An in vitro study of hemicholinium-3 on phospholipid metabolism of Krebs II ascites cells

Hamza, M. H.; Lloveras, J; Ribbes, Gérard; Soula, G; Douste‐Blazy, Louis

doi:10.1016/0006-2952(83)90055-2

Cited by 23 publications

(11 citation statements)

References 20 publications

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“…In the case of HC3, both of these effects could be involved, because it has already been reported to be an inhibitor of choline penetration in other cellular systems, as well as an inhibitor of choline phosphorylation (3,8,16 On the other hand, the choline level is decreased by all of these compounds (Fig. 3).…”

Section: Resultsmentioning

confidence: 94%

Quaternary ammonium compounds efficiently inhibit Plasmodium falciparum growth in vitro by impairment of choline transport

Ancelin¹,

Vial²

1986

Antimicrob Agents Chemother

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Hemicholinium 3, decamethonium, and decyltrimethylammonium previously have been demonstrated to be efficient inhibitors, with 50% inhibitory concentrations of 4 x 10-6, 10-6, and 7 x 10-7 M, respectively. We show that lengthening of the alkyl chain of decyltrimethylammonium by successive additions of two carbon atoms up to hexadecyltrimethylammonium results in a very low 50% inhibitory concentration of 5 x 10-7 M for dodecyltrimethylammonium. Furthermore, hemicholinium 3 and decamethonium exerted their antiplasmodial activity, regardless of the developmental stage of the parasite, whereas decyltrimethylammonium was particularly lethal for the mature forms. After infected erythrocytes with radioactive choline were supplied, the determination of the water-soluble choline-containing compounds, as well as the assay of choline kinase activity, showed that the specific inhibition of phosphatidylcholine biosynthesis is related to the impairment of choline entry into erythrocytes. Thus, the impairment of the transport of choline, a natural polar head group of phospholipids, appears to be lethal for Plasmodium falciparum in vitro and could be a reasonable approach for a new malaria chemotherapy.The urgent need for new therapeutic approaches to Plasmodium falciparum malaria often has been pointed out (18) because of the resistance of both mosquitoes and parasites to various pesticides and conventional drugs (27). We have shown previously that phospholipid (PL) metabolism could constitute an ideal target for a new chemotherapy (25) because of its magnitude (9, 21, 24, 26) and specificity, because little or no PL biosynthesis occurs in mature mammalian erythrocytes (23). In our previous studies we showed that the lethal effect of quaternary ammonium compounds on P. falciparum in vitro involved the inhibition of phosphatidylcholine (PC) biosynthesis from choline, the natural polar head group of PC (2). Furthermore, we have shown that no alteration in the biosynthesis of the other PL, or of proteins or nucleic acids, occurred. In this study we establish that this inhibition of PC biosynthesis is due to an impairment of choline transport into infected erythrocytes. In addition, we show that the bis-onium compounds act regardless of the developmental stage of the parasite, whereas the monoammonium compound that was tested, decyltrimethylammonium, appears to be most lethal for the maturing parasites (i.e., the schizont form). Obtaining Plasmodium knowlesi-infected erythrocytes. Splenectomized Macaca fasciciilaris monkeys (weight, 3 to 6 kg; Sanofi, Montpellier, France), were infected with cryopreserved (20) P. knowlesi Washington, variant 1 (from G. Mitchell, Guy's Hospital, London). On days 6 to 9, highly infected blood cells were collected and then washed with basic medium (medium B: RPMI 1640 supplemented with 25 mM HEPES [pH 7.4] containing 40 ,uM choline and inositol and 140 FLM serine). Leukocytes were eliminated by passage through a cellulose powder column (CF 11; Whatman, Inc., Clifton, N.J.) (10). After two washes with ...

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Section: Resultsmentioning

confidence: 94%

Quaternary ammonium compounds efficiently inhibit Plasmodium falciparum growth in vitro by impairment of choline transport

Ancelin¹,

Vial²

1986

Antimicrob Agents Chemother

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“…However, HC-3 also a ects the biosynthesis of phosphorylcholine (PCho) by competitive inhibition of ChoK. In fact, HC-3 is actually also the most active inhibitor of ChoK known (Hamza et al, 1983;Cannon, 1994). In this study, we have generated new compounds based on the structure of HC-3 with much more potent inhibitory activity towards ChoK.…”

Section: Discussionmentioning

confidence: 99%

“…Hemicholinium-3 (HC-3) is a competitive inhibitor of ChoK due to its structural homology to choline (Hamza et al, 1983). The HC-3 structure, designated in this study as compound 1 (Figure 1), contains a central biphenyl ring to which two choline-like chains containing the quaternary groups are attached forming oxazinium rings in solution (Cannon, 1994).…”

