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Mefloquine induces ROS mediated programmed cell death in malaria parasite: Plasmodium

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Abstract

Recent studies pioneer the existence of a novel programmed cell death pathway in malaria parasite plasmodium and suggest that it could be helpful in developing new targeted anti-malarial therapies. Considering this fact, we evaluated the underlying action mechanism of this pathway in mefloquine (MQ) treated parasite. Since cysteine proteases play a key role in apoptosis hence we performed preliminary computational simulations to determine binding affinity of MQ with metacaspase protein model. Binding pocket identified using computational studies, was docked with MQ to identify it’s potential to bind with the predicted protein model. We further determined apoptotic markers such as mitochondrial dysregulation, activation of cysteine proteases and in situ DNA fragmentation in MQ treated/untreated parasites by cell based assay. Our results showed low mitochondrial membrane potential, enhanced activity of cysteine protease and increased number of fragmented DNA in treated parasites compared to untreated ones. We next tested the involvement of oxidative stress in MQ mediated cell death and found significant increase in reactive oxygen species generation after 24 h of treatment. Therefore we conclude that apart from hemozoin inhibition, MQ is competent to induce apoptosis in plasmodium by activating metacaspase and ROS production.

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Acknowledgments

We gratefully acknowledge to Council of Scientific and Industrial Research Center (CSIR), India for funding to perform this study. The authors also thank to the Director CDRI, for extending all the necessary facilities. Funding received from SPlenDID CSIR Project is also acknowledged. We are also thankful to Mr. A.L. Vishwakarma and Mrs. Rima Ray Sarkar for providing FACS and Confocal microscopy facility. CDRI communication no. 9264.

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Authors and Affiliations

  1. Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India

    Sarika Gunjan, Tanuj Sharma, Hemlata Dwivedi, Bhavana Singh Chauhan, Mohammad Imran Siddiqi & Renu Tripathi

  2. Division of Parasitology, Central Drug Research Institute, CSIR-CDRI, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India

    Sarika Gunjan, Sunil Kumar Singh, Hemlata Dwivedi, Bhavana Singh Chauhan & Renu Tripathi

  3. Division of Molecular and Structural Biology, CSIR-CDRI, Lucknow, India

    Tanuj Sharma & Mohammad Imran Siddiqi

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  1. Sarika Gunjan
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  2. Sunil Kumar Singh
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Correspondence to Renu Tripathi.

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Gunjan, S., Singh, S.K., Sharma, T. et al. Mefloquine induces ROS mediated programmed cell death in malaria parasite: Plasmodium. Apoptosis 21, 955–964 (2016). https://doi.org/10.1007/s10495-016-1265-y

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  • DOI: https://doi.org/10.1007/s10495-016-1265-y

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