Investigação do potencial antitumoral in vitro e in vivo de alcalóides sintéticos metoxipirrólicos

Abstract

The natural alkaloids that present the Chemical core 4-methoxy-2, 2'- bipyrrole has attracted increasing interest from researchers because of their biological potential as antibacterial, antifungal, antiprotozoal, immunosuppressive and anticancer. Mainly from marine organisms and bactéria the class includes prodigiosin and tambjamine. This study investigated the cytotoxic potential of 7 synthetic alkaloids belonging to the tambjamine class (Tambjamine C, E, F, G, H, I and J) in a panei of four human tumor cell lines and peripheral blood mononuclear cells from human (PBMC) by MTT assay. Except for Tamb E, all compounds were cytotoxic against all the lines used, and Tamb I and Tamb J were the most active molecules with IC5o values < 1 pg/mL. The study of the mechanism of action of Tamb I and J (0.3 and 0.6 pg/mL), using human leukemia cells HL-60 as experimental model, demonstrated induction of apoptotic cell death, primarily by activation of the extrinsic pathway characterized by DNA fragmentation, externalization of phosphatidylserine and activation of caspases (3, 7, 8 and 9) determined by staining assays, fluorescence, flow cytometry and electrophoresis. In addition, Tamb J was more potent than Tamb I, especially after 24 h of exposure, which was also observed when combined with trastuzumab on tests against cells that overexpress the ErbB-2 receptor. In tests of DNA relaxation, Tamb J was able to inhibit the catalytic activity of the topoisomerase I and II enzymes which may explain, at least partially, its cytotoxic effects. The antitumor evaluation in mice transplanted with Sarcoma 180 cells demonstrated rates of tumor growth inhibition of 39.9 and 78.8% with doses of 10 and 20 mg/kg/day i.p. of the Tamb J, respectively, after 7 days of treatment. The antitumor effect observed was accompanied by moderate and reversible toxicity of animais, especially at a dose of 20 mg/kg/day, characterized by decreased weight gain, lethargy, diarrhea, spleen toxicity (lymphocyte depletion) and genotoxicity (DNA damage and micronuclei induction). The majority of these modifications are similar to the toxicity observed on the traditional cytotoxic agents, which putting together to the results obtained in vitro tests for Tamb J emphasize the potential of these molecules as template for the production and/or synthesis of new compounds with anticancer properties.