Ponente
Descripción
Neutral Aminopeptidase is an integral membrane metallo-aminopeptidase, essential in several physiological functions, some linked to tumor biology: promotion of proliferation, inhibition of apoptosis, facilitation of invasion and induction of angiogenesis [1], being an interesting target for cancer treatment. The bufadienolides (specifically telocinobufagin and bufalin) are steroids that inhibit the Na+/K+ ATPase pump [2] and have been shown to have marked antitumor activity. Their structure makes them candidates with potential APN inhibitory activity and high selectivity for APN [3]. Dose-response studies were developed to evaluate the potency of porcine APN inhibition (APNp) by both bufadienolides and in each case, inhibition was dose-dependent in the micromolar range. The mechanism of inhibition was classically reversible noncompetitive (α>1). APNp:inhibitor bioinformatic models supported the experimentally identified noncompetitive kinetic mechanism. In selectivity studies of the compounds against other metallopeptidases, none were inhibited, demonstrating their high preference for APN. Assays performed to determine the effect of each of these bufadienolides on the viability/metabolism of APN+ lung cancer cells: A549, H292; LL/2 (LLC1) (taking into account that the bufadienolides under study are novel APNp inhibitors and that the APN enzyme is overexpressed among others, in lung cancer, of high incidence worldwide) showed high cytotoxic effects on these cell lines, in a dose-dependent manner; on A549 (of higher APN activity), the most drastic effects were observed.
