Publications (2)5.28 Total impact
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Article: Modulation of the G2 cell cycle checkpoint by sesquiterpene lactones psilostachyins A and C isolated from the common ragweed Ambrosia artemisiifolia.
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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.Planta Medica 11/2005; 71(10):938-43. · 2.15 Impact Factor -
Article: New okadaic acid analogues from the marine sponge Merriamum oxeato and their effect on mitosis.
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ABSTRACT: Inhibitors of the G2 DNA damage checkpoint can selectively sensitize cancer cells with impaired p53 tumor suppressor activity to killing by DNA-damaging drugs or ionizing radiation and have been proposed as a promising therapeutic strategy. An extract from the Northeastern Pacific marine sponge Merriamum oxeato showed G2 checkpoint inhibitory activity, and fractionation identified the known dinoflagellate toxin dinophysistoxin 1 (1) and the two novel analogues 27-O-acetylokadaic acid (2) and 27-O-acetyldinophysistoxin 1 (3) as the active compounds. The mixture of 1, 2, and 3 was extremely potent at inhibiting the G2 checkpoint (IC(50) = 1 ng/mL) and cellular protein Ser/Thr phosphatases (IC(50) = 1 ng/mL), and it radiosensitized MCF-7 breast cancer cells expressing mutated p53 at all concentrations tested. However, the mixture of 1, 2, and 3 was also very toxic to cells not exposed to DNA damage (IC(50) = 1 ng/mL), making these compounds poor candidates for therapeutic agents to augment the effectiveness of DNA-damaging therapies.Journal of Natural Products 07/2003; 66(6):838-43. · 3.13 Impact Factor
