An MMP-2/MMP-9 inhibitor, 5a, enhances apoptosis induced by ligands of the TNF receptor superfamily in cancer cells

Abstract

Several studies have shown that matrix metalloproteases (MMPs) promote tumor growth, invasion, and metastasis. Consequently, MMP inhibitors have been developed as a new class of anticancer drugs, many of which are in clinical trials. The exact mechanism of the antineoplastic activity of MMP antagonists is unknown. To investigate the mechanism, we hypothesized that MMP inhibitors enhance the actions of apoptosis-inducing agents. To test this hypothesis, we treated breast, melanoma, leukemia, osteosarcoma, and normal breast epithelial cells with (2R)-2-[(4-biphenylsulfonyl)amino]-3-phenylproprionic acid (compound 5a), an organic inhibitor of MMP-2/MMP-9, alone or in combination with TNFa or other apoptotic agents. FACS analysis showed that 5a interacted synergistically with ligands of the TNF receptor superfamily, including TNFa and TNF receptor-like apoptosisinducing ligand (TRAIL), and with a Fas-cross-linking antibody (CH11), UV, paclitaxel, thapsigargin, and staurosporin, to induce apoptosis in a cell-type-specific manner. Other MMP inhibitors did not synergize with TNFa. Compound 5a did not act directly on the mitochondrion or via changes in protein synthesis. Instead, the mechanism requires ligandreceptor interaction and caspase 8 activation. Investigation of the effect of 5a on tumor growth in vivo revealed that continuous treatment of subcutaneous melanoma with a combination of 5a plus TRAIL reduced tumor growth and angiogenesis in nude mice. Our data demonstrate that 5a possesses a novel proapoptotic function, thus providing an alternative mechanism for its antineoplastic action. These observations have important implications for combination cancer therapy.

MMP-2 siRNA induced Fas/CD95-mediated extrinsic II apoptotic pathway in the A549 lung adenocarcinoma cell line

“…Some studies have reported that MMPs promote tumor growth by releasing growth factors from their inactive membrane-bound form (Haro et al, 2000), thereby suggesting that MMP antagonists would inhibit cell growth. On the other hand, different studies have reported that MMPIs inhibit tumor proliferation by inducing apoptosis via the release of ligands such as TRAIL and TNFa from their membrane-bound inactive forms (Nyormoi et al, 2003). In a previous study, we demonstrated that adenoviral-mediated siRNA delivery of MMP-2 inhibited lung cancer growth and metastasis (Chetty et al, 2006).…”

Gelatinase-mediated migration and invasion of cancer cells

“…A combination therapy of MMP-inhibitor together with a cytotoxic drug seems to be a more attractive alternative. Some reports have indicated a synergistic effect of gelatinase selective inhibitors with apoptosis inducing agents in cell culture (Nyormoi et al, 2003). Animal models with a combination therapy have been promising, with reduced metastasis and increased survival (Haq et al, 2000;Yamamoto et al, 2003).…”

On the TRAIL to therapeutic intervention in liver disease

“…97 Tissue inhibitors of MMPs have been suggested to be useful in combination therapy with TRAIL because an MMP-2/ MMP-9 inhibitor caused reduced tumor growth and angiogenesis in nude mice. 98 However, the role of tissue inhibitors of MMPs in combination with TRAIL needs to be further investigated to determine the extent to which these molecules can overcome microenvironmentally induced resistance to TRAIL.…”