Triterpenoids display single agent anti-tumor activity in a transgenic mouse model of chronic lymphocytic leukemia and small B cell lymphoma.
BACKGROUND
The synthetic triterpenoid 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic Acid (CDDO) and derivatives display anti-tumor activity against a variety of cultured tumor cell lines and in mouse xenografts. In this report, we have studied the effects of CDDO and its imidazolide derivative (CDDO-Im) on chronic lymphocytic leukemia (CLL), using patients' CLL cells and a mouse model of CLL and small B cell lymphoma (SBL).


RESULTS
CDDO and CDDO-Im efficiently induced apoptosis of malignant human and mouse B-cells ex vivo, although CDDO-Im was over 10-fold more potent than CDDO. Treating mice with CLL/SBL with liposome-formulated CDDO or CDDO-Im resulted in significant reductions of B cells in blood, spleen and lung. CDDO-Im was shown to be more potent than CDDO, while treatment with empty liposomes had no impact on disease. CDDO-Im treatment initially resulted in an increase of circulating B cells, which correlates with a reduction in resident lymphocytes in spleen, and lungs, suggesting that CDDO-Im induces mobilization of tumor cells from lymphoid organs and infiltrated tissues into the circulation. Analysis of blood cells recovered from treated mice also showed that CDDO-Im is a potent inducer of tumor cells death in vivo. Furthermore, CDDO-Im efficiently eradicated mouse CLL/SBL cells but had little effect on the viability of normal B and T cells in vivo.


CONCLUSIONS
The presented data demonstrate that triterpenoids CDDO and CDDO-Im reduce leukemia and lymphoma burden in vivo in a transgenic mouse model of CLL/SBL, and support the clinical testing of CDDO-based synthetic triterpenoids in patients with CLL.
Kress
Christina L
CL
Burnham Institute for Medical Research, La Jolla, California, United States of America.
Konopleva
Marina
M
Martínez-García
Vanesa
V
Krajewska
Maryla
M
Lefebvre
Sophie
S
Hyer
Marc L
ML
McQueen
Teresa
T
Andreeff
Michael
M
Reed
John C
JC
Zapata
Juan M
JM
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D017353:Gene Deletion; D006801:Humans; D007124:Immunoenzyme Techniques; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects; D047992:TNF Receptor-Associated Factor 2 / Q000502:physiology*
C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D019253:Proto-Oncogene Proteins c-bcl-2; D047992:TNF Receptor-Associated Factor 2; D009828:Oleanolic Acid