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Disuccinyl Betulin Triggers Metacaspase-Dependent Endonuclease G-Mediated Cell Death in Unicellular Protozoan Parasite Leishmania donovani

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Title Disuccinyl Betulin Triggers Metacaspase-Dependent Endonuclease G-Mediated Cell Death in Unicellular Protozoan Parasite Leishmania donovani
 
Creator Chowdhury, Sayan
Mukherjee, Tulika
Roy Chowdhury, Somenath
Sengupta, Souvik
Mukhopadhyay, Sibabrata
Jaisankar, Parasuraman
Majumder, Hemanta K
 
Subject Chemistry
Infectious Diseases and Immunology
 
Description The unicellular organism Leishmania undergoes apoptosis-like cell death in response to external stress or exposure to antileishmanial agents. Here, we showed that 3-O,28-O-disuccinyl betulin (DiSB), a potent topoisomerase type IB
inhibitor, induced parasitic cell death by generating oxidative stress. The characteristic feature of the death process resembled the programmed cell death (PCD) seen in higher eukaryotes. In the current study, the generation of reactive oxygen species (ROS), followed by the depolarization of mitochondrial membrane potential (��m), caused a loss in ATP production in Leishmania
parasites. This further gave positive feedback to produce a large amount of ROS, which in turn caused oxidative DNA
lesions and genomic DNA fragmentation. The treatment of promastigotes with DiSB induced high expression levels of metacaspase protein that led to cell death in this unicellular organism. The PCD was insensitive to benzyloxycarbonyl-Val-Ala-Asp( OMe)-fluoromethylketone (zVAD-fmk), suggesting that the death process was not associated with the activation of caspases.
DiSB treatment translocated Leishmania donovani endonuclease G (LdEndoG) from mitochondria to the nucleus, which was responsible for the DNA degradation process. Conditional antisense knockdown of L. donovani metacaspase (LdMC), as well as EndoG, -subverted death of the parasite and rescued cell cycle arrest in G1 phase. The present study on the effector molecules associated with the PCD pathway of the parasite should help to manifest the mechanisms of PCD and also might be exploited in
antileishmanial chemotherapy.
 
Publisher American Society for Microbiology
 
Date 2014
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/2037/1/ANTIMICROBIAL_AGENTS_AND_CHEMOTHERAPY___58_(_4_)_2186%2D2201;2014[38].pdf
Chowdhury, Sayan and Mukherjee, Tulika and Roy Chowdhury, Somenath and Sengupta, Souvik and Mukhopadhyay, Sibabrata and Jaisankar, Parasuraman and Majumder, Hemanta K (2014) Disuccinyl Betulin Triggers Metacaspase-Dependent Endonuclease G-Mediated Cell Death in Unicellular Protozoan Parasite Leishmania donovani. Antimicrobial Agents and Chemotherapy, 58 (4). pp. 2186-2201.
 
Relation http://dx.doi.org/10.1128/AAC.02193-13
http://www.eprints.iicb.res.in/2037/