Modulation of matrix metalloproteinases implications for cancer therapy

Abstract

Cancer has been tightening its grip across the globe with a million new cases being reported every year worldwide. Matrix metalloproteinases (MMPs) are a group of zincdependent endopeptidases that play a significant role in degradation of the extracellular matrix (ECM), which is associated with several patho-physiological conditions like cancer, arthritis, angiogenesis, tissue repair etc. A finely tuned and tightly controlled proteolytic processing of a variety of signaling molecules by MMPs also assist in the regulation of cell behavior. Aberrant expression of several MMPs is linked with various stages of cancer progression like metastasis and angiogenesis. A coordinated secretion of MMPs is usually counterbalanced by their endogenous modulators that help in maintaining tissue homeostasis in normal cells. In cancer cells, this balance between MMPs and their regulators is lost, resulting in excessive degradation of ECM thereby promoting the migration of cancer cells to different sites. Efforts have been made for the past 3 decades to develop MMP inhibitors (for eg. Batimastat, Marimastat, Prinomastat, Tanomastat etc.) that can be used to halt the spread of cancer. However, to date, no MMP inhibitor has been developed successfully as anti-tumor drugs. A low dose doxycycline formulation is the only MMP inhibitor that has been clinically approved for its ability to inhibit MMPs and treat periodontal inflammation. Natural products and their derivatives have gained a lot of importance over the last few decades due to the emergence of drug-resistance to synthetic drugs. Cashew nut shells, which are otherwise agro-wastes of cashew nut processing industry is a unique source of naturally occurring long-chain hydrocarbon phenols like anacardic acid. Though several bioactive properties of anacardic acid has been studied (anti-bacterial, anti-tumor and antioxidant), their effect on gelatinases (MMP-2 and MMP-9) has not been clearly understood. ...