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Blood, 1 May 2005, Vol. 105, No. 9, pp. 3714-3721.
Prepublished online as a Blood First Edition Paper on January 25, 2005; DOI 10.1182/blood-2004-10-4011.
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NEOPLASIA
Nanomolar concentration of NSC606985, a camptothecin analog, induces leukemic-cell apoptosis through protein kinase C –dependent mechanisms
Man-Gen Song,
Shen-Meng Gao,
Ke-Ming Du,
Min Xu,
Yun Yu,
Yu-Hong Zhou,
Qiong Wang,
Zhu Chen,
Yuan-Shan Zhu, and
Guo-Qiang Chen
From the Department of Pathophysiology, Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University, Shanghai, China; the Health Science Center, Shanghai Institutes for Biological Sciences and Graduate School, Chinese Academy of Sciences, Shanghai, China; the Department of Hematology, Zhong-Shan Hospital, Fu-Dan University, Shanghai, China; and the Department of Medicine/Endocrinology, Weill Medical College of Cornell University, New York, NY.
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 C (PKC) with loss of mitochondrial transmembrane potential (  m) and caspase-3 activation. Cotreatment with rottlerin, a PKC-specific inhibitor, completely blocks NSC606985-induced mitochondrial m loss and caspase-3 activation, while the inhibition of caspase-3 by z-DEVD-fluoromethyl ketone (Z-DEVD-fmk) only partially attenuates PKC activation and apoptosis. These data indicate that NSC606985-induced PKC activation is an early event upstream to mitochondrial m loss and caspase-3 activation, while activated caspase-3 has an amplifying effect on PKC proteolysis. In addition, NSC606985-induced apoptosis by PKC also involves caspase-3–independent mechanisms. Taken together, our results suggest that NSC606985 is a potential agent for the treatment of AML.
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