Suppression of the proliferation and migration of oncogenic ras-dependent cell lines, cultured in a three-dimensional collagen matrix, by flavonoid-structured molecules.
The effects of 7-hydroxycoumarin, genistein and quercetin on two ras-oncogene-driven tumour cells (rat breast adenocarcinoma and human bladder carcinoma) were investigated using cellular (proliferation and migration) and molecular targets (p21ras GTPase activity and intracellular amount of p21ras protein). All three compounds inhibited the growth of both cell lines. Genistein was the most effective substance. Furthermore, 7-hydroxycoumarin and genistein affected the motile machinery of both cell lines because major fractions of the cells were slowed down or stopped locomotion. The phorbol ester, phorbol 12-myristate 13-acetate (PMA), a well-known tumour promoter, increased the locomotion behaviour of the cells; the time of migration, the velocity and the distance of migration increased under the control of PMA. 7-Hydroxycoumarin decreased the relative amount of intracellular p21ras, and concomitantly a PMA-induced decrease of p21ras GTPase activity could be partially antagonized by 7-hydroxycoumarin. Because of the low toxicity and the mode of action evaluated, it is likely that the best role for these substances may be adjuvant therapy of some malignancies following surgery. Profiles directed to migration and proliferation inhibition make these drugs exceptional candidates for chemopreventive strategies in tumours diagnosed as having increased ras oncogene levels.
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Institute of Immunology, University Witten/Herdecke, Germany.
Niggemann
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B
Zänker
K S
KS
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen; D003470:Culture Media; D011905:Genes, ras; D019833:Genistein; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007202:Indicators and Reagents / Q000378:metabolism; D007529:Isoflavones / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010084:Oxidation-Reduction; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology*; D051381:Rats; D013778:Tetrazolium Salts / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014468:Umbelliferones / Q000494:pharmacology*; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
D000970:Antineoplastic Agents; D003470:Culture Media; D007202:Indicators and Reagents; D007529:Isoflavones; D013778:Tetrazolium Salts; D014468:Umbelliferones; C059087:2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-((phenylamino)carbonyl)-2H-tetrazolium hydroxide; C031477:7-hydroxycoumarin; D006160:Guanosine Triphosphate; D003094:Collagen; D011794:Quercetin; D019833:Genistein; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)