RT Journal Article
SR Electronic
T1 Polygamain, a New Microtubule Depolymerizing Agent That Occupies a Unique Pharmacophore in the Colchicine Site
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 431
OP 439
DO 10.1124/mol.111.075838
VO 81
IS 3
A1 R. M. Hartley
A1 J. Peng
A1 G. A. Fest
A1 S. Dakshanamurthy
A1 D. E. Frantz
A1 M. L. Brown
A1 S. L. Mooberry
YR 2012
UL http://molpharm.aspetjournals.org/content/81/3/431.abstract
AB Bioassay-guided fractionation was used to isolate the lignan polygamain as the microtubule-active constituent in the crude extract of the Mountain torchwood, Amyris madrensis. Similar to the effects of the crude plant extract, polygamain caused dose-dependent loss of cellular microtubules and the formation of aberrant mitotic spindles that led to G2/M arrest. Polygamain has potent antiproliferative activities against a wide range of cancer cell lines, with an average IC50 of 52.7 nM. Clonogenic studies indicate that polygamain effectively inhibits PC-3 colony formation and has excellent cellular persistence after washout. In addition, polygamain is able to circumvent two clinically relevant mechanisms of drug resistance, the expression of P-glycoprotein and the βIII isotype of tubulin. Studies with purified tubulin show that polygamain inhibits the rate and extent of purified tubulin assembly and displaces colchicine, indicating a direct interaction of polygamain within the colchicine binding site on tubulin. Polygamain has structural similarities to podophyllotoxin, and molecular modeling simulations were conducted to identify the potential orientations of these compounds within the colchicine binding site. These studies suggest that the benzodioxole group of polygamain occupies space similar to the trimethoxyphenyl group of podophyllotoxin but with distinct interactions within the hydrophobic pocket. Our results identify polygamain as a new microtubule destabilizer that seems to occupy a unique pharmacophore within the colchicine site of tubulin. This new pharmacophore will be used to design new colchicine site compounds that might provide advantages over the current agents.