In vitro and in vivo antitumoral activity of alkylphosphonates

Ries, Uwe J.; Fleer, E. A. M.; Breiser, A.; Unger, Clemens; Stekar, J; Fenneberg, Karin; Eibl, H.

doi:10.1016/0959-8049(93)90583-2

Cited by 9 publications

(3 citation statements)

References 15 publications

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“…These compounds are directly absorbed into both plasma and intracellular membranes, where they accumulate [28]. It might be assumed therefore that they interfere with membrane lipid composition and metabolic processes, although the effects of HePC on cell proliferation and metabolism may well differ depending upon the cell type or line [29] and/or the uptake rate into the cell [30]. Nevertheless, one consistent finding is that HePC causes a reduction in the biosynthesis of PC.…”

Section: Discussionmentioning

confidence: 99%

Hexadecylphosphocholine inhibits phosphatidylcholine synthesis via both the methylation of phosphatidylethanolamine and CDP-choline pathways in HepG2 cells

Jiménez-López

Carrasco

Segovia

et al. 2004

The International Journal of Biochemistry & Cell Biology

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Section: Discussionmentioning

confidence: 99%

Hexadecylphosphocholine inhibits phosphatidylcholine synthesis via both the methylation of phosphatidylethanolamine and CDP-choline pathways in HepG2 cells

Jiménez-López

Carrasco

Segovia

et al. 2004

The International Journal of Biochemistry & Cell Biology

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“…Compared to miltefosine, erucylphosphocholine contains a longer hydrocarbon chain with a cis double bond and perifosine presents a piperidine moiety instead of the choline head group [1]. A wide variety of molecular mechanisms have been proposed to explain the antitumor activity of distinct membrane-directed APLs [14], whose action appears to depend on the cell type [15], the uptake rate into the cell [16] and the compound under study. Due to their chemical structure, APLs easily insert into lipid membranes and resist catabolic degradation; the level of partitioning into lipid bilayers depends on the degree of unsaturation of phospholipid alkyl chains and the amount of cholesterol.…”

Section: Reviewmentioning

confidence: 99%

Alterations in the homeostasis of phospholipids and cholesterol by antitumor alkylphospholipids

et al. 2010

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The alkylphospholipid analog miltefosine (hexadecylphosphocholine) is a membrane-directed antitumoral and antileishmanial drug belonging to the alkylphosphocholines, a group of synthetic antiproliferative agents that are promising candidates in anticancer therapy. A variety of mechanisms have been suggested to explain the actions of these compounds, which can induce apoptosis and/or cell growth arrest. In this review, we focus on recent advances in our understanding of the actions of miltefosine and other alkylphospholipids on the human hepatoma HepG2 cell line, with a special emphasis on lipid metabolism. Results obtained in our laboratory indicate that miltefosine displays cytostatic activity and causes apoptosis in HepG2 cells. Likewise, treatment with miltefosine produces an interference with the biosynthesis of phosphatidylcholine via both CDP-choline and phosphatidylethanolamine methylation. With regard to sphingolipid metabolism, miltefosine hinders the formation of sphingomyelin, which promotes intracellular accumulation of ceramide. We have demonstrated for the first time that treatment with miltefosine strongly impedes the esterification of cholesterol and that this effect is accompanied by a considerable increase in the synthesis of cholesterol, which leads to higher levels of cholesterol in the cells. Indeed, miltefosine early impairs cholesterol transport from the plasma membrane to the endoplasmic reticulum, causing a deregulation of cholesterol homeostasis. Similar to miltefosine, other clinically-relevant synthetic alkylphospholipids such as edelfosine, erucylphosphocholine and perifosine show growth inhibitory effects on HepG2 cells. All the tested alkylphospholipids also inhibit the arrival of plasma-membrane cholesterol to the endoplasmic reticulum, which induces a significant cholesterogenic response in these cells, involving an increased gene expression and higher levels of several proteins related to the pathway of biosynthesis as well as the receptor-mediated uptake of cholesterol. Thus, membrane-targeted alkylphospholipids exhibit a common mechanism of action through disruption of cholesterol homeostasis. The accumulation of cholesterol within the cell and the reduction in phosphatidylcholine and sphingomyelin biosyntheses certainly alter the ratio of choline-bearing phospholipids to cholesterol, which is critical for the integrity and functionality of specific membrane microdomains such as lipid rafts. Alkylphospholipid-induced alterations in lipid homeostasis with probable disturbance of the native membrane structure could well affect signaling processes vital to cell survival and growth.

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“…These multifaceted effects are transmitted by an ever growing body of disturbed intracellular signalling cascades, such as inhibition of phosphatidylcholine metabolism (specifically CTP:phosphocholine cytidyltransferase (CCT) activity), inhibition of PLA 2 , C, and D, inhibition of proteinkinase C (PKC), inhibition of mitogen‐activated protein kinase (MAPK)/extracellular signal‐regulated kinase (ERK)/phosphoinositide‐3‐kinase (PI‐3K) pathways via interference with Raf‐1 localisation to the membrane, induction of apoptosis or opening of voltage dependent Ca 2+ channels . The particular mechanism of action and the rate of uptake of the chosen APL via the membranes into the cells seem to depend on the specific cell type .…”

Section: Introductionmentioning

confidence: 99%

Modified phospholipids: From detergents towards small molecular response modifiers

Hildmann

Danker

2014

Euro J Lipid Sci & Tech

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Natural living cell membrane phospholipids undergo rapid and continuous turnover that provides essential signalling pathways controlling cell survival. Derived from (lyso)phosphatidylcholine, alkylphopspholipids (APL) were synthesized as metabolically stable analogues 50 years ago. The nature of the chemical structure of APLs allows them to be inserted into membranes easily and partition into the membrane bilayers according to the degree of unsaturation of phospholipid alkyl chains. In an effort to overcome the severe side effects of existing anti-tumour drugs, novel APLs with variations in alkyl side chain length, glycerol backbone, ester versus ether bonds, and different polar headgroups were developed to combine high anti-proliferative capacity with reduced cytotoxicity. The platelet activating factor (PAF) is a natural alkylphospholipid. Substituting the sn-2 position of platelet activating factor with an ether linked C2 spacer coupled to inositol created Inositol-C2-PAF. The effects of Inositol-C2-PAF can be divided into short-term and long-term effects. Short-term effects include the inhibition of phosphorylation events, resulting in inhibition of cell proliferation and reduced cell migration. Long-term effects of Inositol-C2-PAF, which are characterised by changes in gene expression, include up-regulation of biological processes linked to cell differentiation or system development.

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In vitro and in vivo antitumoral activity of alkylphosphonates

Cited by 9 publications

References 15 publications

Hexadecylphosphocholine inhibits phosphatidylcholine synthesis via both the methylation of phosphatidylethanolamine and CDP-choline pathways in HepG2 cells

Hexadecylphosphocholine inhibits phosphatidylcholine synthesis via both the methylation of phosphatidylethanolamine and CDP-choline pathways in HepG2 cells

Alterations in the homeostasis of phospholipids and cholesterol by antitumor alkylphospholipids

Modified phospholipids: From detergents towards small molecular response modifiers

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