Protein kinase C is not involved in the cytotoxic action of 1-octadecyl-2-O-methyl-sn-glycerol-3-phosphocholine in HL-60 and K562 cells

Heesbeen, Ellen C.; Verdonck, Leo F.; Staal, Gerard E.J.; Rijksen, Gert

doi:10.1016/0006-2952(94)90521-5

Cited by 20 publications

(5 citation statements)

References 14 publications

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“…However, inhibition of PKC did not necessarily match with the antiproliferative activity of miltefosine, and PKC-depleted cells did not alter their sensitivity towards the drug (19). Phosphatidylcholine biosynthesis has been shown to be inhibited by miltefosine (17).…”

Section: Discussionmentioning

confidence: 95%

Possible Mechanism of Miltefosine-Mediated Death of Leishmania donovani

Verma

Dey

2004

Antimicrob Agents Chemother

212

132

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Miltefosine causes leishmanial death, but the possible mechanism(s) of action is not known. The mode of action of miltefosine was investigated in vitro in Leishmania donovani promastigotes as well as in extra-and intracellular amastigotes. Here, we demonstrate that miltefosine induces apoptosis-like death in L. donovani based on observed phenomena such as nuclear DNA condensation, DNA fragmentation with accompanying ladder formation, and in situ labeling of DNA fragments by the terminal deoxyribonucleotidyltransferasemediated dUTP-biotin nick end labeling method. Understanding of miltefosine-mediated death will facilitate the design of new therapeutic strategies against Leishmania parasites.Miltefosine (1-O-hexadecylphosphocholine), an alkylphosphocholine and a membrane-active synthetic ether-lipid analogue originally developed for the treatment of cutaneous metastasis from mammary carcinomas (21, 32), has proved to be an effective treatment for human visceral leishmaniasis (25,38,(52)(53)(54)(55). It has been hailed as potentially the first oral treatment of human leishmaniasis (8,15,16,20,25,31,47,50). The leishmaniacidal activities of miltefosine have been associated with perturbation of the alkyl-phospholipid metabolism and the biosynthesis of alkyl-anchored glycolipids and glycoproteins (33,34). Although potential antitumor cell mechanisms of action of miltefosine have been elaborated in mammalian cells (13,44), its exact mode(s) of cytotoxicity has not been determined in Leishmania spp. (9,25,39,46,48,55). It has been known to induce apoptotic death in various cancer cell lines (13,28,32,43,60). However, it is not yet established whether miltefosine can bring about apoptosis-like death in all the forms of Leishmania parasite.There are now increasing numbers of reports regarding unicellular organisms undergoing apoptosis-like death, whose induction is not obligatory but activated under threatening circumstances (1,36,49). Cell death resembling metazoan apoptosis has been reported in several parasitic protozoans (4,10,30,36,49,59,61). Apoptosis greatly affects the host-parasite relationship, since the survival of the parasite inside the vector as well as in the macrophage requires strict control of the population of the parasite (12, 58). Apoptosis could be a useful mechanism to avoid killing of the entire population (36) and thus influence the chemotherapeutic strategies to limit the parasite (11).In the present study we sought to determine the mode of action of miltefosine in Leishmania donovani promastigotes as well as extra-and intracellular amastigotes. We have demonstrated that miltefosine causes apoptosis-like death in L. donovani. Our data set the stage for future development of this class of drug for better treatment of leishmaniasis. MATERIALS AND METHODSReagents. Miltefosine was a kind gift from Zentaris (Frankfurt, Germany). RPMI 1640 culture medium was from Gibco BRL. Fetal calf serum was obtained from Biological Industries (Kibbutz Beit Haemek, Israel). ApoAlert DNA fragmentation assay kit was ...

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Section: Discussionmentioning

confidence: 95%

Possible Mechanism of Miltefosine-Mediated Death of Leishmania donovani

Verma

Dey

2004

Antimicrob Agents Chemother

212

132

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“…However, a major role for these signalling pathways in the antitumour action of ET-18-OCH 3 can be questioned, as some inactive analogues show similar actions on these signalling pathways, there is a lack of correlation between the ether lipid doses required to show the above inhibitory effects and those needed for antitumour activity, and inhibitory actions on the above signalling pathways are observed in both ether lipid sensitive and resistant cells. In addition, contradictory results have been reported showing either activation, inhibition or no effect on PKC by ET-18-OCH 3 [65,169,[171][172][173][174][175][176][177], and cells depleted of PKC activity show similar sensitivity or resistance to ET-18-OCH 3 as cells expressing PKC activity [172].…”

Section: Apoptotic and Survival Signalling In Et-18-och 3 Antitumour mentioning

confidence: 86%

ET-18-OCH3 (Edelfosine): A Selective Antitumour Lipid Targeting Apoptosis Through Intracellular Activation of Fas / CD95 Death Receptor

