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J. Biol. Chem., Vol. 279, Issue 50, 52366-52375, December 10, 2004

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Camptothecin-induced Imbalance in Intracellular Cation Homeostasis Regulates Programmed Cell Death in Unicellular Hemoflagellate Leishmania donovani^*

Nilkantha Sen, Benu Brata Das, Agneyo Ganguly, Tanmoy Mukherjee¶, Santu Bandyopadhyay||, and Hemanta K. Majumder**

From the Division of Molecular Parasitology, ^¶Division of Infectious Disease, and ^||Division of Immunology, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata 700 032, India

Leishmania, a unicellular trypanosomatid protozoan parasite, causes a wide range of human diseases ranging from the localized self-healing cutaneous lesions to fatal visceral leishmaniasis. However, it undergoes a process of programmed cell death during treatment with the topoisomerase I poison camptothecin (CPT). The present study shows that CPT-induced formation of reactive oxygen species increases the level of cytosolic calcium through the release of calcium ions from intracellular stores as well as by influx of extracellular calcium. Elevation of cytosolic calcium is responsible for depolarization of mitochondrial membrane potential (_m), which is followed by a significant decrease in intracellular pH levels. CPT-induced oxidative stress also causes impairment of the Na⁺-K⁺-ATPase pump and subsequently decreases the intracellular K⁺ level in leishmanial cells. A decrease in both intracellular pH and K⁺ levels propagates the apoptotic process through activation of caspase 3-like proteases by rapid formation of cytochrome c-mediated apoptotic complex. In addition to caspase-like protease activation, a lower level of intracellular K⁺ also enhances the activation of apoptotic nucleases at the late stage of apoptosis. This suggests that the physiological level of pH and K⁺ are inhibitory for apoptotic DNA fragmentation and caspase-like protease activation in leishmanial cells. Moreover, unlike mammalian cells, the intracellular ATP level gradually decreases with an increase in the number of apoptotic cells after the loss of _m. Taken together, the elucidation of biochemical events, which tightly regulate the process of growth arrest and death of Leishmania donovani promastigotes, allows us to define a more comprehensive view of cell death during treatment with CPT.

Received for publication, June 16, 2004 , and in revised form, September 1, 2004.

This paper is dedicated to the memory of Prof. A. N. Bhaduri, former director and coordinator of the Leishmania Programme of the Indian Institute of Chemical Biology, Kolkata, India.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a senior research fellowship from the Council for Scientific and Industrial Research, Government of India.

^** To whom correspondence should be addressed. Tel.: 91-33-2412-3207; Fax: 91-33-2473-5197; E-mail: hkmajumder{at}iicb.res.in.

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