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Dihydrobetulinic Acid Induces Apoptosis in Leishmania donovani by Targeting DNA Topoisomerase I and II: Implications in Antileishmanial Therapy

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Title Dihydrobetulinic Acid Induces Apoptosis in Leishmania donovani by Targeting DNA Topoisomerase I and II: Implications in Antileishmanial Therapy
 
Creator Chowdhury, Arnab Roy
Mandal, Suparna
Goswami, Anindya
Ghosh, Monidipa
Mandal, Labanya
Chakraborty, Debabani
Ganguly, Agneyo
Tripathi, Gayatri
Mukhopadhyay, Sibabrata
Bandyopadhyay, Santu
Majumder, Hemanta K
 
Subject Chemistry
Infectious Diseases and Immunology
 
Description Leishmaniasis is the second-most dreaded parasitic disease in the modern world, behind malaria. The lack of effective vaccines
demand improved chemotherapy along with the development of lead compounds and newer targets. We report
here that the pentacyclic triterpenoid, dihydrobetulinic acid (DHBA), is a novel lead compound for antileishmanial therapy.
It acts by targeting DNA topoisomerases. DNA topoisomerase I and II activity was studied using relaxation and decatenation
assays. Mechanistic studies were based on the decreased mobility of enzyme-bound DNA compared with free DNA and
the differential mobility of nicked and supercoiled monomers in 1% agarose gel. Pulsed field gradient gel electrophoresis,
confocal microscopy, and transmission electron microscopy were performed to assess cytotoxicity of the compound and
ultrastructural damage of the parasite. Apoptosis was studied by the isolation of DNA from DHBA-treated parasites and subsequent
electrophoresis in 1% agarose gel. DHBA inhibits growth of Leishmania donovani promastigotes and amastigotes
with an IC50 of 2.6 and 4.1 �M respectively. The compound is a dual inhibitor of DNA topoisomerases that fails to induce DNA
cleavage and acts by preventing the formation of enzyme-DNA binary complex, ultimately inducing apoptosis. Treatment
of infected golden hamsters with the compound markedly reduces (> 92%) parasitic burden, both in spleen and liver.
Interestingly, the 17-decarboxylated analogue, dihydrolupeol, does not inhibit DNA topoisomerase I and II, has no effect on
parasitic growth, and also fails to induce apoptosis. DHBA is a potent antileishmanial agent that induces apoptosis by primarily
targeting DNA topoisomerases. Therefore it is a strong candidate for use in designing new antileishmanial drugs
 
Date 2003
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/1631/1/Molecular_Medicine%2C_2003.pdf
Chowdhury, Arnab Roy and Mandal, Suparna and Goswami, Anindya and Ghosh, Monidipa and Mandal, Labanya and Chakraborty, Debabani and Ganguly, Agneyo and Tripathi, Gayatri and Mukhopadhyay, Sibabrata and Bandyopadhyay, Santu and Majumder, Hemanta K (2003) Dihydrobetulinic Acid Induces Apoptosis in Leishmania donovani by Targeting DNA Topoisomerase I and II: Implications in Antileishmanial Therapy. Molecular Medicine, 9 (1-2). pp. 26-36.
 
Relation http://dx.doi.org/
http://www.eprints.iicb.res.in/1631/