Section: Generation Of New Choline Kinase Inhibitorsmentioning

confidence: 99%

“…The oxazinium rings are thought to host the HC-3 inhibitory activity (Cannon, 1994). Although HC-3 is best known as a competitive inhibitor for choline uptake by blocking the high-a nity sodium and chloride-dependent transport system (Guyenet et al, 1973;Polak et al, 1977;Zlatkine et al, 1993), it can also a ect choline acetyltransferase and choline kinase (Hamza et al, 1983;Cannon, 1994). We have taken advantage of the inhibitory action of HC-3 against ChoK in this study to improve its action as ChoK inhibitor.…”

Section: Generation Of New Choline Kinase Inhibitorsmentioning

confidence: 99%

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Choline kinase inhibitors as a novel approach for antiproliferative drug design

Saniger²,

et al. 1997

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Recent progress in deciphering the molecular basis of carcinogenesis is of utmost importance to the development of new anticancer strategies. To this end, it is essential to understand the regulation of both normal cell proliferation and its alterations in cancer cells. We have previously demonstrated that in ras-transformed cells there is an increased level of phosphorylcholine (PCho) resulting from a constitutive activation on choiline kinase (ChoK). The importance of ChoK for the regulation of cell proliferation has also been proposed since an inhibitor for this enzyme, hemicholinium-3 (HC-3), drastically reduces entry into the S phase after stimulation with growth factors. Here we report the synthesis of several new compounds which are highly speci®c inhibitors for ChoK, with up to 1000-fold or 600-fold increased inhibitory activity, compared to HC-3 under ex vivo or in vitro conditions respectively. These novel compounds also drastically reduce entry into the S phase after stimulation with speci®c growth factors. A more profound inhibition of cell proliferation was observed in ras-, src-and mos-transformed cells in the presence of ChoK inhibitors, compared to their parental, untransformed NIH3T3 cells. By contrast, this e ect was not observed in fos-transformed cells. While ras, src and mos transformation is associated with elevated levels of ChoK activity, fos-induced transformation does not a ect ChoK activity. The inhibitory e ect on proliferation of the new compounds correlates with their ability to inhibit the production of phosphorylcholine in whole cells, a proposed novel second messenger for cell proliferation. These results strongly support a critical role of choline kinase in the regulation of cell growth and makes this enzyme a novel target for the design of new antiproliferative and anticancer drugs.

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“…5) has been a prototype for ChoK inhibitors [97]. Prior to its study as a ChoK inhibitor, HC-3 was used as a research tool for its ability to inhibit acetylcholine synthesis in the nervous system [98].…”

Section: Choline Kinase Inhibitionmentioning

confidence: 99%

Choline kinase alpha—Putting the ChoK-hold on tumor metabolism

Arlauckas

Popov

Delikatny

2016

Progress in Lipid Research

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It is well established that lipid metabolism is drastically altered during tumor development and response to therapy. Choline kinase alpha (ChoKα) is a key mediator of these changes, as it represents the first committed step in the Kennedy pathway of phosphatidylcholine biosynthesis and ChoKα expression is upregulated in many human cancers. ChoKα activity is associated with drug resistant, metastatic, and malignant phenotypes, and represents a robust biomarker and therapeutic target in cancer. Effective ChoKα inhibitors have been developed and have recently entered clinical trials. ChoKα's clinical relevance was, until recently, attributed solely to its production of second messenger intermediates of phospholipid synthesis. The recent discovery of a non-catalytic scaffolding function of ChoKα may link growth receptor signaling to lipid biogenesis and requires a reinterpretation of the design and validation of ChoKα inhibitors. Advances in positron emission tomography, magnetic resonance spectroscopy, and optical imaging methods now allow for a comprehensive understanding of ChoKα expression and activity in vivo. We will review the current understanding of ChoKα metabolism, its role in tumor biology and the development and validation of targeted therapies and companion diagnostics for this important regulatory enzyme. This comes at a critical time as ChoKα-targeting programs receive more clinical interest.

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An in vitro study of hemicholinium-3 on phospholipid metabolism of Krebs II ascites cells

Cited by 23 publications

References 20 publications

Quaternary ammonium compounds efficiently inhibit Plasmodium falciparum growth in vitro by impairment of choline transport

Quaternary ammonium compounds efficiently inhibit Plasmodium falciparum growth in vitro by impairment of choline transport

Choline kinase inhibitors as a novel approach for antiproliferative drug design

Choline kinase alpha—Putting the ChoK-hold on tumor metabolism

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