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Luteolin, an Emerging Anti-Cancer Flavonoid, Poisons Eukaryotic DNA Topoisomerase

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Title Luteolin, an Emerging Anti-Cancer Flavonoid, Poisons Eukaryotic DNA Topoisomerase
 
Creator Roychowdhury, Arnab
Sharma, Shalini
Mandal, Suparna
Goswami, Anindya
Mukhopadhyay, Sibabrata
Majumder, Hemanta K
 
Subject Chemistry
Infectious Diseases and Immunology
 
Description Luteolin, a naturally occurring ¯avonoid, 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 IImediated
apoptosis. In the present study, we show that luteolin
completely inhibits the catalytic activity of eukaryotic DNA
topoisomerase I at a concentration of 40 lM, with an IC&! of
5 lM. Preincubation of enzyme with luteolin before adding a
DNA substrate increases the inhibition of the catalytic activity
(IC&!¯0.66 lM). Treatment of DNA with luteolin before addition
of topoisomerase I reduces this inhibitory effect. Subsequent
¯uorescence tests show that luteolin not only interacts directly
with the enzyme but also with the substrateDNA,and intercalates
at a very high concentration ("250 lM) 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 ®rst 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.
 
Date 2002
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/1162/1/BIOCHEMICAL_JOURNAL__Volume_366___Pages_653%2D661___[27].pdf
Roychowdhury, Arnab and Sharma, Shalini and Mandal, Suparna and Goswami, Anindya and Mukhopadhyay, Sibabrata and Majumder, Hemanta K (2002) Luteolin, an Emerging Anti-Cancer Flavonoid, Poisons Eukaryotic DNA Topoisomerase. Biochemical Journal, 366. pp. 653-661.
 
Relation http://dx.doi.org/10.1042/BJ20020098
http://www.eprints.iicb.res.in/1162/