title: Luteolin, an abundant dietary component is a potent anti-leishmanial agent that acts by inducing topoisomerase II-mediated kinetoplast DNA cleavage leading to apoptosis.
abstract: BACKGROUND
  Plant-derived flavonoids, which occur abundantly in our daily dietary intake, possess antitumor, antibacterial, and free radical scavenging properties. They form active constituents of a number of herbal and traditional medicines. Several flavonoids have been shown to exert their action by interacting with DNA topoisomerases and promoting site-specific DNA cleavage. Therefore, flavonoids are potential candidates in drug design. We report here that, although the flavonoids luteolin and quercetin are potent antileishmanial agents, luteolin has great promise for acting as a lead compound in the chemotherapy of leishmaniasis, a major concern in developing countries.
  
  
  METHODS
  Kinetoplast DNA (kDNA) minicircle cleavage in drug-treated parasites was measured by electrophoresis of the total cellular DNA, followed by Southern hybridization using 32P labeled kDNA as a probe. Cell cycle progression and apoptosis were measured by flow cytometry using propidium iodide and fluorescein isothiocyanate (FITC)-labeled Annexin V.
  
  
  RESULTS
  Luteolin and quercetin inhibited the growth of Leishmania donovani promastigotes and amastigotes in vitro, inhibited DNA synthesis in promastigotes, and promoted topoisomerase-II-mediated linearization of kDNA minicircles. The IC50 values of luteolin and quercetin were 12.5 microM and 45.5 microM, respectively. These compounds arrest cell cycle progression in L. donovani promastigotes, leading to apoptosis. Luteolin has no effect on normal human T-cell blasts. Both luteolin and quercetin reduced splenic parasite burden in animal models.
  
  
  CONCLUSIONS
  Luteolin and quercetin are effective antileishmanial agents. Quercetin has nonspecific effects on normal human T cells, but luteolin appears nontoxic. So, luteolin can be a strong candidate for antileishmanial drug design.
authors.affiliation: Molecular Parasitology Laboratory, Indian Institute of Chemical Biology, Calcutta.
authors.forename: B
authors.initials: B
authors.lastname: Mittra
authors.forename: A
authors.initials: A
authors.lastname: Saha
authors.forename: A R
authors.initials: AR
authors.lastname: Chowdhury
authors.forename: C
authors.initials: C
authors.lastname: Pal
authors.forename: S
authors.initials: S
authors.lastname: Mandal
authors.forename: S
authors.initials: S
authors.lastname: Mukhopadhyay
authors.forename: S
authors.initials: S
authors.lastname: Bandyopadhyay
authors.forename: H K
authors.initials: HK
authors.lastname: Majumder
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006224:Cricetinae; D053938:DNA Fragmentation / Q000187:drug effects; D018105:DNA, Kinetoplast / Q000378:metabolism*; D004032:Diet; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007893:Leishmania donovani / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000469:parasitology; D047311:Luteolin; D011794:Quercetin / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D059005:Topoisomerase II Inhibitors
chemical_list: D000981:Antiprotozoal Agents; D018105:DNA, Kinetoplast; D004791:Enzyme Inhibitors; D005419:Flavonoids; D059005:Topoisomerase II Inhibitors; D011794:Quercetin; D047311:Luteolin