TY - JOUR
T1 - Triterpenoids display single agent anti-tumor activity in a transgenic mouse model of chronic lymphocytic leukemia and small B cell lymphoma
AU - Kress, Christina L.
AU - Konopleva, Marina
AU - Martínez-García, Vanesa
AU - Krajewska, Maryla
AU - Lefebvre, Sophie
AU - Hyer, Marc L.
AU - McQueen, Teresa
AU - Andreeff, Michael
AU - Reed, John C.
AU - Zapata, Juan M.
PY - 2007/6/27
Y1 - 2007/6/27
N2 - Background. The synthetic triterpenoid 2-Cyano-3,12-Dioxooleana-1,9-Dien-28Oic 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 8 cell lymphoma (SBL). Principal Findings. CDDO an 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 ahd 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. Significance. The presented data demonstrate that triterpenoids CCDO and CDDO-Im reduce leukemia and lymphoma burden in vivo in a transgenic mouse model of CLL/SBL, and suppprt the clinical testing of CDDO-based synthetic triterpenoids in patients with CLL.
AB - Background. The synthetic triterpenoid 2-Cyano-3,12-Dioxooleana-1,9-Dien-28Oic 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 8 cell lymphoma (SBL). Principal Findings. CDDO an 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 ahd 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. Significance. The presented data demonstrate that triterpenoids CCDO and CDDO-Im reduce leukemia and lymphoma burden in vivo in a transgenic mouse model of CLL/SBL, and suppprt the clinical testing of CDDO-based synthetic triterpenoids in patients with CLL.
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U2 - 10.1371/journal.pone.0000559
DO - 10.1371/journal.pone.0000559
M3 - Article
C2 - 17593960
AN - SCOPUS:39349100310
SN - 1932-6203
VL - 2
JO - PloS one
JF - PloS one
IS - 6
M1 - e559
ER -