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 mat rix (ECM) components and play an important role in embryo development, morp hogenesis and tissue remodelling, as well as in tumour invasion and metasta sis. Synthetic MMP inhibitors (MMPIs) were designed to prevent tumour cell- induced changes in ECM and thereby achieve antitumour activity. Several MMP Is have entered clinical trials but the preliminary results did not meet th e expectations. Recent evidence suggests that MMPs may have more diverse ro les than originally believed, influencing angiogenesis, cytokine secretion, as well as tumour cell growth and survival. In particular, synthetic MMPls may directly induce apoptosis of cancer cells via their inhibitory effect on the shedding of Fas Ligand (FasL), a transmembrane member of the TNF sup erfamily that kills susceptible cells through its receptor, Fas. Several ty pes of cancers have been shown to express FasL and to shed it from their su rface as a soluble form, which is significantly less potent in promoting ap optosis. MMP-7 was recently reported to catalyse this process. Conversely, inhibition of Fast-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 Fa st. By inhibiting the proteolytic cleavage of Fast, MMPIs can potentiate th e killing effect of traditional chemotherapeutic drugs. These studies there fore demonstrate a direct link between DNA-damaging chemotherapeutic drugs, the apoptosis-inducing Fas/FasL system and the proteolytic activity of MMP s and have important therapeutic implications. For example, the proteolytic activity of MMP-7, which is broadly expressed in primary and especially me tastatic human malignancies, may contribute to tumour resistance to cytotox ic agents; targeting and inactivating MMP-7 may, therefore, enhance the eff icacy of conventional cancer chemotherapy.