Luteolin, a naturally occurring flavonoid, is abundant in our daily dietary intake. It exhibits a wide spectrum of pharmacological properties, but little is known about its biochemical targets other than the fact that it induces topoisomerase II-mediated apoptosis. In the present study, we show that luteolin completely inhibits the catalytic activity of eukaryotic DNA topoisomerase I at a concentration of 40μM, with an IC50 of 5μM. Preincubation of enzyme with luteolin before adding a DNA substrate increases the inhibition of the catalytic activity (IC50 = 0.66μM). Treatment of DNA with luteolin before addition of topoisomerase I reduces this inhibitory effect. Subsequent fluorescence tests show that luteolin not only interacts directly with the enzyme but also with the substrate DNA, and intercalates at a very high concentration (>250μM) without binding to the minor groove. Direct interaction between luteolin and DNA does not affect the assembly of the enzyme–DNA complex, as evident from the electrophoretic mobility-shift assays. Here we show that the inhibition of topoisomerase I by luteolin is due to the stabilization of topoisomerase-I DNA-cleavable complexes. Hence, luteolin is similar to camptothecin, a class I inhibitor, with respect to its ability to form the topoisomerase I-mediated ‘cleavable complex'. But, unlike camptothecin, luteolin interacts with both free enzyme and substrate DNA. The inhibitory effect of luteolin is translated into concanavalin A-stimulated mouse splenocytes, with the compound inducing SDS–K+-precipitable DNA–topoisomerase complexes. This is the first report on luteolin as an inhibitor of the catalytic activity of topoisomerase I, and our results further support its therapeutic potential as a lead anti-cancer compound that poisons topoisomerases.
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September 2002
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Research Article|
September 01 2002
Luteolin, an emerging anti-cancer flavonoid, poisons eukaryotic DNA topoisomerase I
Arnab Roy CHOWDHURY;
Arnab Roy CHOWDHURY
∗Molecular Parasitology Laboratory, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700 032, India,
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Shalini SHARMA;
Shalini SHARMA
∗Molecular Parasitology Laboratory, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700 032, India,
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Suparna MANDAL;
Suparna MANDAL
†Department of Medicinal Chemistry, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700 032, India
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Anindya GOSWAMI;
Anindya GOSWAMI
1
∗Molecular Parasitology Laboratory, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700 032, India,
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Sibabrata MUKHOPADHYAY;
Sibabrata MUKHOPADHYAY
†Department of Medicinal Chemistry, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700 032, India
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Hemanta K. MAJUMDER
Hemanta K. MAJUMDER
2
∗Molecular Parasitology Laboratory, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700 032, India,
2To whom correspondence should be addressed (e-mail [email protected]).
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Publisher: Portland Press Ltd
Received:
January 13 2002
Revision Received:
April 23 2002
Accepted:
May 23 2002
Accepted Manuscript online:
May 23 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 366 (2): 653–661.
Article history
Received:
January 13 2002
Revision Received:
April 23 2002
Accepted:
May 23 2002
Accepted Manuscript online:
May 23 2002
Citation
Arnab Roy CHOWDHURY, Shalini SHARMA, Suparna MANDAL, Anindya GOSWAMI, Sibabrata MUKHOPADHYAY, Hemanta K. MAJUMDER; Luteolin, an emerging anti-cancer flavonoid, poisons eukaryotic DNA topoisomerase I. Biochem J 1 September 2002; 366 (2): 653–661. doi: https://doi.org/10.1042/bj20020098
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