title: Miltefosine resistance in Leishmania donovani involves suppression of oxidative stress-induced programmed cell death.
abstract: Miltefosine (MIL), an alkylphospholipid, is the first orally administrable anti-leishmanial drug. But due to its long half-life, miltefosine is highly vulnerable for resistance. Hence it is important to understand the mechanism of resistance and to elucidate its action on Leishmania. Here we investigate the miltefosine induced process of programmed cell death in wild type (miltefosine sensitive) and in laboratory generated resistant strains of Leishmania donovani. Results indicate that miltefosine induced apoptosis like death in a time and dose dependent manner in wild-type cells, but not in MIL-resistant cell line. The miltefosine resistant cells remained protected against miltefosine-induced loss of mitochondrial membrane potential, gradual ATP loss and cytochrome C release from mitochondria into the cytosol. Comparative transcriptomic study showed significantly increased expression of FeSODA and SIR2 genes, putatively involved in oxidative stress associated apoptotic cell death. We hypothesize that oxidative stress mediated apoptosis as an alternative mechanism of miltefosine resistance.
authors: Division of Clinical Microbiology, All India Institute of Medical Sciences, New Delhi, India.
authors: Jyotsna
authors: J
authors: Mishra
authors: Sarman
authors: S
authors: Singh
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D020869:Gene Expression Profiling; D007893:Leishmania donovani / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D007898:Leishmaniasis, Visceral / Q000188:drug therapy; D008264:Macrophages / Q000469:parasitology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
chemical_list: D000981:Antiprotozoal Agents; D010767:Phosphorylcholine; C039128:miltefosine; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D013482:Superoxide Dismutase; D037761:Sirtuins
keywords: Apoptosis; Leishmania donovani; Miltefosine resistance; Oxidative stress; Visceral leishmaniasis