As a promising new class of anticancer drugs, camptothecins have advanced to the forefront of several areas of therapeutic and developmental
chemotherapy. In the present study, we report that
NSC606985, a rarely studied
camptothecin analog, induces apoptosis in
acute myeloid leukemia (AML) cells NB4 and U937 and inhibits the proliferation without cell death in breakpoint cluster region-Abelson murine
leukemia (bcr-abl)
kinase-carrying leukemic K562 cells. For apoptosis induction or growth arrest, nanomolar concentrations of
NSC606985 are sufficient. At such low concentrations, this agent also significantly inhibits the clonogenic activity of hematopoietic progenitors from patients with AML. For apoptosis induction,
NSC606985 rapidly induces the proteolytic activation of
protein kinase Cdelta (PKCdelta) with loss of mitochondrial transmembrane potential (DeltaPsim) and
caspase-3 activation. Cotreatment with
rottlerin, a PKCdelta-specific inhibitor, completely blocks NSC606985-induced mitochondrial DeltaPsim loss and
caspase-3 activation, while the inhibition of
caspase-3 by z-DEVD-fluoromethyl
ketone (
Z-DEVD-fmk) only partially attenuates PKCdelta activation and apoptosis. These data indicate that NSC606985-induced PKCdelta activation is an early event upstream to mitochondrial DeltaPsim loss and
caspase-3 activation, while activated
caspase-3 has an amplifying effect on PKCdelta proteolysis. In addition, NSC606985-induced apoptosis by PKCdelta also involves caspase-3-independent mechanisms. Taken together, our results suggest that
NSC606985 is a potential agent for the treatment of AML.