Inhibition of DNA unwinding and ATPase activities of human DNA helicase II by chemotherapeutic agents.
DNA helicases catalyze the unwinding of duplex DNA and thus play important roles in the processing of DNA, little is known about the effects of various cytotoxic or antitumor chemotherapeutic agents on purified human DNA helicases. We have determined the effect of actinomycin C1, VP-16, camptothecin, ethidium bromide, ellipticine, nogalamycin, novobiocin, genistein, m-AMSA, aphidicolin and daunorubicin on the enzymatic activities of purified human DNA helicase II which was identified as Ku autoantigen. Ku contains DNA helicase, ATPase and DNA end binding activities. Our data have shown that out of several chemotherapeutic agents tested ethidium bromide, actinomycin C1, daunorubicin and nogalamycin were inhibitors of DNA unwinding activity of human DNA helicase II with ID50 values of 8.44 microM, 11.68 microM, 6.23 microM and 0.42 microM respectively. These inhibitors also inhibited the ATPase activity but not the DNA binding activity of this helicase. This inhibition could be due to binding of these drugs to DNA, thereby impeding the movement of the helicase for unwinding action which may be their most important pharmacological function against cancer cells.
Tuteja
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International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, India. narendra@icgebnd.ernet.in
Phan
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Tuteja
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Ochem
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Falaschi
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D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000677:Amsacrine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016590:Aphidicolin / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004265:DNA Helicases; D003609:Dactinomycin / Q000031:analogs & derivatives / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D004611:Ellipticines / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004996:Ethidium / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D019833:Genistein; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D009621:Nogalamycin / Q000494:pharmacology; D009675:Novobiocin / Q000494:pharmacology; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D004611:Ellipticines; D004791:Enzyme Inhibitors; D007529:Isoflavones; D059004:Topoisomerase I Inhibitors; D000677:Amsacrine; C030013:cactinomycin; C034192:ellipticine; D009675:Novobiocin; D003609:Dactinomycin; D016590:Aphidicolin; D005047:Etoposide; D004247:DNA; D019833:Genistein; D000251:Adenosine Triphosphatases; D004265:DNA Helicases; D004996:Ethidium; D009621:Nogalamycin; D002166:Camptothecin; D003630:Daunorubicin