Modulation of the G₂Cell Cycle Checkpoint by Sesquiterpene Lactones Psilostachyins A and C Isolated from the Common RagweedAmbrosia artemisiifolia

Abstract

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.

G2 Checkpoint Kinase Inhibitors Exert Their Radiosensitizing Effects Prior to the G2/M Transition

“…5,30,[37][38][39] This arrest is reversible-most cells resume cell cycle progression spontaneously by 24 hrs post-IR. G 2 -arrested cells can be forced to enter mitosis prematurely when treated with G 2 checkpoint kinase inhibitors between 16 and 24 hrs after IR.…”

“…G 2 -arrested cells can be forced to enter mitosis prematurely when treated with G 2 checkpoint kinase inhibitors between 16 and 24 hrs after IR. 5,30,[37][38][39] To determine whether treatment with checkpoint inhibitors of G 2 -arrested cells lacking p53 function provides radiosensitization, HCT116p53 -/-and MCF-7mp53 cells were irradiated with 0, 2, 4 or 6 Gy and 16 hrs later exposed for 8 hrs (i.e., 16-24 hrs) to concentrations of caffeine (2 mM) or isogranulatimide (10 mM), known to cause maximal G 2 checkpoint abrogation between 16 and 24 hrs after IR (see Fig. 1 for an overview of the experimental design).…”

“…1 for an overview of the experimental design). 5,30,[37][38][39] At 24 hrs, drugs were washed away, cells were cultured for 10 days and clonogenic survival was determined.…”

Trypanocidal and Leishmanicidal Activities of Sesquiterpene Lactones from Ambrosia tenuifolia Sprengel (Asteraceae)

“…Psilostachyin has demonstrated molluscicidal activity (35), inhibition of nitrite accumulation in cell cultures, and inhibition of the G 2 DNA damage checkpoint (9,28). Peruvin inhibits the aromatase enzyme activity in human placental microsomes (2).…”

V. Amygdalina: Folk Medicine, Analysis, and Potential Application for Cancer Treatment

“…Since then, more recent studies not only corroborated, but have extended their reports by finding new active components and their modes of actions. After an exhaustive review of studies and reports, the following represent the VA and SLs' anticancer activity literature: Many SLs (vernomydaline, vernolide, vernodaline, vernolepin, helenalin, elephantopin, eriofertopin, psilostachyins A, psilostachyins C, 2,3-dihydrohelenalin, bis-helenalinyl malonate, parthenolid, telekin, artemisinin, ergolide, Cynaropicrin and others) have been identified as anticancer agents [12][13][14][15][16][17][18][19][20][21][22]. (Fig.…”