Matrix metalloproteinase inhibitors as anticancer agents

doi:10.1016/j.biocel.2007.11.007

The International Journal of Biochemistry & Cell Biology

Volume 40, Issues 6–7, June–July 2008, Pages 1156-1168

https://doi.org/10.1016/j.biocel.2007.11.007 Get rights and content

Abstract

The important role of matrix metalloproteinases (MMPs) in the process of carcinogenesis is well established. However, despite very promising activity in a plethora of preclinical models, MMP inhibitors (MMPIs) failed to demonstrate a statistically significant survival advantage in advanced stage clinical trials in most human malignancies. Herein, we review the implication of MMPs in carcinogenesis, outline the pharmacology and current status of various MMPIs as anticancer agents and discuss the etiologies for the discrepancy between their preclinical and clinical evaluation. Finally, strategies for effective incorporation of MMPIs in current anticancer therapies are proposed.

Introduction

The matrix metalloproteinase (MMP) family consists of more than 25 structurally related, zinc-dependent, endopeptidases that are capable of degrading various components of the extracellular matrix (ECM) (Nagase & Woessner, 1999; Woessner, 1994). MMPs occupy a pivotal role in the ECM remodelling that accompanies several physiologic processes – such as wound healing, bone resorption, uterine involution and organogenesis – as well as pathologic conditions including inflammatory, vascular and autoimmune disorders, and carcinogenesis (Egeblad & Werb, 2002; Kahari & Saarialho-Kere, 1999).

The prospect of targeting the MMPs as a therapeutic strategy against cancer was recognized 25 years ago when Liotta et al. (1980) demonstrated that the metastatic potential of various tumors correlated with the ability of cancer cells to degrade basement membrane collagen. Since that time, several MMP inhibitors (MMPIs) were developed and evaluated as anticancer agents in various human malignancies (Coussens, Fingleton, & Matrisian, 2002; Hidalgo & Eckhardt, 2001). However, despite very promising preclinical data, the clinical trials of MMPIs failed to demonstrate a statistically significant survival advantage in most tumor types. Herein, we review the implication of MMPs in carcinogenesis, outline the pharmacology and current status of various MMPIs as anticancer agents and discuss the reasons for the discrepancy between their preclinical and clinical evaluation. Finally, we propose strategies for effective incorporation of MMPIs in current anticancer therapies.

Section snippets

Implication of MMPs in carcinogenesis

Tumor invasion and metastasis is a multistep process that involves proteolytic degradation of the ECM, alteration of the cell–cell and cell–ECM interactions, and migration of the cancer cell through the basement membrane (Folkman, 1995; Kleiner & Stetler-Stevenson, 1999; Liotta et al., 1980). Several in vivo and in vitro studies have demonstrated the important role of MMPs in these processes. In that regard, overexpression of various MMPs can markedly increase the invasive behaviour of tumor

Pharmacologic inhibition of MMPs

Several steps in the synthesis, secretion, activation and enzymatic activity of MMPs are amenable to pharmacological intervention. Firstly, synthesis of MMPs is tightly regulated at the transcriptional level (Westermarck & Kahari, 1999). Extracellular stimuli including growth factors, cytokines and adhesion molecules activate the three classes of mitogen-activated protein kinases (MAPKs) – the extracellular signal-regulated kinases 1 and 2 (ERK1, 2), the stress-activated Jun N-terminal kinases

Evaluation of MMPIs as anticancer agents

The clinical development of MMPIs was from the beginning very problematic. In dose-escalation, safety-determining (Phase I) trials these drugs produced dose-limiting musculoskeletal toxicities (pain and inflammation) which had not been observed during preclinical evaluation (Whittaker, Floyd, Brown, & Gearing, 1999). Although reversible upon discontinuation of the drugs, the musculoskeletal pain was unresponsive to non-narcotic analgesics leading to limitation of duration of treatment and

Etiologies for the poor clinical performance of MMPIs

Given the promising activity of MMPIs in a plethora of preclinical models, their poor performance in phase III clinical trials was definitely unexpected. Multiple etiologies have been proposed for this discrepancy. The first reason is the fact that animal models of cancer cannot always predict the clinical outcome of human tumors. This is especially true in the case of MMPIs, as there are differences between mouse and human MMP biology. For example, deletion of MMP-2 in mice produces no

Conclusions—future prospects

The important role of MMPs in the process of carcinogenesis is well established. Nevertheless, phase III clinical trials of MMPIs as anticancer agents failed to reach their endpoints of progressive-free and overall survival. Although this cast a shadow over MMPIs in general, the prospect of targeting MMPs for anti-cancer therapy should not be undermined. In that regard, important lessons can be learned from the clinical development of MMPIs.

Firstly, future targeting of MMPs should occur in the

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