Induction of tumour cell apoptosis by matrix metalloproteinase inhibitors: new tricks from a (not so) old drug.

Matrix metalloproteinases (MMPs) regulate the turnover of extracellular matrix (ECM) components and play an important role in embryo development, morphogenesis and tissue remodelling, as well as in tumour invasion and metastasis. Synthetic MMP inhibitors (MMPIs) were designed to prevent tumour cell-induced changes in ECM and thereby achieve antitumour activity. Several MMPIs have entered clinical trials but the preliminary results did not meet the expectations. Recent evidence suggests that MMPs may have more diverse roles than originally believed, influencing angiogenesis, cytokine secretion, as well as tumour cell growth and survival. In particular, synthetic MMPIs may directly induce apoptosis of cancer cells via their inhibitory effect on the shedding of Fas Ligand (FasL), a transmembrane member of the TNF superfamily that kills susceptible cells through its receptor, Fas. Several types of cancers have been shown to express FasL and to shed it from their surface as a soluble form, which is significantly less potent in promoting apoptosis. MMP-7 was recently reported to catalyse this process. Conversely, inhibition of FasL-shedding by a synthetic MMPI results in apoptosis of Fas-sensitive cancer cells. More importantly, DNA-damaging anticancer agents, such as adriamycin, kill cancer cells, at least in part, by upregulating FasL. By inhibiting the proteolytic cleavage of FasL, MMPIs can potentiate the killing effect of traditional chemotherapeutic drugs. These studies therefore demonstrate a direct link between DNA-damaging chemotherapeutic drugs, the apoptosis-inducing Fas/FasL system and the proteolytic activity of MMPs and have important therapeutic implications. For example, the proteolytic activity of MMP-7, which is broadly expressed in primary and especially metastatic human malignancies, may contribute to tumour resistance to cytotoxic agents; targeting and inactivating MMP-7 may, therefore, enhance the efficacy of conventional cancer chemotherapy.