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

Cell Death Differ. 2003 May;10(5):558-69. doi: 10.1038/sj.cdd.4401209.


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 TNFalpha or other apoptotic agents. FACS analysis showed that 5a interacted synergistically with ligands of the TNF receptor superfamily, including TNFalpha and TNF receptor-like apoptosis-inducing 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 TNFalpha. Compound 5a did not act directly on the mitochondrion or via changes in protein synthesis. Instead, the mechanism requires ligand-receptor 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Apoptosis Regulatory Proteins
  • Caspase 8
  • Caspase 9
  • Caspases / drug effects
  • Caspases / metabolism
  • Cytokines / pharmacology
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Intracellular Membranes / drug effects
  • Intracellular Membranes / physiology
  • Ligands
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinase Inhibitors*
  • Membrane Glycoproteins / pharmacology
  • Membrane Potentials / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mitochondria / drug effects
  • Mitochondria / enzymology
  • Mitochondria / physiology
  • Neoplasm Transplantation
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / pathology
  • Phenylalanine / analogs & derivatives
  • Phenylalanine / pharmacology*
  • Receptors, Tumor Necrosis Factor / metabolism
  • Sulfonamides / pharmacology*
  • TNF-Related Apoptosis-Inducing Ligand
  • Time Factors
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / enzymology
  • Tumor Necrosis Factor-alpha / pharmacology
  • Xenograft Model Antitumor Assays


  • 2-((4-biphenylsulfonyl)amino)-3-phenylpropionic acid
  • Apoptosis Regulatory Proteins
  • Cytokines
  • Enzyme Inhibitors
  • Ligands
  • Matrix Metalloproteinase Inhibitors
  • Membrane Glycoproteins
  • Receptors, Tumor Necrosis Factor
  • Sulfonamides
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tnfsf10 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Phenylalanine
  • CASP8 protein, human
  • CASP9 protein, human
  • Casp8 protein, mouse
  • Casp9 protein, mouse
  • Caspase 8
  • Caspase 9
  • Caspases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9