Publication

Abstract : Gelatinases (MMP-2 and MMP-9) play a significant role in cancer progression by cleaving the major components of the extracellular matrix thereby promoting the migration of tumor cells. Majority of the MMP inhibitors reported are zinc chelating compounds which bind to the catalytic zinc via hydroxamate, carboxylate, thiol or phosphonic acid moieties. The extensive homology between catalytic domains of the MMPs makes these effective zinc binding inhibitors non-selective and toxic. To overcome such non selective toxicity, novel non-zinc binding MMP inhibitors have been developed.(I-3,II-3)-Biflavones form a small group of dimeric flavonoids which have not been extensively studied due to their limited occurrence. Among several differently substituted biflavones having hydroxy, methoxy, furano and cinnamyl moieties,(I-3,II-3)-biacacetin showed maximum inhibition of gelatinases without interfering with the zinc in the catalytic site.This novel non-zinc binding interaction of (I-3,II-3)-biacacetin was further confirmed by treating the cells with ZnCl2 along with(I-3,II-3)-biacacetin and showing that the inhibition remained unaffected even in the presence of ZnCl2.(I-3,II-3)-biacacetin showed significant reduction in migration of highly metastatic fibrosarcoma cell line, HT1080. The mechanism of (I-3,II-3)-biacacetinmediated modulation of cell migration through inhibition of gelatinases was further established by treating the cells with phorbol myristate acetate (PMA)along with (I-3,II-3)-biacacetinand using the same conditioned media for the migration assay. (I-3,II-3)-biacacetininhibitedPMA-stimulated gelatinase activity as well as migration of HT1080 cells in a concentration-dependent manner.These results suggests the use of (I-3,II-3)-biacacetin as a novel template for design and synthesis of analogswith improved potency and selectivity.