Mollinedo¹,

Gajate²,

Martín‐Santamaría³

et al. 2004

CMC

123

103

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Synthetic ether-linked analogues of phosphatidylcholine and lysophosphatidylcholine, collectively named as antitumour lipids (ATLs), were initially synthesized in the late 60s, but have attracted a renewed interest since the finding that the ether lipid 1-O -octadecyl-2-O -methyl-rac-glycero-3-phosphocholine (ET-18-OCH 3 , edelfosine), a synthetic analogue of 2-lysophosphatidylcholine considered the ATL prototype, induces a selective apoptotic response in tumour cells, sparing normal cells. Unlike most chemotherapeutic agents currently used, ET-18-OCH 3 does not interact with DNA, but act at the cell membrane, and thereby its effects seem to be independent of the proliferative state of target cells. Each part of the molecular structure of ET-18-OCH 3 is important for its optimal proapoptotic activity. Recent progress has unveiled the molecular mechanism underlying the apoptotic action of ET-18-OCH 3 , involving membrane rafts and Fas/CD95 death receptor, and has led to the proposal of a two-step model for the ET-18-OCH 3 selective action on cancer cells, namely: a) ET-18-OCH 3 uptake into the tumour cell, but not in normal cells; b) intracellular activation of Fas/CD95 through its translocation and capping into membrane rafts. ET-18-OCH 3 constitutes the first antitumour drug acting through the intracellular activation of the Fas/CD95 death receptor. Computational docking studies have allowed us to propose a molecular model for the putative interaction of ET-18-OCH 3 with the intracellular Fas/CD95 death domain. This novel mechanism of action represents a new way to target tumour cells in cancer chemotherapy and can be of interest as a new framework in designing novel and more selective proapoptotic antitumour drugs.

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“…Suggestion has been made about the mitotic-signal transduction and second messenger generation via inhibition of protein kinase C (PKC) as one of the possible mode of action [105]. However, PKC depleted cells did not alter their sensitivity towards the drug [106]. Miltefosine inhibits phosphatidylcholine and sphingomyelin biosynthesis [107] and the translocation of CTP: phosphocholine biosynthesis, from its inactive cytosolic form to its active membrane-bound form [108].…”

Section: Alkylphospholipidsmentioning

confidence: 99%

Chemotherapy of Leishmaniasis: Past, Present and Future

Mishra¹,

Saxena²,

Singh³

2007

CMC

239

138

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Leishmaniasis is a parasitic disease caused by hemoflagellate, Leishmania spp. The parasite is transmitted by the bite of an infected female phlebotomine sandfly. The disease is prevalent throughout the world and in at least 88 countries. Nearly 25 compounds are reported to have anti-leishmanial effects but not all are in use. The pentavalent antimony compounds have remained mainstay for nearly 75 years. Pentavalent antimony is a prodrug that is reduced by glutathione to active trivalent species catalyzed by thiol-dependent-reductase. However, emergence of resistance led to the use of other compounds--amphotericin B, pentamidine, paromomycin, allopurinol etc. Amphotericin B, an antifungal macrolide polyene is characterized by the hydrophilic polyhydroxyl and hydrophobic polyene faces on it long axis. Presently, it is the only drug with highest cure rate. It acts on membrane sterols resulting in parasite cell lysis. Its lipid formulations have been developed to minimize side effects. Other anti-fungals like ketoconazole, fluconazole and terbinafine are found less effective. Recently, anticancer alkylphosphocholines have been found most effective oral compounds. These act as membrane synthetic ether-lipid analogues, and consist of alkyl chains in the lipid portions. Most promising of these are miltefosine (hexadecylphosphocholine), edelfosine (ET-18-OCH(3)) and ilmofosine (BM 41.440). However, the recent focus has been on identifying newer therapeutic targets in the parasite such as DNA topoisomerases. The present review describes the current understanding of different drugs against leishmaniasis, their chemistry, mode of action and the mechanism of resistance in the parasite. Future perspectives in the area of new anti-leishmanial drug targets are also enumerated. However, due to the vastness of the topic main emphasis is given on visceral leishmaniasis.

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Protein kinase C is not involved in the cytotoxic action of 1-octadecyl-2-O-methyl-sn-glycerol-3-phosphocholine in HL-60 and K562 cells

Cited by 20 publications

References 14 publications

Possible Mechanism of Miltefosine-Mediated Death of Leishmania donovani

Possible Mechanism of Miltefosine-Mediated Death of Leishmania donovani

ET-18-OCH3 (Edelfosine): A Selective Antitumour Lipid Targeting Apoptosis Through Intracellular Activation of Fas / CD95 Death Receptor

Chemotherapy of Leishmaniasis: Past, Present and Future

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