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

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.

Derivatives of the antimalarial drug mefloquine are broad spectrum antifungal molecules with activity against drug-resistant clinical isolates

“…Feng et al found that MEF was among a large set of clinically used drugs that dissipate the proton motive force across the mitochondrial membrane of eukaryotic cells, including S. cerevisiae (40). The anti-malarial activity of MEF has been attributed to mitochondrial dysregulation and production of reactive oxygen species (ROS) (45). A similar mitochondrial effect has been reported in cervical cancer cell lines and results in a decrease in ATP levels as well as increased cellular ROS that lead to cell death (46).…”

Extracellular Vesicles Could Carry an Evolutionary Footprint in Interkingdom Communication

“…Traditionally, programed cell death (PCD) is defined as a genetically regulated mechanism that is used by multicellular organisms for homeostasis and development (Gunjan et al, 2016). However, in recent years, there has been increasing interest in death regulation in protozoan parasites, generating debate around the traditional classification of programed cell death (PCD) pathways (Proto et al, 2013).…”

“…Thus, understanding of the PCD mechanisms that take place during microbial infections is an exciting field of study, given that death signals might be used in therapeutic treatments. For example, Plasmodium, Trypanosoma, and Leishmania parasites present PCD features under distinct experimental conditions (Duszenko et al, 2006;Gunjan et al, 2016;Mandal et al, 2016;Basmaciyan et al, 2017;de Castro et al, 2017;Wei et al, 2018).…”

Expression of cysteine proteinases and cystatins in parasites and use of cysteine proteinase inhibitors in parasitic diseases. Part III: Protozoa (2): Plasmodium spp.

“…The investigators concluded that mefloquine induced apoptosis through MCA activation and production of reactive oxygen species, beside its main mechanism of action, i.e. inhibition of hemozoin formation [88] .…”