Mechanism of antitumor action in vitro of a flavone nitroderivative. In vivo effect on a murine mammary adenocarcinoma

CÁRDENAS, M; BLANK, V.; ZOTTA, E; MARDER, M.; ROGUIN, L.P.

Montevideo, Uruguay.

Congreso; I Reunión Latinoamericana de Química Medicinal; 2007

We have previously demonstrated that the 2´-nitroflavone (2´-NF) exerts a strong antimitogenic activity in various human and murine tumor cell lines, without disturbing the proliferation of non-neoplasic cells. In order to elucidate the mechanism of antitumor action in vitro, we studied the ability of 2´-NF to induce cell cycle arrest and/or apoptosis in HeLa cells (human cervix adenocarcinoma). The analysis of cell cycle phase distribution showed an increase in the number of cells in S and G2 phases after exposure to 2´-NF. In addition, this compound induced apoptosis through activation of caspases 3, 8 and 9, without significant changes in the expression of Bcl-2 family proteins. In order to study its in vivo antitumor action, female BALB/c mice were first injected subcutaneously with 300 000 cells derived from a murine mammary tumor (LM3). After 7 days, 10 or 40 mg/kg of 2´-NF dissolved in 0.2 ml of vehicle (5% DMSO, 0.05% Tween-80, NaCl 0.15 M) were administrated i.p. twice a week for 3 weeks. During the treatment, tumor sizes were measured every 3 days and then, tumors were excised, measured and weighted. On average, treated-mice tumor volume was reduced 65 and 42 % (p<0.01) with 10 and 40 mg/kg doses, respectively. Besides, tumors weight decreased between 60 and 50 % (p<0.01) under the same treatment conditions. In addition, toxicity studies performed in different organ-tissues from animals injected with 40 mg/kg of 2´-NF showed no histological alterations. Taken together, our results suggest the potential therapeutic use of 2´-NF as an antitumor agent, capable of inducing cell cycle arrest and apoptosis in vitro and inhibiting tumor proliferation in vivo without generating systemic toxic effects.