Triterpenoids Display Single Agent Activity in a Mouse Model of CLL/SBL.

The synthetic triterpenoid 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic Acid (CDDO) induces apoptosis of leukemia cells through a novel mechanism and has recently entered Phase I human clinical trials. We studied the effects of CDDO and its imidazolide derivative (CDDO-Im) on cultured human chronic lymphocytic leukemia (CLL) cells and on B cells from TRAF2DN/Bcl-2 transgenic mice, a new mouse model of CLL and small B cell lymphoma (SBL). Both triterpenoids efficiently induced death of malignant human and mouse B-cells ex vivo, although CDDO-Im was over 10-fold more potent than CDDO. Treating TRAF2DN/Bcl-2 mice that had developed leukemia with liposome-formulated CDDO or CDDO-Im resulted in significant reductions of B cells in blood, spleen and lung, with CDDO-Im more potent than CDDO, while treatment with empty liposomes had no impact on disease. Analysis of blood cells recovered from treated mice showed that CDDO-Im is a potent inducer of cell dead in vivo. Furthermore, CDDO-Im efficiently eradicated mouse CLL cells but had a lesser effect on the viability of normal B cells. These results demonstrate that triterpenoids CDDO and CDDO-Im reduce leukemia and lymphoma burden in vivo in a transgenic mouse model of CLL/SBL and suggest that CDDO-based synthetic triterpenoids should be tested for clinical activity in patients with CLL. Our results also provide evidence of the suitability of our mouse model of CLL/SBL as a preclinical platform for chemotherapeutic drug testing.