Hexadecylphosphocholine, a New Ether Lipid Analogue Studies on the Antineoplastic Activity in Vitro and in Vivo

Unger, Clemens; Damenz, W.; Fleer, E. A. M.; Kim, D. J.; Breiser, A.; Hilgard, P.; Engel, Jürgen; Nagel, G. A.; Eibl, Hansjörg

doi:10.3109/02841868909111249

Cited by 100 publications

(45 citation statements)

References 16 publications

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“…On the basis of these unique features, several clinical trials with oral perifosine are being conducted worldwide (5,6). Although ALKs have demonstrated antitumoral effects in in vitro and in vivo models (1,2,7,8), the exact mechanism of action remains elusive (2,9,10).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Activation of p21waf1/cip1 by Alkylphospholipids

et al. 2004

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Alkylphospholipids (ALKs) are a novel class of antitumor agents with an unknown mechanism of action. The first ALK tested in the clinic, miltefosine, has been approved recently in Europe for the local treatment of patients with cutaneous metastasis. Perifosine, the only available oral ALK, is being studied currently in human cancer clinical trials. We have shown previously that perifosine induces p21 waf1/cip1 in a p53-independent fashion and that induction of p21 waf1/cip1 is required for the perifosineinduced cell cycle arrest because cell lines lacking p21 waf1/cip1 are refractory to perifosine. In this report, we investigated the mechanism by which perifosine induces p21 waf1/cip1 protein expression. We observed that perifosine induces the accumulation of p21 waf1/cip1 mRNA without affecting p21 waf1/cip1 mRNA stability. Using several p21 waf1/cip1 promoter-driven luciferase reporter plasmids, we observed that perifosine activates the 2.4-kb full-length p21 waf1/cip1 promoter as well as a p21 promoter construct lacking p53-binding sites, suggesting that perifosine activates the p21 waf1/cip1 promoter independent of p53. The minimal p21 promoter region required for perifosine-induced p21 promoter activation contains four consensus Sp1-binding sites. Mutations in each particular Sp1 site block perifosine-induced p21 waf1/cip1 expression. Moreover, we showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of Sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased Sp1 binding and enhanced p21 waf1/cip1 transcription. These results represent a novel mechanism by which alkylphospholipids modulate transcription, and may contribute to the discovery of new signal transduction pathways crucial for normal and neoplastic cell cycle control.

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Section: Introductionmentioning

confidence: 99%

Transcriptional Activation of p21waf1/cip1 by Alkylphospholipids

et al. 2004

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“…Alkylphosphocholines (APCs), a group of compounds consisting of phosphocholine esterified to various long-chain aliphatic alcohols, exhibit in vitro and in vivo antineoplastic activities (6,28). In addition, they are active against several protozoan parasites such as Leishmania donovani (1,17), Trypanosoma cruzi (23), and Entamoeba histolytica (24).…”

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confidence: 99%

Cytotoxic Activities of Alkylphosphocholines against Clinical Isolates of Acanthamoeba spp

Walochnik¹,

Duchêne

Seifert

et al. 2002

Antimicrob Agents Chemother

112

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Free-living amoebae of the genus Acanthamoeba are causing serious chronic conditions such as destructive keratitis in contact lens wearers or granulomatous amoebic encephalitis in individuals with compromised immune systems. Both are characterized by the lack of availability of sufficiently effective and uncomplicated, manageable treatments. Hexadecylphosphocholine (miltefosine) is licensed for use as a topical antineoplastic agent, but it is also active in vitro against several protozoan parasites, and it was applied very successfully for the treatment of human visceral leishmaniasis. The aim of our study was to evaluate the efficacy of hexadecylphosphocholine and other alkylphosphocholines (APCs) against Acanthamoeba spp. The in vitro activities of eight different APCs against three Acanthamoeba strains of various pathogenicities were determined. All substances showed at least amoebostatic effects, and some of them disrupted the amoebae, as shown by the release of cytoplasmic enzyme activity. Hexadecylphosphocholine exhibited the highest degree of cytotoxicity against trophozoites, resulting in complete cell death at a concentration as low as 40 M, and also displayed significant cysticidal activity. Hexadecylphosphocholine may be a promising new candidate for the topical treatment of Acanthamoeba keratitis and, conceivably, even for the oral treatment of granulomatous amoebic encephalitis.

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“…Recently, hexadecylphosphocholine (HPC; miltefosine), an alkylphosphocholine originally developed as an anticancer drug (29), has proved to be an effective treatment for VL in clinical trials in India (15,27). Oral treatment with HPC at 100 mg/day for 4 weeks was effective in treating 114 of 120 VL cases (15) and cases that had not responded to prior antimonial therapy (27).…”

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confidence: 99%

Activities of Hexadecylphosphocholine (Miltefosine), AmBisome, and Sodium Stibogluconate (Pentostam) against Leishmania donovani in Immunodeficient scid Mice

Escobar

Yardley

Croft

2001

Antimicrob Agents Chemother

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In both scid and BALB/c mouse-Leishmania donovani models, hexadecyphosphocholine (miltefosine) and AmBisome had similar levels of activity. In contrast, sodium stibogluconate (Pentostam) was significantly less active against L. donovani in scid mice than in BALB/c mice. The in vitro anti-leishmanial activity of miltefosine was similar in peritoneal macrophages derived from both scid and BALB/c mice, whereas Pentostam and AmBisome were significantly more active in the latter.

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Hexadecylphosphocholine, a New Ether Lipid Analogue Studies on the Antineoplastic Activity in Vitro and in Vivo

Cited by 100 publications

References 16 publications

Transcriptional Activation of p21waf1/cip1 by Alkylphospholipids

Transcriptional Activation of p21waf1/cip1 by Alkylphospholipids

Cytotoxic Activities of Alkylphosphocholines against Clinical Isolates of Acanthamoeba spp

Activities of Hexadecylphosphocholine (Miltefosine), AmBisome, and Sodium Stibogluconate (Pentostam) against Leishmania donovani in Immunodeficient scid Mice

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