Tubulin-Perturbing Naphthoquinone Spiroketals
2008
Several natural and synthetic naphthoquinone spiroketals are potent inhibitors of the thioredoxin-thioredoxin reductase redox system. Based on the antimitotic and weak antitubulin actions noted for SR-7 ([8-(furan-3-ylmethoxy)- 1-oxo-1,4-dihydronaphthalene-4-spiro-2′-naphtho[1″,8″-de] [1′,3′][dioxin]), a library of related compounds was screened for tubulin-perturbing properties. Two compounds, TH-169 (5′-hydroxy- 4′H-spiro[1,3-dioxolane-2,1′-naphthalen]-4′-one) and TH-223 (5′-methoxy-4′H-spiro[1,3-dioxane-2,1′-naphthalen] -4′-one), had substantial effects on tubulin assembly and were antiproliferative at low micromolar concentrations. TH-169 was the most potent at blocking GTP-dependent polymerization of 10 μm tubulin in vitro with a remarkable 50% inhibitory concentration of ca. 400 nm. It had no effect on paclitaxel-induced microtubule assembly and did not cause microtubule hypernucleation. TH-169 failed to compete with colchicine for binding to β-tubulin. The 50% antiproliferative concentration of TH-169 against human cancer cells was at or slightly below 1 μm. Flow cytometry showed that 1 μm TH-169 caused an increase in G2/M and hypodiploid cells. TH-169 eliminated the PC-3 cells' polyploid population and increased their expression of p21WAF1and Hsp70 in a concentration-dependent manner. The antiproliferative effect of TH-169 was irreversible and independent of changes in caspases, actin, tubulin, glyceraldehyde phosphate dehydrogenase or Bcl-xS/L. This structurally simple naphthoquinone spiroketal represents a small molecule, tubulin-interactive agent with a novel apoptotic pathway and attractive biological function. © 2008 The Authors.
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