Dykellic acid inhibits drug-induced caspase-3-like protease activation.
Dykellic acid is a novel microbial metabolite isolated from the broth of Westerdykella multispora F50733. Investigations on the molecular function of dykellic acid revealed that this compound partially inhibits calcium influx, resulting in a decrease in Ca(2+)-dependent endonuclease activation and DNA fragmentation induced by camptothecin. In our experiments, active caspase-3-like protease cleavage of procaspase-3, PARP, and cytosolic cytochrome c was inhibited by dykellic acid in a concentration-dependent manner when the apoptosis was induced by camptothecin as well as doxorubicin. We confirmed that dykellic acid did not bind to camptothecin using surface plasmon resonance analysis. These results suggest that dykellic acid inhibits drug-induced apoptosis via a caspase-3-like protease-suppressing mechanism. Our data provide important information on the mechanism of action of dykellic acid and indicate that this compound may be employed in the treatment of specific caspase-3-like protease-mediated diseases.
Lee
Sang-Han
SH
Korea Research Institute of Bioscience & Biotechnology, Taejon 305-333, Republic of Korea. sang@mail.kribb.re.kr
Youk
Eun-Soo
ES
Lee
Ho-Jae
HJ
Kho
Yung-Hee
YH
Kim
Hwan Mook
HM
Kim
Sung-Uk
SU
D017209:Apoptosis; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002166:Camptothecin / Q000378:metabolism / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D003574:Cytochrome c Group / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004720:Endonucleases / Q000378:metabolism; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D008855:Microscopy, Electron, Scanning; D008956:Models, Chemical; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology*; D011753:Pyrones / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence; D020349:Surface Plasmon Resonance; D013997:Time Factors; D020298:U937 Cells
D003574:Cytochrome c Group; D004792:Enzyme Precursors; D011422:Propionates; D011753:Pyrones; C406051:dykellic acid; D011065:Poly(ADP-ribose) Polymerases; D004720:Endonucleases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D002118:Calcium; D002166:Camptothecin