkaline version) and micronucleus assays. In S-180 cells, CI50 of CIT was 3.77 μg/mL, while at 12.5 and 100 μg/mL, CIT was as cytotoxic as doxorubicin (2 μg/mL). At 0.5, 1.0 and 2.0 μg/mL, it induced genotoxicity and mutagenicity in S-180 cells, especially at 2 μg/mL, triggering oxidative damage similar to hydrogen peroxide (10 mM). The antitumor effects were evidenced by a marked increase in S-180 cells apoptosis and necrosis due to clastogenic and/or aneugenic cytogenetic effects (micronucleus formation), as well as by induction of nucleoplasm bridges and nuclear buds, culminating in S-180 apoptosis and necrosis. CIT has potential as drug candidate for antitumor purposesbyinvolving cytogenetic mechanisms.


Keywords


Sarcoma 180; Citrinin; Cytogenetic; Apoptosis.

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