Dykellic acid inhibits drug-induced caspase-3-like protease activation

• Published in: Biochemical and biophysical research communications Vol. 302; no. 3; pp. 539 - 544
• Main Authors: Lee, Sang-Han, Youk, Eun-Soo, Lee, Ho-Jae, Kho, Yung-Hee, Kim, Hwan Mook, Kim, Sung-Uk
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14-03-2003
• Subjects: Apoptosis; Apoptosis inhibitor; Blotting, Western; Calcium - metabolism; Camptothecin; Camptothecin - metabolism; Camptothecin - pharmacology; Caspase 3; Caspase-3-like protease; Caspases - metabolism; Cell Line; Cytochrome c Group - metabolism; Cytosol - enzymology; DNA Fragmentation; Dose-Response Relationship, Drug; Dykellic acid; Endonucleases - metabolism; Enzyme Activation; Enzyme Precursors - metabolism; HL-60 Cells; Humans; Inhibitor; Jurkat Cells; Microscopy, Electron, Scanning; Models, Chemical; Poly(ADP-ribose) Polymerases - metabolism; Propionates - pharmacology; Pyrones - pharmacology; Spectrometry, Fluorescence; Surface Plasmon Resonance; Time Factors; U937 Cells; Camptothecin; Apoptosis inhibitor; Caspase-3-like protease; Inhibitor; Dykellic acid
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/S0006-291X(03)00210-9

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.