Reactive oxygen species and imbalance of calcium homeostasis contributes to curcumin induced programmed cell death in Leishmania donovani
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Curcumin, a polyphenol compound, has been recognized as a promising anti-cancer drug. The purpose of the present study was to investigate the cytotoxicity of curcumin to Leishmania donovani, the causative agent for visceral leishmaniasis. Flow cytometric analysis revealed that curcumin induced cell cycle arrest at G2/M phase. Incubation of Leishmania promastigotes with curcumin caused exposure of phosphatidylserine to the outer leaflet of plasma membrane. This event is preceded by curcumin-induced formation of reactive oxygen species (ROS) and elevation 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 (ΔΨm), release of Cytochrome c into the cytosol and concomitant nuclear alterations that included deoxynucleotidyltransferase-mediated dUTP end labeling (TUNEL) and DNA fragmentation. Taken together, these data indicate that curcumin has promising antileishmanial activity that is mediated by programmed cell death and, accordingly, merits further investigation as a therapeutic option for the treatment of leishmaniasis.
KeywordsLeishmaniadonovani Curcumin ROS NAC Calcium homeostasis
Reactive oxygen species
Terminal deoxynucleotidyltransferase enzyme-mediated dUTP end labeling
We thank Prof. S. Roy, the Director of our institute, for his interest in this work. We thank Dr. G. Tripathi for her help regarding the confocal microscopic work. This work was supported by the grants from Network Project NWP-0038 Council for Scientific and Industrial Research (CSIR), Government of India to HKM. R.D. was supported by Senior Research Fellowship from CSIR, Government of India.
- 6.Su CC, Chen GW, Lin JG, Wu LT, Chung JG (2006) Curcumin inhibits cell migration of human colon cancer colo 205 cells through the inhibition of nuclear factor kappa B/p65 and down-regulates cyclooxygenase-2 and matrix metalloproteinase-2 expressions. Anticancer Res 26:1281–1288Google Scholar
- 27.Mukherjee SB, Das M, Sudhandiran G, Shaha C (2002) Increase in cytosolic Ca2+ levels through the activation of non-selective cation channels induced by oxidative stress causes mitochondrial depolarization leading to apoptosis-like death in Leishmania donovani promastigotes. J Biol Chem 277:24717–24727. doi: 10.1074/jbc.M201961200 PubMedCrossRefGoogle Scholar
- 35.Sen N, Das BB, Ganguly A, Mukherjee T, Bandyopadhyay S, Majumder HK (2004) Camptothecin-induced imbalance in intracellular cation homeostasis regulates programmed cell death in unicellular hemoflagellate Leishmania donovani. J Biol Chem 279:52366–52375. doi: 10.1074/jbc.M406705200 PubMedCrossRefGoogle Scholar
- 37.Scheffler IE (1999) Mitochondria. Wiley-Liss, New YorkGoogle Scholar
- 49.Bilmen JG, Khan SZ, Javed MH, Michelangeli F (2001) Inhibition of the SERCA Ca2+ pumps by curcumin. Curcumin putatively stabilizes the interaction between the nucleotide-binding and phosphorylation domains in the absence of ATP. Eur J Biochem 268:6318–6327. doi: 10.1046/j.0014-2956.2001.02589.x PubMedCrossRefGoogle Scholar