Luteolin, an emerging anti-cancer flavonoid, poisons eukaryotic DNA topoisomerase I

Arnab Roy Chowdhury, Shalini Sharma, Suparna Mandal, Anindya Goswami, Sibabrata Mukhopadhyay, Hemanta K. Majumder

Research output: Contribution to journalArticle

152 Scopus citations

Abstract

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 40 μM, with an IC50 of 5 μM. Preincubation of enzyme with luteolin before adding a DNA substrate increases the inhibition of the catalytic activity (IC50 = 0.66 μM). 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 (> 250 μM) 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.

Original languageEnglish (US)
Pages (from-to)653-661
Number of pages9
JournalBiochemical Journal
Volume366
Issue number2
DOIs
StatePublished - Sep 1 2002
Externally publishedYes

Keywords

  • Cleavable complex
  • DNA intercalator
  • Inhibitor
  • Topoisomerase poison

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Chowdhury, A. R., Sharma, S., Mandal, S., Goswami, A., Mukhopadhyay, S., & Majumder, H. K. (2002). Luteolin, an emerging anti-cancer flavonoid, poisons eukaryotic DNA topoisomerase I. Biochemical Journal, 366(2), 653-661. https://doi.org/10.1042/BJ20020098