Mouse embryonic fibroblast cells from transgenic mice overexpressing tNOX exhibit an altered growth and drug response phenotype.
Mouse embryonic fibroblast (MEF) cells prepared from transgenic mice overexpressing a cancer-specific and growth-related cell surface NADH oxidase with protein disulfide-thiol interchange activity grew at rates approximately twice those of wild-type embryonic fibroblast cells. Growth of transgenic MEF cells overexpressing tNOX was inhibited by low concentrations of the green tea catechin (-)-epigallocatechin-3-gallate (EGCg) or the synthetic isoflavene phenoxodiol. Both are putative tNOX-targeted inhibitors with anti-cancer activity. With both EGCg and phenoxodiol, growth inhibition was followed after about 48 h by apoptosis. Growth of wild-type mouse fibroblast cells from the same strain was unaffected by EGCg and phenoxodiol and neither compound induced apoptosis even at concentrations 100-1,000-fold higher than those that resulted in apoptotic death in the transgenic MEF cells. The findings validate earlier reports of evidence for tNOX presence as contributing to unregulated growth of cancer cells as well as the previous identification of the tNOX protein as the molecular target for the anti-cancer activities attributed to both EGCg and phenoxodiol. The expression of tNOX emerges as both necessary and sufficient to account for the cancer cell-specific growth inhibitions by both EGCg and phenoxodiol.
Yagiz
Kader
K
Department of Foods and Nutrition, Purdue University, West Lafayette, IN 47907, USA.
Wu
Lion-Ying
LY
Kuntz
Charles P
CP
James Morré
D
D
Morré
Dorothy M
DM
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D048430:Cell Shape; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D007529:Isoflavones / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D010084:Oxidation-Reduction; D010641:Phenotype
D016588:Anticarcinogenic Agents; D007529:Isoflavones; D002392:Catechin; C471183:phenoxodiol; C045651:epigallocatechin gallate; D009247:NADH, NADPH Oxidoreductases; C431909:tumor-associated NADH oxidase