Anticancer action of cubé insecticide: correlation for rotenoid constituents between inhibition of NADH:ubiquinone oxidoreductase and induced ornithine decarboxylase activities.
Rotenone and rotenoid-containing botanicals, important insecticides and fish poisons, are reported to have anticancer activity in rats and mice. The toxic action of rotenone is attributed to inhibition of NADH:ubiquinone oxidoreductase activity and the purported cancer chemopreventive effect of deguelin analogs has been associated with inhibition of phorbol ester-induced ornithine decarboxylase (ODC) activity. This study defines a possible relationship between these two types of activity important in evaluating the toxicology of rotenoid pesticides and the suitability of the anticancer model. Fractionation of cubé resin (the commercial rotenoid pesticide) establishes that the activity in both assays is due primarily to rotenone (IC50 = 0.8-4 nM), secondarily to deguelin, and in small part to rotenolone and tephrosin. In addition, the potency of 29 rotenoids from cubé insecticide for inhibiting NADH:ubiquinone oxidoreductase in vitro assayed with bovine heart electron transport particles satisfactorily predicts their potency in vivo in the induced ODC assay using noncytotoxic rotenoid concentrations with cultured MCF-7 human breast cancer cells (r = 0.86). Clearly the molecular features of rotenoids essential for inhibiting NADH:ubiquinone oxidoreductase are similar to those for blocking ODC induction. This apparent correlation extends to 11 flavonoids and stilbenoids from cubé resin (r = 0.98) and genistein and resveratrol except for lower potency and less selectivity than the rotenoids relative to cytotoxicity. These findings on cubé insecticide constituents and our earlier study comparing rotenone and pyridaben miticide indicate that inhibition of NADH:ubiquinone oxidoreductase activity lowers the level of induced ODC activity leading to the antiproliferative effect and anticancer action.
Fang
N
N
Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, California 94720-3112, USA.
Casida
J E
JE
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D042967:Electron Transport Complex I; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007306:Insecticides / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009955:Ornithine Decarboxylase / Q000378:metabolism*; D051381:Rats; D012402:Rotenone / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D014475:Uncoupling Agents / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; D007306:Insecticides; D014475:Uncoupling Agents; D012402:Rotenone; D009247:NADH, NADPH Oxidoreductases; D009955:Ornithine Decarboxylase; D042967:Electron Transport Complex I