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Original Article

Iron enhances generation of free radicals by Artemisinin causing a caspase-independent, apoptotic death in Leishmania donovani promastigotes

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Pages 1289-1295 | Received 09 Mar 2010, Published online: 06 Sep 2010
 

Abstract

An increasing incidence of unresponsiveness to antimonials in Leishmaniasis has led to identification of plant-derived anti-leishmanial compounds like Artemisinin. Since iron-mediated generation of free radicals sustains the anti-malarial activity of Artemisinin, this study investigated whether similar mechanisms accounted for its activity in Leishmania promastigotes. Artemisinin effectively disrupted the redox potential via an increased generation of free radicals along with a decrease in levels of non-protein thiols. Attenuation of its IC50 by a free radical scavenger N-acetyl l-cysteine and an iron chelator desferoxamine established the pivotal role of free radicals and of the potentiating effect of iron. An enhanced Fluo-4 fluorescence reflected Artemisinin-induced mobilization of intracellular calcium, which triggered apoptosis. However, the absence of any detectable caspase activity indicated that the leishmanicidal activity of Artemisinin is mediated by an iron-dependent generation of reactive intermediates, terminating in a caspase-independent, apoptotic mode of cell death.

Acknowledgements

We thank Professor Sasanka Chakrabarti, Head, Department of Biochemistry, I.P.G.M.E. & R for his valuable suggestions.

Declaration of interest: This work received financial assistance from the Indian Council of Medical Research (ICMR) and Department of Science & Technology, Government of India. Ms Rupashree Sen and Ms Piu Saha are recipients of a Senior Research Fellowship from ICMR, Government of India.

This paper was first published online on Early Online on 5 July 2010.

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