title: The synthetic triterpenoid CDDO-Imidazolide suppresses experimental liver metastasis.
abstract: Survival following diagnosis of liver metastasis remains poor and improved treatment strategies to combat liver metastases are needed. Synthetic triterpenoids, including 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Imidazolide or CDDO-Im), have been shown to inhibit primary tumor growth and lung metastasis in experimental models. Oral administration of CDDO-Im results in relatively high liver concentrations, suggesting that CDDO-Im may provide an approach to treatment of liver metastases. Here we assessed the effect of CDDO-Im on liver metastasis, using B16F1 (mouse melanoma) and HT-29 (human colon carcinoma) cells. In vitro, nanomolar concentrations of CDDO-Im arrested proliferation or induced cell death in both cell lines. In vivo, cells were injected via a surgically exposed mesenteric vein to target cells to the liver of mice. Mice were then treated with CDDO-Im (800 mg/kg diet) or vehicle control. Livers were removed at endpoint and metastatic burden was quantified by standard histology. In addition, a novel whole liver magnetic resonance imaging (MRI) technique was used to assess the effect of CDDO-Im on growing metastases as well as on non-dividing, solitary cancer cells present in the same livers. CDDO-Im treatment significantly decreased liver metastasis burden in both HT-29 (n = 8 treated, 10 control) and B16F1 (n = 15 treated, 16 control) injected mice (>60%, P < 0.05), but did not reduce the numbers of solitary B16F1 cancer cells (hypo-intensity) in the same livers (P = 0.9). This study demonstrates that CDDO-Im may be useful for the treatment metastatic liver disease as it successfully inhibits growth of actively proliferating liver metastases.
authors.affiliation: London Regional Cancer Program, 790 Commissioners Road East, Office A4-903B, London, ON N6A 4L6, Canada.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Townson
authors.forename: Ian C
authors.initials: IC
authors.lastname: Macdonald
authors.forename: Karen T
authors.initials: KT
authors.lastname: Liby
authors.forename: Lisa
authors.initials: L
authors.lastname: Mackenzie
authors.forename: David W
authors.initials: DW
authors.lastname: Dales
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Hedley
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Foster
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sporn
authors.forename: Ann F
authors.initials: AF
authors.lastname: Chambers
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D005260:Female; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000473:pathology*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D014315:Triterpenes / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D007093:Imidazoles; D014315:Triterpenes; D009828:Oleanolic Acid