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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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Submitted October 19, 2004
Accepted December 30, 2004
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*
Department of Pathophysiology, Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University, Shanghai, China; Health Science Center, Shanghai Institutes for Biological Sciences and Graduate School, Chinese Academy of Sciences, Shanghai, China
Department of Pathophysiology, Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University, Shanghai, China
Health Science Center, Shanghai Institutes for Biological Sciences and Graduate School, Chinese Academy of Sciences, Shanghai, China
Department of Hematology, Zhong-Shan Hospital, Fu-Dan University, Shanghai, China
Department of Pathophysiology, Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University, Shanghai, China; Department of Medicine/Endocrinology, Weill Medical College of Cornell University, New York, NY, USA
* Corresponding author; email: chengq{at}shsmu.edu.cn.
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 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 AML patients. 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. Co-treatment 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-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 via 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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