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

Abstract

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.

Near infrared fluorescent imaging of choline kinase alpha expression and inhibition in breast tumors

“…Prior reports indicated MN58b to be tolerable when dosed daily for 5 days at 5 mg/kg, but lethal at 10 mg/kg [49]. An optimized bis-pyridinium ChoKα inhibitor was recently shown effective at 10 mg/kg daily for 3 days, and body weight measurements indicated no adverse toxicities [50]. Both JAS239 and MN58b were capable of significantly reducing intratumoral tCho and increasing PUFA resonances associated with apoptosis [23, 45].…”

Overexpression of CHKA contributes to tumor progression and metastasis and predicts poor prognosis in colorectal carcinoma

“…Knockdown of CHKA by RNAi has been demonstrated to induce differentiation and reduce proliferation [12, 40], prevent mitotic entry [8], selectively trigger cancer cell apoptosis [41], suppress migration and invasion [21, 22, 31], and sensitize cancer cells to chemotherapeutics [22, 42]. Consistently, pharmacological inhibitors of CHKA has also displayed antiproliferative, proapoptotic and antitumoral effects against multiple tumor-derived cancer cells as well as tumor xenografts [18, 23, 32, 43–46]. Indeed, one CHKA inhibitor, designated as TCD-717 or RSM-932A, has recently completed Phase I clinical trials for the treatment of advanced solid tumors (ClinicalTrial.gov Identifier: NCT01215864) [27].…”

Novel Therapeutic Targets in Rheumatoid Arthritis

“…Choline kinase blockade resulted in robust reduction of interleukins 6 and 8; which were secreted by the fibroblastlike synoviocytes (Friday & Fox 2016). The selective small-molecule; ICL-CCIC-0019 is a novel inhibitor of choline kinase which decreases the mitochondria function and citrate synthase expression (Trousil et al 2016). Likewise, bispyridinium cyclophanes are potential templates for the inhibition of human choline kinase (Conejo-Garcia et al 2005).…”