Efeito antitumoral e antiangiogênico da BthMP, uma metaloprotease isolada da peçonha de Bothrops moojeni

Abstract

Lung cancer is the second most prevalent type of cancer and the first in number of deaths worldwide. In this context, several studies have shown that toxins isolated from snake venom have been investigated with the aim of developing future drugs for cancer therapy. Thus, we evaluated the antitumor and antiangiogenic effects of BthMP, a PI metalloprotease isolated from Bothrops moojeni venom on lung cancer cells and Human Umbilical Vein Endothelial Cells (HUVEC). BthMP was cytotoxic to lung cancer cells (A549) showing inhibition of colony formation by the clonogenic assay and increased levels of LDH at concentrations of 40 and 5μg/mL. Furthermore, at these same concentrations, BthMP inhibited the invasion, migration and adhesion of A549 cells in addition to increasing the levels of reactive oxygen and nitric oxide species. Interestingly, the toxin did not interfere in the cytotoxicity and adhesion processes of non-tumorigenic lung cells (Beas) BthMP inhibited the adhesion, migration of HUVECs and angiogenesis in vitro dependent on VEGF, an essential pro-angiogenic factor. In addition, the toxin was able to inhibit the angiogenic process through an ex vivo assay of the aortic ring. Finally, it was possible to observe that the inactivation of the catalytic activity of the toxin abolished the inhibition of the migration of A549 cells induced by the metalloprotease, demonstrating that the antitumor activity of the metalloprotease is associated with its catalytic activity. Therefore, these results demonstrate that BthMP toxin has a significant antitumor and antiangiogenic effect on lung cancer and endothelial cells and represents an important biotechnological tool targeting a new form of cancer therapy.