17 research outputs found

    The novel choline kinase inhibitor ICL-CCIC-0019 reprograms cellular metabolism and inhibits cancer cell growth.

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    The glycerophospholipid phosphatidylcholine is the most abundant phospholipid species of eukaryotic membranes and essential for structural integrity and signaling function of cell membranes required for cancer cell growth. Inhibition of choline kinase alpha (CHKA), the first committed step to phosphatidylcholine synthesis, by the selective small-molecule ICL-CCIC-0019, potently suppressed growth of a panel of 60 cancer cell lines with median GI50 of 1.12 μM and inhibited tumor xenograft growth in mice. ICL-CCIC-0019 decreased phosphocholine levels and the fraction of labeled choline in lipids, and induced G1 arrest, endoplasmic reticulum stress and apoptosis. Changes in phosphocholine cellular levels following treatment could be detected non-invasively in tumor xenografts by [18F]-fluoromethyl-[1,2–2H4]-choline positron emission tomography. Herein, we reveal a previously unappreciated effect of choline metabolism on mitochondria function. Comparative metabolomics demonstrated that phosphatidylcholine pathway inhibition leads to a metabolically stressed phenotype analogous to mitochondria toxin treatment but without reactive oxygen species activation. Drug treatment decreased mitochondria function with associated reduction of citrate synthase expression and AMPK activation. Glucose and acetate uptake were increased in an attempt to overcome the metabolic stress. This study indicates that choline pathway pharmacological inhibition critically affects the metabolic function of the cell beyond reduced synthesis of phospholipids

    Of tennis courts and fireplaces: Neurath's internment on the Isle of Man and his politics of design

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    Otto Neurath’s version of functionalism is one that begins with people “as we find them,” a proposition first set out in his 1917 essay “The Converse Taylor System.” Any attempt to redesign the existing furnishings of everyday life must take into account “functions” that go beyond the obvious purpose of objects: functions that are to do with sociability, happiness, familiarity, the love of “coziness,” and that address the diversity and contradictoriness of people. This essay considers how Neurath applied and made use of these ideas about design in 1940s Britain, during and after his internment on the Isle of Man between 1940–1941 and in talks, papers and correspondence from this period. It does not focus on the Isotype Institute, which would usually be considered his principal intervention in design, but on his commentary on everyday objects and practices. In particular it centres on four items – tennis courts, fireplaces, chairs and shoes – and through these elaborates some of the connections between Neurath’s ideas about the design of everyday life, and the significance of everyday practices, and his logical empiricism
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