The Choline Kinase Inhibitor Hemicholinium-3 Can Inhibit Mitogen-Induced DNA Synthesis Independent of Its Effect on Phosphocholine Formation

Crilly, Karan S.; Tomono, Masahiro; Kiss, Zoltán

doi:10.1006/abbi.1998.0601

Cited by 10 publications

(10 citation statements)

References 21 publications

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“…Choline, phosphocholine, and phosphatidylcholine were extracted from the cells by a combination of the methods described earlier (18,35). Cells were lysed in 5% trichloroacetic acid and then subjected to three cycles of freeze-thawing for complete lysis of the cells (35).…”

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confidence: 99%

“…Supernatant containing phosphocholine and choline was extracted five times with diethyl ether to remove trichloroacetic acid, and then the pH of the aqueous phase was adjusted with 0.1 N NaOH to pH 7. For separation of choline and phosphocholine, the aqueous phase was vigorously mixed with 300 mg of Dowex-50W [H ϩ ] resin which binds only choline (18). Resin was allowed to settle, and supernatant containing phosphocholine was mixed in 10 ml of scintillation fluid.…”

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confidence: 99%

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Inhibition of Plasmodium falciparum Choline Kinase by Hexadecyltrimethylammonium Bromide: a Possible Antimalarial Mechanism

Choubey

Maity

Guha

et al. 2007

Antimicrob Agents Chemother

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Choline kinase is the first enzyme in the Kennedy pathway (CDP-choline pathway) for the biosynthesis of the most essential phospholipid, phosphatidylcholine, in Plasmodium falciparum. In addition, choline kinase also plays a pivotal role in trapping essential polar head group choline inside the malaria parasite. Recently, Plasmodium falciparum choline kinase (PfCK) has been cloned, overexpressed, and purified. However, the function of this enzyme in parasite growth and survival has not been evaluated owing to the lack of a suitable inhibitor. Purified recombinant PfCK enabled us to identify an inhibitor of PfCK, hexadecyltrimethylammonium bromide (HDTAB), which has a very close structural resemblance to hexadecylphosphocholine (miltefosin), the well-known antiproliferative and antileishmanial drug. HDTAB inhibited PfCK in a dose-dependent manner and offered very potent antimalarial activity in vitro against Plasmodium falciparum. Moreover, HDTAB exhibited profound antimalarial activity in vivo against the rodent malaria parasite Plasmodium yoelii (N-67 strain). Interestingly, parasites at the trophozoite and schizont stages were found to be particularly sensitive to HDTAB. The stage-specific antimalarial effect of HDTAB correlated well with the expression pattern of PfCK in P. falciparum, which was observed by reverse transcription-PCR and immunofluorescence microscopy. Furthermore, the antimalarial activity of HDTAB paralleled the decrease in phosphatidylcholine content, which was found to correlate with the decreased phosphocholine generation. These results suggest that inhibition of choline kinase by HDTAB leads to decreased phosphocholine, which in turn causes a decrease in phosphatidylcholine biosynthesis, resulting in death of the parasite.

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Inhibition of Plasmodium falciparum Choline Kinase by Hexadecyltrimethylammonium Bromide: a Possible Antimalarial Mechanism

Choubey

Maity

Guha

et al. 2007

Antimicrob Agents Chemother

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“…The HC-3, which is being used from three decades, is a potent competitive inhibitor of the high affinity choline transport system [14]. The strong evidences have shown that II inhibits the effects of growth factors on DNA-synthesis [15][16][17]. But its use was restricted because of unavoidable side effects like toxic respiratory paralysis effect [3,18].…”

Section: Introductionmentioning

confidence: 99%

Potential choline kinase inhibitors: A molecular modeling study of bis-quinolinium compounds

Srivani

Sastry

2009

Journal of Molecular Graphics and Modelling

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“…Furthermore, it has been demonstrated that the generation of PCho from choline by ChoK is an essential process for growth factors to exert their mitogenic action. As a result, ChoK has been emerged as a novel target for anticancer therapy in recent times [13,14].…”

Section: Introductionmentioning

confidence: 99%

2D and 3D Quantitative Structure‐Activity Relationship Studies on a Series of bis‐Pyridinium Compounds as Choline Kinase Inhibitors

2006

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Two-dimensional (2D) and three-dimensional (3D) quantitative structure activity relationship (QSAR) studies have been carried out on a series of 55 bis-pyridinium compounds to find out the structural requirements of choline kinase (ChoK) inhibitors. The best predictions were obtained from the model where 44 compounds were considered in the training set and the remaining 11 in the test set. The results that are obtained from 2D and 3D-QSAR studies may provide useful insights into the roles of various substitution patterns on the bis-pyridinium skeleton and may also help to design more potent compounds.

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The Choline Kinase Inhibitor Hemicholinium-3 Can Inhibit Mitogen-Induced DNA Synthesis Independent of Its Effect on Phosphocholine Formation

Cited by 10 publications

References 21 publications

Inhibition of Plasmodium falciparum Choline Kinase by Hexadecyltrimethylammonium Bromide: a Possible Antimalarial Mechanism

Inhibition of Plasmodium falciparum Choline Kinase by Hexadecyltrimethylammonium Bromide: a Possible Antimalarial Mechanism

Potential choline kinase inhibitors: A molecular modeling study of bis-quinolinium compounds

2D and 3D Quantitative Structure‐Activity Relationship Studies on a Series of bis‐Pyridinium Compounds as Choline Kinase Inhibitors

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