Modulating TRAIL-Mediated Apoptosis in Prostate Cancer Using Synthetic Triterpenoids

摘要

We have identified a group of synthetic triterpenoids, 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 induce apoptosis in breast and prostate cancer cells. Moreover, sub-lethal doses(nanomolar range) of triterpenoids sensitize TRAIL-resistant breast and prostate cancer cells to TRAIL-mediated apoptosis. For example, in T47D and MDA-MB-468 breast cancer cells, TRAIL falls to initiate caspase-8 processing and consequently does not initiate TRAIL-mediated apoptosis. Concomitant treatment with CDDO or CDDO-Im reverses the TRAIL-resistant phenotype, leading to rapid induction of TRAIL- mediated apoptosis, while having no adverse effects on normal human mammary epithelial cells (HMEC). Mechanistically, CDDO and CDDO-Im 1)down-regulate the anti-apoptotic protein c-FLIP, which inhibits caspase-8 activation at the DISC (death-inducing signaling complex), 2) and induce up-regulation of the death receptors DR4 and DR5 on the cell surface. The combination of CDDO-Im and Trail treatment, we found no significant toxicity in mouse tissues or hematological parameters. In conclusion, triterpenoids used either alone, or in combination with TRAIL, represent a promising new cancer therapy, deserving of further pre- clinical testing.