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Cholesterol-lowering drug, in combination with chromium chloride, induces early apoptotic signals in intracellular L. donovani amastigotes, leading to death

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Abstract

Leishmania establishes a successful parasitism by evading both oxidative and non-oxidative killing pathways, and its drug resistance against the currently available therapeutics demands for a safe and cheap drug. Since the parasite synthesizes ergosterol instead of cholesterol, using the same biochemical pathway and enzymes, an inhibitor of HMG-CoA-Reductase, Lovastatin, has been tried for its anti-Leishmanial effect. Lovastatin, being an inhibitor of HMG-CoA-Reductase, inhibits infection by cholesterol depletion, while chromium chloride complexes, at their higher concentrations, are reported to exhibit cytotoxicity. In intracellular amastigotes, cytotoxicity has been checked by assessing various manifestation of cell death, viz. DNA fragmentation, AnnexinV-FITC binding and JC-1 fluorescence ratio. Release of hydrogen peroxide (HPO) and nitric oxide (NO) has been assessed in live cell. Lovastatin and CrCl3.6H2O in combination has appeared to be ineffective on promastigotes but has induced cytotoxic effect on the intracellular amastigotes through up-regulation of cellular signalling mechanisms. CrCl3.6H2O stimulates generation of NO, leading to reduction of the number of intracellular amastigote, while Lovastatin shows HPO-mediated killing of the same, keeping the host cell unaffected. This novel therapeutic approach, involving two known safe compounds in suboptimal doses, may resolve human visceral Leishmaniasis.

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Acknowledgements

We acknowledge Dr Santu Bandyopadhyay, Chief Scientist, Indian Institute of Chemical Biology, Jadavpur, Kolkata, for his support in FACS analysis. We also acknowledge Dr Nahid Ali, Ms Roma Sinha and Mr Anirban Manna, Indian Institute of Chemical Biology, Jadavpur, Kolkata, for their support and for providing L. donovani AG83-sensitive strain used in this study. We also acknowledge Department of Biotechnology (DBT) (Grant No. BT/PR15025/GBD/27/284/2010 (Order-I) dated 16.06.2011), India, for their financial support in this study.

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Authors and Affiliations

  1. Department of Biotechnology, National Institute of Technology Durgapur, Durgapur, West Bengal, India

    Amit Kumar Verma, Bhakti Laha, Monika Pandey, Uttariya Pal & Monidipa Ghosh

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  1. Amit Kumar Verma
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  2. Bhakti Laha
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  3. Monika Pandey
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  4. Uttariya Pal
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  5. Monidipa Ghosh
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Correspondence to Monidipa Ghosh.

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Corresponding editor: Amit Chattopadhyay

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Verma, A.K., Laha, B., Pandey, M. et al. Cholesterol-lowering drug, in combination with chromium chloride, induces early apoptotic signals in intracellular L. donovani amastigotes, leading to death. J Biosci 42, 427–438 (2017). https://doi.org/10.1007/s12038-017-9690-9

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  • DOI: https://doi.org/10.1007/s12038-017-9690-9

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