Dissociation of the effects of the antitumour ether lipid ET‐18‐OCH<sub>3</sub> on cytosolic calcium and on apoptosis

Alonso, Marı́a Teresa; Gajate, Consuelo; Mollinedo, Faustino; Modolell, Manuel; Alvarez, Javier; García‐Sancho, Javier

doi:10.1038/sj.bjp.0701271

Cited by 15 publications

(2 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Edelfosine (10 µM) was unable to induce apoptosis in J774 cells following 24 h incubation (<2% apoptosis), and caused less than 15% apoptosis after 48 h incubation. This is in stark contrast to the high sensitivity of other monocyte-like cell lines to edelfosine, such as human U937 cells [28] , [55] , [56] , which undergo rapid apoptosis and can therefore not be used as host cells to analyze the effect of ALPs on intracellular parasites residing in macrophages. Incubation of J774 macrophages with PTE-ET showed that the fluorescent edelfosine analog was taken up into the cell ( Figure 3A ).…”

Section: Resultsmentioning

confidence: 92%

In Vitro and In Vivo Efficacy of Ether Lipid Edelfosine against Leishmania spp. and SbV-Resistant Parasites

et al. 2012

Self Cite

View full text Add to dashboard Cite

BackgroundThe leishmaniases are a complex of neglected tropical diseases caused by more than 20 Leishmania parasite species, for which available therapeutic arsenal is scarce and unsatisfactory. Pentavalent antimonials (SbV) are currently the first-line pharmacologic therapy for leishmaniasis worldwide, but resistance to these compounds is increasingly reported. Alkyl-lysophospoholipid analogs (ALPs) constitute a family of compounds with antileishmanial activity, and one of its members, miltefosine, has been approved as the first oral treatment for visceral and cutaneous leishmaniasis. However, its clinical use can be challenged by less impressive efficiency in patients infected with some Leishmania species, including L. braziliensis and L. mexicana, and by proneness to develop drug resistance in vitro.Methodology/Principal FindingsWe found that ALPs ranked edelfosine>perifosine>miltefosine>erucylphosphocholine for their antileishmanial activity and capacity to promote apoptosis-like parasitic cell death in promastigote and amastigote forms of distinct Leishmania spp., as assessed by proliferation and flow cytometry assays. Effective antileishmanial ALP concentrations were dependent on both the parasite species and their development stage. Edelfosine accumulated in and killed intracellular Leishmania parasites within macrophages. In vivo antileishmanial activity was demonstrated following oral treatment with edelfosine of mice and hamsters infected with L. major, L. panamensis or L. braziliensis, without any significant side-effect. Edelfosine also killed SbV-resistant Leishmania parasites in in vitro and in vivo assays, and required longer incubation times than miltefosine to generate drug resistance.Conclusions/SignificanceOur data reveal that edelfosine is the most potent ALP in killing different Leishmania spp., and it is less prone to lead to drug resistance development than miltefosine. Edelfosine is effective in killing Leishmania in culture and within macrophages, as well as in animal models infected with different Leishmania spp. and SbV-resistant parasites. Our results indicate that edelfosine is a promising orally administered antileishmanial drug for clinical evaluation.

show abstract

Section: Resultsmentioning

confidence: 92%

In Vitro and In Vivo Efficacy of Ether Lipid Edelfosine against Leishmania spp. and SbV-Resistant Parasites

et al. 2012

Self Cite

View full text Add to dashboard Cite

show abstract

“…It must be noted that edelfosine, 2-APB and tetracaine are not entirely selective for their targets. Thus, edelfosine, in addition to inhibiting PLC, also activates platelet-activating factor (PAF) receptors [ 48 ]. While 2-APB inhibits the IP 3 Rs without an effect on the RyRs [ 49 ], it also inhibits TRPC3, 6 and 7 channels in VSMCs [ 50 ].…”

