Nanomolar concentration of NSC606985, a camptothecin analog, induces leukemic-cell apoptosis through protein kinase Cδ–dependent mechanisms

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Abstract
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 Cδ (PKCδ) with loss of mitochondrial transmembrane potential (ΔΨm) and caspase-3 activation. Cotreatment with rottlerin, a PKCδ-specific inhibitor, completely blocks NSC606985-induced mitochondrial ΔΨm loss and caspase-3 activation, while the inhibition of caspase-3 by z-DEVD-fluoromethyl ketone (Z-DEVD-fmk) only partially attenuates PKCδ activation and apoptosis. These data indicate that NSC606985-induced PKCδ activation is an early event upstream to mitochondrial ΔΨm loss and caspase-3 activation, while activated caspase-3 has an amplifying effect on PKCδ proteolysis. In addition, NSC606985-induced apoptosis by PKCδ also involves caspase-3–independent mechanisms. Taken together, our results suggest that NSC606985 is a potential agent for the treatment of AML.