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Vol. 59, Issue 5, 1094-1099, May 2001
Dana-Farber Cancer Institute, Harvard Medical School, Boston,
Massachusetts (Y.I., P.P., R.D., S.K., D.K.), and Norris Cotton Cancer
Center and Department of Pharmacology, Dartmouth Medical School,
Hanover, New Hampshire (M.B.S.)
The oleanane triterpenoid
2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) is a
multifunctional molecule that induces monocytic differentiation of
human myeloid leukemia cells and inhibits proliferation of diverse
human tumor cell lines. The present studies on human osteosarcoma cells
demonstrate that CDDO induces mitochondrial cytochrome c
release, caspase-3 activation, and internucleosomal DNA fragmentation.
Overexpression of the caspase-8 inhibitor CrmA blocked CDDO-induced
cytochrome c release and apoptosis. By contrast, overexpression of the antiapoptotic Bcl-xL protein blocked
CDDO-induced cytochrome c release, but only partly
inhibited caspase-3 activation and apoptosis. In concert with these
findings, we demonstrate that CDDO: 1) activates caspase-8 and thereby
caspase-3 by a cytochrome c-independent mechanism and 2)
induces cytochrome c release by caspase-8-dependent
cleavage of Bid. The results also demonstrate that treatment of
osteosarcoma cells with CDDO induces differentiation, as assessed by
alkaline phosphatase activity and osteocalcin production, and that this
response is abrogated in cells that overexpress CrmA. These findings
demonstrate that CDDO induces both osteoblastic differentiation and
apoptosis by caspase-8-dependent mechanisms.
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