Section: Resultsmentioning

confidence: 99%

Vascular Kv7 channels control intracellular Ca2+ dynamics in smooth muscle

et al. 2020

View full text Add to dashboard Cite

show abstract

Involvement of mitochondria and caspase-3 in ET-18-OCH3-induced apoptosis of human leukemic cells

et al. 2000

Self Cite

View full text Add to dashboard Cite

The induction of cell death in leukemic HL‐60 cells by the ether lipid 1‐O‐octadecyl‐2‐O‐methyl‐rac‐glycero‐3‐phosphocholine (ET‐18‐OCH3; edelfosine) followed the typical apoptotic changes in ultrastructural morphology, including blebbing, chromatin condensation, nuclear membrane breakdown and extensive vacuolation. Using a cytofluorimetric approach, we found that ET‐18‐OCH3 induced disruption of the mitochondrial transmembrane potential (ΔΨm) followed by production of reactive oxygen species (ROS) and DNA fragmentation in leukemic cells. ET‐18‐OCH3 also induced caspase‐3 activation in human leukemic cells, as assessed by cleavage of caspase‐3 into the p17 active form and cleavage of the caspase‐3 substrate poly(ADP‐ribose) polymerase (PARP). ET‐18‐OCH3 analogues unable to induce apoptosis failed to disrupt ΔΨm and to activate caspase‐3. ET‐18‐OCH3‐resistant Jurkat cells generated from sensitive Jurkat cells showed no caspase‐3 activation and did not undergo ΔΨm disruption upon ET‐18‐OCH3 incubation. Cyclosporin A partially inhibited ΔΨm dissipation, caspase activation and apoptosis in ET‐18‐OCH3‐treated leukemic cells. Overexpression of bcl‐2 by gene transfer prevented ΔΨm collapse, ROS generation, caspase activation and apoptosis in ET‐18‐OCH3‐treated leukemic T cells. Pretreatment with the caspase inhibitor Z‐Asp‐2,6‐dichlorobenzoyloxymethylketone prevented ET‐18‐OCH3‐induced PARP proteolysis and DNA fragmentation, but not ΔΨm dissipation. ET‐18‐OCH3 did not affect the expression of caspases and bcl‐2‐related genes. ET‐18‐OCH3‐induced apoptosis did not require protein synthesis. Our data indicate that ΔΨm dissipation and caspase‐3 activation are critical events of the apoptotic cascade triggered by the antitumor ether lipid ET‐18‐OCH3, and that the sequence of events in the apoptotic action of ET‐18‐OCH3 on human leukemic cells is: ΔΨm disruption, caspase‐3 activation and internucleosomal DNA degradation. Int. J. Cancer 86:208–218, 2000. © 2000 Wiley‐Liss, Inc.

show abstract

Dissociation of the effects of the antitumour ether lipid ET‐18‐OCH₃ on cytosolic calcium and on apoptosis

Cited by 15 publications

References 21 publications

In Vitro and In Vivo Efficacy of Ether Lipid Edelfosine against Leishmania spp. and SbV-Resistant Parasites

In Vitro and In Vivo Efficacy of Ether Lipid Edelfosine against Leishmania spp. and SbV-Resistant Parasites

Vascular Kv7 channels control intracellular Ca2+ dynamics in smooth muscle

Involvement of mitochondria and caspase-3 in ET-18-OCH3-induced apoptosis of human leukemic cells

Contact Info

Product

Resources

About

Dissociation of the effects of the antitumour ether lipid ET‐18‐OCH3 on cytosolic calcium and on apoptosis

Cited by 15 publications

References 21 publications

In Vitro and In Vivo Efficacy of Ether Lipid Edelfosine against Leishmania spp. and SbV-Resistant Parasites

In Vitro and In Vivo Efficacy of Ether Lipid Edelfosine against Leishmania spp. and SbV-Resistant Parasites

Vascular Kv7 channels control intracellular Ca2+ dynamics in smooth muscle

Involvement of mitochondria and caspase-3 in ET-18-OCH3-induced apoptosis of human leukemic cells

Contact Info

Product

Resources

About

Dissociation of the effects of the antitumour ether lipid ET‐18‐OCH₃ on cytosolic calcium and on apoptosis