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A 9-aminoacridine derivative induces growth inhibition of Ehrlich ascites carcinoma cells and antinociceptive effect in mice

Affiliation
Post Graduation Program in Bioactive Natural and Synthetic Products ,Federal University of Paraíba ,João Pessoa ,Brazil
Mangueira, Vivianne M.;
Affiliation
Post Graduation Program in Bioactive Natural and Synthetic Products ,Federal University of Paraíba ,João Pessoa ,Brazil
de Sousa, Tatyanna K. G.;
Affiliation
Post Graduation Program in Bioactive Natural and Synthetic Products ,Federal University of Paraíba ,João Pessoa ,Brazil
Batista, Tatianne M.;
Affiliation
Post Graduation Program in Bioactive Natural and Synthetic Products ,Federal University of Paraíba ,João Pessoa ,Brazil
de Abrantes, Renata A.;
Affiliation
Post Graduation Program in Bioactive Natural and Synthetic Products ,Federal University of Paraíba ,João Pessoa ,Brazil
Moura, Ana Paula G.;
Affiliation
Post Graduation Program in Bioactive Natural and Synthetic Products ,Federal University of Paraíba ,João Pessoa ,Brazil
Ferreira, Rafael C.;
Affiliation
Post Graduation Program in Bioactive Natural and Synthetic Products ,Federal University of Paraíba ,João Pessoa ,Brazil
de Almeida, Reinaldo N.;
Affiliation
Post Graduation Program in Bioactive Natural and Synthetic Products ,Federal University of Paraíba ,João Pessoa ,Brazil
Braga, Renan M.;
Affiliation
Post Graduation Program in Bioactive Natural and Synthetic Products ,Federal University of Paraíba ,João Pessoa ,Brazil
Leite, Fagner Carvalho;
Affiliation
Department of Morphology ,Federal University of Rio Grande do Norte ,Natal ,Brazil
Medeiros, Karina C. de P.;
Affiliation
Drug Development and Synthesis Laboratory ,Department of Pharmacy ,State University of Paraíba ,João Pessoa ,Brazil
Cavalcanti, Misael Azevedo T.;
Affiliation
Drug Development and Synthesis Laboratory ,Department of Pharmacy ,State University of Paraíba ,João Pessoa ,Brazil
Moura, Ricardo O.;
Affiliation
Post Graduation Program in Bioactive Natural and Synthetic Products ,Federal University of Paraíba ,João Pessoa ,Brazil
Silvestre, Geovana F. G.;
Affiliation
Post Graduation Program in Bioactive Natural and Synthetic Products ,Federal University of Paraíba ,João Pessoa ,Brazil
Batista, Leônia M.;
Affiliation
Post Graduation Program in Bioactive Natural and Synthetic Products ,Federal University of Paraíba ,João Pessoa ,Brazil
Sobral, Marianna V.

Acridine derivatives have been found with anticancer and antinociceptive activities. Herein, we aimed to evaluate the toxicological, antitumor, and antinociceptive actions of N’-(6-chloro-2-methoxyacridin-9-yl)-2-cyanoacetohydrazide (ACS-AZ), a 9-aminoacridine derivative with antimalarial activity. The toxicity was assessed by acute toxicity and micronucleus tests in mice. The in vivo antitumor effect of ACS-AZ (12.5, 25, or 50 mg/kg, intraperitoneally, i.p.) was determined using the Ehrlich tumor model, and toxicity. The antinociceptive efficacy of the compound (50 mg/kg, i.p.) was investigated using formalin and hot plate assays in mice. The role of the opioid system was also investigated. In the acute toxicity test, the LD 50 (lethal dose 50%) value was 500 mg/kg (i.p.), and no detectable genotoxic effect was observed. After a 7-day treatment, ACS-AZ significantly ( p < 0.05) reduced tumor cell viability and peritumoral microvessels density, suggesting antiangiogenic action. In addition, ACS-AZ reduced ( p < 0.05) IL-1β and CCL-2 levels, which may be related to the antiangiogenic effect, while increasing ( p < 0.05) TNF-α and IL-4 levels, which are related to its direct cytotoxicity. ACS-AZ also decreased ( p < 0.05) oxidative stress and nitric oxide (NO) levels, both of which are crucial mediators in cancer known for their angiogenic action. Moreover, weak toxicological effects were recorded after a 7-day treatment (biochemical, hematological, and histological parameters). Concerning antinociceptive activity, ACS-AZ was effective on hotplate and formalin (early and late phases) tests ( p < 0.05), characteristic of analgesic agents with central action. Through pretreatment with the non-selective (naloxone) and μ1-selective (naloxonazine) opioid antagonists, we observed that the antinociceptive effect of ACS-AZ is mediated mainly by μ1-opioid receptors ( p < 0.05). In conclusion, ACS-AZ has low toxicity and antitumoral activity related to cytotoxic and antiangiogenic actions that involve the modulation of reactive oxygen species, NO, and cytokine levels, in addition to antinociceptive properties involving the opioid system.

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License Holder: Copyright © 2022 Mangueira, de Sousa, Batista, de Abrantes, Moura, Ferreira, de Almeida, Braga, Leite, Medeiros, Cavalcanti, Moura, Silvestre, Batista and Sobral.

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