The synthetic triterpenoid CDDO-Imidazolide suppresses experimental liver metastasis

摘要

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.