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Blood, 1 January 2002, Vol. 99, No. 1, pp. 326-335
NEOPLASIA
Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and
differentiation in acute myelogenous leukemia
Marina Konopleva,
Twee Tsao,
Peter Ruvolo,
Irina Stiouf,
Zeev Estrov,
Clinton E. Leysath,
Shourong Zhao,
David Harris,
Shirong Chang,
C. Ellen Jackson,
Mark Munsell,
Nanjoo Suh,
Gordon Gribble,
Tadashi Honda,
W. Stratford May,
Michael B. Sporn, and
Michael Andreeff
From the Department of Blood and Marrow
Transplantation, Section of Molecular Hematology and Therapy, and the
Departments of Bioimmunotherapy and Biostatistics, The University
of Texas M. D. Anderson Cancer Center, Houston, TX; The University
of Florida, Gainesville; Department of Medicine, Dartmouth College,
Department of Chemistry and Dartmouth Medical School, Department of
Pharmacology, Hanover, NH.
It has been shown that the novel synthetic triterpenoid CDDO
inhibits proliferation and induces differentiation and apoptosis in
myeloid leukemia cells. In the current study the effects of the C-28
methyl ester of CDDO, CDDO-Me, were analyzed on cell growth and
apoptosis of leukemic cell lines and primary acute myelogenous leukemia
(AML). CDDO-Me decreased the viability of leukemic cell lines,
including multidrug resistant (MDR)-1-overexpressing, p53null HL-60-Dox and of primary AML cells, and it
was 3- to 5-fold more active than CDDO. CDDO-Me induced a loss of
mitochondrial membrane potential, induction of caspase-3
cleavage, increase in annexin V binding and DNA fragmentation,
suggesting the induction of apoptosis. CDDO-Me induced pro-apoptotic
Bax protein that preceded caspase activation. Furthermore,
CDDO-Me inhibited the activation of ERK1/2, as determined by the
inhibition of mitochondrial ERK1/2 phosphorylation, and it blocked
Bcl-2 phosphorylation, rendering Bcl-2 less anti-apoptotic. CDDO-Me
induced granulo-monocytic differentiation in HL-60 cells and monocytic
differentiation in primary cells. Of significance, colony formation of
AML progenitors was significantly inhibited in a dose-dependent
fashion, whereas normal CD34+ progenitor cells were less
affected. Combinations with ATRA or the RXR-specific ligand LG100268
enhanced the effects of CDDO-Me on cell viability and terminal
differentiation of myeloid leukemic cell lines. In conclusion, CDDO-Me
is an MDR-1- and a p53-independent compound that exerts strong
antiproliferative, apoptotic, and differentiating effects in myeloid
leukemic cell lines and in primary AML samples when given in
submicromolar concentrations. Differential effects of CDDO-Me on
leukemic and normal progenitor cells suggest that CDDO-Me has potential
as a novel compound in the treatment of hematologic malignancies.
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