Pyrrocidine A, a metabolite of endophytic fungi, has a potent apoptosis-inducing activity against HL60 cells through caspase activation via the Michael addition.

Abstract

Pyrrocidine A is a known antimicrobial compound produced by endophytic fungi and has a unique 13-membered macrocyclic alkaloid structure with an α,β-unsaturated carbonyl group. We have previously reported that pyrrocidine A shows potent cytotoxicity against human acute promyelocytic leukemia HL60 cells, and the activity is 70-fold higher than that of pyrrocidine B which is the analog lacking the α,β-unsaturated carbonyl group. Pyrrocidine A induced nuclear condensation, DNA fragmentation and caspase activation in HL60 cells. Since the DNA fragmentation was suppressed by pretreatment with the pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone (z-VAD-fmk), caspase-mediated apoptosis contributes to pyrrocidine A-induced cytotoxicity. JFCR39 human cancer cells panel indicated that the mechanism of action of pyrrocidine A is different from other clinical anticancer drugs, and this compound broadly inhibited the growth of various cancer cell lines. The apoptosis induction by pyrrocidine A was suppressed by both N-acetyl-l-cysteine (NAC) and glutathione, both of which are thiol-containing antioxidants. Furthermore, pyrrocidine A directly bound to N-acetyl-l-cysteine methyl ester (NACM) through the Michael-type addition at the α,β-unsaturated carbonyl group and was detected by HPLC and liquid chromatography-ESI-tandem MS (LC-ESI-MS/MS) analyses. This indicates that this moiety is crucial for the potent apoptosis-inducing activity of pyrrocidine A.

• Authors: Shota Uesugi, Nozomi Fujisawa, Jun Yoshida, Mitsuru Watanabe, Shingo Dan, Takao Yamori, Yoshihito Shiono, Ken-ichi Kimura
• Journal: The Journal of antibiotics (J Antibiot (Tokyo)) Vol. 69 Issue 3 Pg. 133-40 (Mar 2016) ISSN: 1881-1469 [Electronic] England
• PMID: 26506860 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Chloromethyl Ketones
• Anti-Infective Agents
• Antineoplastic Agents
• Bridged-Ring Compounds
• Caspase Inhibitors
• Oligopeptides
• Pyrrolidinones
• Reactive Oxygen Species
• benzyloxycarbonyl-valyl-alanyl-aspartic acid
• benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
• pyrrocidine A
• pyrrocidine B
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Amino Acid Chloromethyl Ketones (pharmacology)
• Anti-Infective Agents (pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Bridged-Ring Compounds (pharmacology)
• Caspase Inhibitors (pharmacology)
• DNA Fragmentation (drug effects)
• HL-60 Cells
• Humans
• Hypocreales (chemistry)
• Oligopeptides (pharmacology)
• Pyrrolidinones (pharmacology)
• Reactive Oxygen Species
• Tandem Mass Spectrometry