Nanomolar concentration of NSC606985, a camptothecin analog, induces leukemic-cell apoptosis through protein kinase Cdelta-dependent mechanisms.
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.
Song
Man-Gen
MG
Department of Pathophysiology, Shanghai Institute of , Chong-Qing South Rd, Shanghai 200025, China.
Gao
Shen-Meng
SM
Du
Ke-Ming
KM
Xu
Min
M
Yu
Yun
Y
Zhou
Yu-Hong
YH
Wang
Qiong
Q
Chen
Zhu
Z
Zhu
Yuan-Shan
YS
Chen
Guo-Qiang
GQ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D053148:Caspase 3; D020169:Caspases; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006801:Humans; D007425:Intracellular Membranes / Q000502:physiology; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology*; D008564:Membrane Potentials; D008928:Mitochondria / Q000502:physiology / Q000648:ultrastructure; D011493:Protein Kinase C / Q000378:metabolism*; D051745:Protein Kinase C-delta
D000970:Antineoplastic Agents; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D002166:Camptothecin