Genistein as an inducer of tumor cell differentiation: possible mechanisms of action.
Decreased activity of either topoisomerases or tyrosine kinases has been implicated in the differentiation of a number of cell types. It is therefore conceivable that genistein, because of its reported ability to inhibit these activities in vitro, may be an inducer of cellular differentiation. We investigated this possibility in human promyelocytic HL-60 and erythroid K-562 leukemia cells and in human SK-MEL-131 melanoma cells. Our results indicated that genistein, in a dose-dependent manner, inhibited cell multiplication and induced cell differentiation. The maturing HL-60 cells acquired granulocytic and monocytic markers. The differentiating K-562 cells stained positively with benzidine, which indicates the production of hemoglobin, an erythroid marker. Following genistein treatment, maturing SK-MEL-131 melanoma cells formed dendrite-like structures and exhibited increased tyrosinase activity and melanin content. Experiments were designed to identify the molecular mechanism of genistein's action. Data from our laboratory suggest that this isoflavone triggers the pathway that leads to cellular differentiation by stabilizing protein-linked DNA strand breakage. Other possible mechanisms reported in the literature are discussed.
Constantinou
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A
Department of Surgical Oncology, College of Medicine, University of Illinois at Chicago 60612.
Huberman
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E
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D004247:DNA / Q000378:metabolism; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D019833:Genistein; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology*; D008957:Models, Genetic; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004968:Estrogens, Non-Steroidal; D007529:Isoflavones; D004247:DNA; D019833:Genistein