Modulation of the G2 cell cycle checkpoint by sesquiterpene lactones psilostachyins A and C isolated from the common ragweed Ambrosia artemisiifolia.
A phenotypic cell-based assay for inhibitors of the G (2) DNA damage checkpoint was used to screen plant extracts from the US National Cancer Institute Natural Products Repository. It revealed activity in a methanol extract from the common ragweed Ambrosia artemisiifolia. Assay-guided fractionation led to the identification of the sesquiterpene lactones psilostachyins A and C as novel checkpoint inhibitors. Elimination of their alpha,beta-unsaturated carbonyl group caused a loss of activity, suggesting that the compounds can bind covalently to target proteins through Michael addition. Psilostachyins A and C also blocked cells in mitosis and caused the formation of aberrant microtubule spindles. However, the compounds did not interfere with microtubule polymerization in vitro. The related sesquiterpene lactones psilostachyin B, paulitin and isopaulitin were also isolated from the same extract but showed no checkpoint inhibition. The identification of the target(s) of psilostachyins A and C may provide further insight into the signalling pathways involved in cell cycle arrest and mitotic progression.
Sturgeon
Christopher M
CM
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
Craig
Kyle
K
Brown
Colleen
C
Rundle
Natalie T
NT
Andersen
Raymond J
RJ
Roberge
Michel
M
D031164:Ambrosia; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016195:G2 Phase; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
D000972:Antineoplastic Agents, Phytogenic; D010936:Plant Extracts; D012717:Sesquiterpenes