Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2L) has been shown to induce apoptosis specifically in cancer cells while sparing normal tissues. Unfortunately not all cancer cells respond to TRAIL; therefore, TRAIL sensitizing agents are currently being explored. We have identified synthetic triterpenoids, including 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its derivative 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole (CDDO-Im), which sensitize TRAIL-resistant cancer cells to TRAIL-mediated apoptosis. Here we show that TRAIL-treated T47D and MDA-MB-468 breast cancer cells fail to initiate detectable caspase-8 processing and, consequently, do not initiate TRAIL-mediated apoptosis. Concomitant treatment with CDDO or CDDO-Im reverses the TRAIL-resistant phenotype, promoting robust caspase-8 processing and induction of TRAIL-mediated apoptosis in vitro. The combination of triterpenoids and monoclonal anti-TRAIL receptor-1 (DR4) antibody also induces apoptosis of breast cancer cells in vitro. From a mechanistic standpoint, we show that CDDO and CDDO-Im down-regulate the antiapoptotic protein c-FLIP(L), and up-regulate cell surface TRAIL receptors DR4 and DR5. CDDO and CDDO-Im, when used in combination with TRAIL, have no adverse affect on cultured normal human mammary epithelial cells. Moreover, CDDO-Im and TRAIL are well tolerated in mice and the combination of CDDO-Im and TRAIL reduces tumor burden in vivo in an MDA-MB-468 tumor xenograft model. These data suggest that CDDO and CDDO-Im may be useful for selectively reversing the TRAIL-resistant phenotype in cancer but not normal cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibodies, Monoclonal / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Caspase 8
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Caspases / metabolism
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Down-Regulation / drug effects
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Drug Synergism
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Female
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Humans
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Imidazoles / administration & dosage
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Imidazoles / pharmacology*
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Membrane Glycoproteins / administration & dosage
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Membrane Glycoproteins / pharmacology*
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Oleanolic Acid / administration & dosage
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Oleanolic Acid / analogs & derivatives*
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Oleanolic Acid / pharmacology*
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor / agonists
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Receptors, Tumor Necrosis Factor / biosynthesis
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Receptors, Tumor Necrosis Factor / immunology
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Recombinant Proteins / administration & dosage
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Recombinant Proteins / pharmacology
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Necrosis Factor-alpha / administration & dosage
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Tumor Necrosis Factor-alpha / pharmacology*
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Up-Regulation / drug effects
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Xenograft Model Antitumor Assays
Substances
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1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
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2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid
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Antibodies, Monoclonal
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Apoptosis Regulatory Proteins
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Imidazoles
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Membrane Glycoproteins
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor
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Recombinant Proteins
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TNF-Related Apoptosis-Inducing Ligand
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TNFRSF10A protein, human
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TNFRSF10B protein, human
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TNFSF10 protein, human
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Tnfrsf10b protein, mouse
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Tnfsf10 protein, mouse
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Tumor Necrosis Factor-alpha
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Oleanolic Acid
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CASP8 protein, human
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Casp8 protein, mouse
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Caspase 8
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Caspases