Cardiotoxin III induces c-jun N-terminal kinase-dependent apoptosis in HL-60 human leukaemia cells.
Cardiotoxin III (CTX III), a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, has been reported to have anticancer activity. The molecular effects of CTX III on HL-60 cells were dissected in the present study. We found that the antiproliferative action of CTX III on HL-60 cells was mediated through apoptosis, as characterized by an increase of sub G1 population, DNA fragmentation and poly(ADP-ribose) polymerase (PARP) cleavage. Upregulation of Bax, downregulation of Bcl-2, the release of mitochondrial cytochrome c to cytosol and the activations of capase-9 and -3 were noted, while CTX III had no appreciable effect on the levels of Bcl-X(L) and Bad proteins. Moreover, c-Jun N-terminal kinase (JNK) was activated shortly after CTX III treatment in HL-60 cells. Consistently, the SP600125 compound, an anthrapyrazolone inhibitor of JNK, suppressed apoptosis induced by CTX III. As expected, this JNK inhibitor also attenuated the modulation of Bax and Bcl-2, as well as the cytosolic appearance of cytochrome c and the activation of caspase-3 and caspase-9 that induced by CTX III. These findings suggest that CTX III can induce apoptosis in HL-60 cells via the mitochondrial caspase cascade and the activation of JNK is critical for the initiation of the apoptotic death of HL-60 cells.
Chien
Ching-Ming
CM
Faculty of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.
Yang
Sheng-Huei
SH
Yang
Chun-Chieh
CC
Chang
Long-Sen
LS
Lin
Shinne-Ren
SR
D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D004179:Cobra Cardiotoxin Proteins / Q000502:physiology* / Q000627:therapeutic use; D004789:Enzyme Activation / Q000502:physiology; D018922:HL-60 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*
D000970:Antineoplastic Agents; D004179:Cobra Cardiotoxin Proteins; C082202:cardiotoxin III, Naja naja atra; D048031:JNK Mitogen-Activated Protein Kinases