Synthetic triterpenoids cooperate with tumor necrosis factor-related apoptosis-inducing ligand to induce apoptosis of breast cancer cells

Cancer Res. 2005 Jun 1;65(11):4799-808. doi: 10.1158/0008-5472.CAN-04-3319.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Caspase 8
  • Caspases / metabolism
  • Down-Regulation / drug effects
  • Drug Synergism
  • Female
  • Humans
  • Imidazoles / administration & dosage
  • Imidazoles / pharmacology*
  • Membrane Glycoproteins / administration & dosage
  • Membrane Glycoproteins / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Oleanolic Acid / administration & dosage
  • Oleanolic Acid / analogs & derivatives*
  • Oleanolic Acid / pharmacology*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor / agonists
  • Receptors, Tumor Necrosis Factor / biosynthesis
  • Receptors, Tumor Necrosis Factor / immunology
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / pharmacology
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha / administration & dosage
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Up-Regulation / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
  • 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid
  • Antibodies, Monoclonal
  • Apoptosis Regulatory Proteins
  • Imidazoles
  • Membrane Glycoproteins
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • Recombinant Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10A protein, human
  • TNFRSF10B protein, human
  • TNFSF10 protein, human
  • Tnfrsf10b protein, mouse
  • Tnfsf10 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Oleanolic Acid
  • CASP8 protein, human
  • Casp8 protein, mouse
  • Caspase 8
  • Caspases