Research Papers:

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

Sebastian Trousil, Maciej Kaliszczak, Zachary Schug, Quang-De Nguyen, Giampaolo Tomasi, Rosy Favicchio, Diana Brickute, Robin Fortt, Frazer J. Twyman, Laurence Carroll, Andrew Kalusa, Naveenan Navaratnam, Thomas Adejumo, David Carling, Eyal Gottlieb and Eric O. Aboagye _

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Oncotarget. 2016; 7:37103-37120. https://doi.org/10.18632/oncotarget.9466

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Sebastian Trousil1, Maciej Kaliszczak1, Zachary Schug2, Quang-De Nguyen1, Giampaolo Tomasi1, Rosy Favicchio1, Diana Brickute1, Robin Fortt1, Frazer J. Twyman1, Laurence Carroll1, Andrew Kalusa1, Naveenan Navaratnam3, Thomas Adejumo3, David Carling3, Eyal Gottlieb2, Eric O. Aboagye1

1Comprehensive Cancer Imaging Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK

2Cancer Research UK, Beatson Institute, Garscube Estate, Glasgow, UK

3Cellular Stress Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Campus, London, UK

Correspondence to:

Eric O. Aboagye, email: [email protected]

Keywords: choline kinase, metabolism, mitochondrial function, cancer, positron emission tomography

Received: November 14, 2015     Accepted: April 25, 2016     Published: May 19, 2016


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.

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