Recent Patents on Anti-Cancer Drug Discovery, 2006, 1, 91-103 91 1574-8928/06 $100.00+.00 © 2006 Bentham Science Publishers Ltd. Natural Bio-Drugs as Matrix Metalloproteinase Inhibitors: New Perspectives on the Horizon? Ferdinando Mannello* Istituto di Istologia ed Analisi di Laboratorio, Università Studi “Carlo Bo”, Urbino, Italy Received: July 15, 2005; Accepted: August 15, 2005; Revised: August 23, 2005 Abstract: The matrix metalloproteinases (MMPs), belonging to the family of proteolytic enzymes, are well-known for their ability to degrade the extracellular matrix, and are involved in many aspects of both physiological cellular processes and pathological situations, such as tumor growth, invasion and metastasis. MMPs have been considered prognostic factors in various types of cancer as well as promising targets for cancer therapy. Although preclinical studies of a number of different synthetic MMP inhibitors have been identified as cytostatic and anti-angiogenic agents and have begun clinical testing, the past years have produced a consistent number of disappointments and limited successes. In view of their specific implication in malignant tissues, several natural compounds were utilized, and the results were so satisfactory as to encourage several clinical trials in order to improve efficacy and to reduce the side effect profile. The natural protection against cancer has been receiving a great deal of attention, and the critical examination of previous studies shed light on new information about the source and function of MMPs, focusing the attention on the identification of MMP targets in tumors. This review discusses the current knowledge and research in the field of natural MMP inhibitor as innovative therapeutic intervention in cancer. Keywords: Biodrugs, Cancer, Clinical Trials, Gelatinases, Matrix Metalloproteinases, Natural Compounds, Nutraceuticals, Protease Inhibitors, Therapeutic strategies. INTRODUCTION Cancer is one of the leading causes of death and disease world-wide [1]. At the same time, clinicians and researchers are focusing more on the concept of targeted therapies and the finding of new and relevant prognostic factors to better delineate treatment options in cancer patients. Clinicians use a number of factors to stratify cancer patients at diagnosis, in order to accurately define risk profiles and plan the most appropriate treatment. Along with patient and tumor characteristics (such as age at diagnosis, tumor size, and lymph node status), an increasing number of molecular prognostic factors, (named tumor "biomarkers"), are being developed for use in patient outcome and treatment determinations [2]. These markers must have some defining characteristics, such as ease of specimen collection and a reproducible assay that is rapid and inexpensive [3]. Although hundreds of these biomarkers have been reported, few are proving to be useful in the clinic. Large amounts of data have been obtained relative to matrix metalloproteinase (MMP) overexpression in various tumor types when compared to normal tissues [4], and several studies have provided evidence that certain MMPs in specific cancers can be useful as indicators of disease progression, thereby *Address correspondence to this author at the Istituto di Istologia ed Analisi di Laboratorio, Facoltà di Scienze MFN, Via E. Zeppi, Università degli Studi di Urbino “Carlo Bo”, 61029 Urbino (PU), Italy; Tel: +39-0722- 351479; Fax: +39-0722-322370; E-mail: f.mannello@uniurb.it improving treatment strategies and management of specific cancers [5]. THE MATRIX METALLOPROTEINASE FAMILY The MMPs are a family of structurally and functionally related endoproteinases that are collectively capable of degrading most of the components of the extracellular matrix (ECM) [3, 6]. These enzymes share common functional domains and activation mechanisms as they depend on Ca and Zn ions and are active at neutral pH. As shown in Fig. (1), the structure organization of all MMPs presents a pre- peptide sequence that directs their secretion in the extracellular environment and a pro-peptide domain that maintains them in their zymogenic form. The pro-peptide keeps the enzyme in an inactive/latent state through the interaction of a cysteine residue with the catalytic zinc. Complete activation is obtained when this interaction is disrupted by chaotropic agents or by cleavage of the propeptide by other MMPs or proteinases [7]. MMPs possess a variable hinge region that links the catalytic domain, to a hemopexin-like domain which may be involved in substrate specificity [3]. Moreover, the family of MMPs has evolved by incorporating and/or deleting structural and functional domains. For instance, two MMPs (known as gelatinases), present the insertion of three fibronectin type II repeats in the catalytic domain which are involved in substrate binding. Other MMPs, known as membrane type MMPs (MT-MMP), have a hydrophobic amino acid stretch that crosses the cell membrane docking them to the cell surface. Finally, some members of this ever-growing family contain in their