Efeitos antitumoral e antinociceptivo do n’-(6-cloro-2-metoxiacridin-9-il)-2-cianoacetohidrazide (ACS-AZ), um novo derivado acridínico

Abstract

Cancer is considered one of the most common causes of mortality in the world and designates a set of diseases determined by the presence of cells with morphological and biochemical modifications, and with a sustained proliferation. Problems in the efficacy, safety and development of treatment resistance stimulates the research of new molecules with antitumor potential. In addition, pathophysiological effects associated with cancer, such as pain, are also treated with low effectiveness. Acridine derivatives are described as having several biological activities, among them, antitumor and antinociceptive activities. This study aimed to investigate the toxicity, the antitumor and the antinociceptive activities, as well as the possible mechanisms of action involved in the effect of the unpublished acridine derivative n’-(6-chloro-2-methoxy-acridin-9-yl)-2-cyanoacetohidrazide (ACS-AZ). Initially, the acute non-clinical toxicity evaluation of ACS-AZ in mice per intraperitoneal route (i.p.) were performed. ACS-AZ (300 or 2000 mg / kg) and its LD50 (50% lethal dose) was estimated around 500 mg / kg, according the guide n. 423 of the Organization for Economic Co-operation and Development (OECD). For the evaluation of the ACS-AZ (150 mg / kg, i.p.) genotoxicity, the micronucleus assay in the peripheral blood of mice were performed, ACS-AZ (150 mg / kg, i.p.) did not induce an increase in the number of micronucleated erythrocytes, suggesting low genotoxicity in vivo. ACS-AZ (25 or 50 mg / kg) after seven days of treatment (i.p.) showed significant in vivo antitumor activity in Ehrlich Ascitic Carcinoma (CAE) model, considering all parameters evaluated (volume, mass and cell viability) (p<0,05). Regarding the mechanisms of antitumor action, it was observed that ACS-AZ reduced peritumoral vascular microdensity (p<0,05), as well as the levels of IL-1β cytokines and CCL-2 chemokine (p<0,05), and also increased the levels of TNF-α and IL-4 (p <0.05) showing that ACS-AZ was able to modulate the inflammatory tumor microenvironment to exercise its anti-tumor effect. Considering the large role of the oxidative stress in tumor propagation, the effect of ACS-AZ was evaluated by the fluorometric test of 2-70-dichlorofluorescein diacetate (DCFH-DA). Reduction of the oxidative stress level after treatment with ACS-AZ (50 mg / kg) (p <0.05) was observed, suggesting antioxidant effects. Furthermore, ACS-AZ (50 mg / kg) was shown to reduce nitric oxide (NO) production (p <0.05), a key mediator involved in growth, angiogenesis and tumor metastasis. Among all the parameters of toxicity evaluated (metabolic, biochemical, hematological and histological parameters), it was observed that ACS-AZ (50 mg / kg) induced only mild hepatotoxicity, characterized by the detection of mild grade steatosis and degenerative processes in hepatic tissue. Regarding the antinociceptive tests, ACS-AZ (50 mg / kg, i.p.) showed potent central-acting antinociceptive activity in hot plate tests and, in both phases of the formalin test (p <0.05), involving the participation of the opioid pathway in this response. Therefore, it is possible to infer that ACS-AZ presents low toxicity, antitumor activity via antiangiogenic and immunomodulatory effects, and antinociceptive activity involving the opioid pathway.