Effets des extraits de Ficus umbellata Vahl (Moraceae) sur des modèles de cancers du sein et de l’ovaire et élucidation des mécanismes d’action : étude in vitro et in vivo

Abstract

Ficus umbellata Vahl (Moraceae) is a plant used in Cameroonian pharmacopoeia in the treatment of some physiological disorders related to menopause. Previous works carried out have shown that the aqueous and methanol extracts of Ficus umbellata barks have antiestrogenic/estrogenic effects in vitro and in vivo. The aim of the present work was therefore to evaluate the effects of Ficus umbellata on some breast and ovarian cancer models. For this purpose, the cytotoxic potential of Ficus umbellata extracts as well as their chemopreventive potential on an estrogen dependent cancer model were evaluated. Subsequently, the quantification of some secondary metabolites present in the aqueous and methanol extracts was carried out. The second part consisted in elucidating the mechanisms of action through which the methanol extract of Ficus umbellata pass to induce its anticancer activity and in the third part, the bioactive constituents of the methanol extract of Ficus umbellata were identified and their mechanism of action was elucidated. As results, the methanol extract showed a high content of total phenols, flavonoids in comparison with the aqueous extract. The in vitro study showed that the methanol extract induced cytotoxicity with CC50 comprise between 100 and 250 µg/mL compared to the aqueous extract which did not induce cytotoxicity up to 300 µg/mL on most of the tested cells. The in vivo study showed that aqueous (200 mg/kg) and methanol (50 mg/kg) extracts of F. umbellata reduced ovarian tumor incidence (10%), total tumor burden (58% and 46%) respectively, mean burden weight (57.8% and 45.6%) respectively; reduced MDA level and increased glutathione level in all tested groups. Elucidation of the mechanism of action of the methanol extract showed that it did not induce any effect on the cell cycle of MDA-MB-231 and PA-1 cells after 12 h, 24 h and 48 h; significantly (p ˂ 0.001) induced apoptosis on said cells. Methanol extract significantly inhibited cell migration (p ˂ 0.001) and invasion (p < 0.01) on MDA-MB-231 cells at 180 µg/mL. From the bio-guided fractionation, three compounds were isolated including a triterpene, a coumarin and an acid. The triterpene showed better cytotoxic potential on all cells tested with CC50 of 8.8 and 13.18 µg/mL on MDA MB-231 and PA-1 cells respectively. Elucidation of the mechanism of action of triterpene showed that it induces apoptosis, inhibits proliferation, invasion, migration and angiogenesis of breast and ovarian cancer cells. All these results suggest that Ficus umbellata has a cytotoxic potential and the isolated triterpene is the active constituent responsible, at least in part, for the antitumor and cytotoxic effects observed with this extract.