title: The lignan niranthin poisons Leishmania donovani topoisomerase IB and favours a Th1 immune response in mice.
abstract: Niranthin, a lignan isolated from the aerial parts of the plant Phyllanthus amarus, exhibits a wide spectrum of pharmacological activities. In the present study, we have shown for the first time that niranthin is a potent anti-leishmanial agent. The compound induces topoisomerase I-mediated DNA-protein adduct formation inside Leishmania cells and triggers apoptosis by activation of cellular nucleases. We also show that niranthin inhibits the relaxation activity of heterodimeric type IB topoisomerase of L. donovani and acts as a non-competitive inhibitor interacting with both subunits of the enzyme. Niranthin interacts with DNA-protein binary complexes and thus stabilizes the 'cleavable complex' formation and subsequently inhibits the religation of cleaved strand. The compound inhibits the proliferation of Leishmania amastigotes in infected cultured murine macrophages with limited cytotoxicity to the host cells and is effective against antimony-resistant Leishmania parasites by modulating upregulated P-glycoprotein on host macrophages. Importantly, besides its in vitro efficacy, niranthin treatment leads to a switch from a Th2- to a Th1-type immune response in infected BALB/c mice. The immune response causes production of nitric oxide, which results in almost complete clearance of the liver and splenic parasite burden after intraperitoneal or intramuscular administration of the drug. These findings can be exploited to develop niranthin as a new drug candidate against drug-resistant leishmaniasis.
authors.affiliation: Molecular Parasitology Laboratory, Indian Institute of Chemical Biology, Jadavpur, Kolkata, India.
authors.forename: Sayan
authors.initials: S
authors.lastname: Chowdhury
authors.forename: Tulika
authors.initials: T
authors.lastname: Mukherjee
authors.forename: Rupkatha
authors.initials: R
authors.lastname: Mukhopadhyay
authors.forename: Budhaditya
authors.initials: B
authors.lastname: Mukherjee
authors.forename: Souvik
authors.initials: S
authors.lastname: Sengupta
authors.forename: Sharmila
authors.initials: S
authors.lastname: Chattopadhyay
authors.forename: Parasuraman
authors.initials: P
authors.lastname: Jaisankar
authors.forename: Syamal
authors.initials: S
authors.lastname: Roy
authors.forename: Hemanta K
authors.initials: HK
authors.lastname: Majumder
mesh_terms: D000818:Animals; D000840:Anisoles / Q000302:isolation & purification / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000302:isolation & purification / Q000494:pharmacology*; D002478:Cells, Cultured; D004264:DNA Topoisomerases, Type I / Q000008:administration & dosage*; D004149:Dioxoles / Q000302:isolation & purification / Q000494:pharmacology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D005260:Female; D007893:Leishmania donovani / Q000187:drug effects* / Q000201:enzymology; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000276:immunology; D008099:Liver / Q000469:parasitology; D008264:Macrophages / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000378:metabolism; D059208:Parasite Load; D029803:Phyllanthus / Q000737:chemistry; D013154:Spleen / Q000469:parasitology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000840:Anisoles; D000981:Antiprotozoal Agents; D004149:Dioxoles; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; C475932:niranthin; D004264:DNA Topoisomerases, Type I