Oncotarget

Research Papers:

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

Sean P. Arlauckas, Manoj Kumar, Anatoliy V. Popov, Harish Poptani and Edward J. Delikatny _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2017; 8:16518-16530. https://doi.org/10.18632/oncotarget.14965

Metrics: PDF 743 views  |   HTML 910 views  |   ?  


Abstract

Sean P. Arlauckas1, Manoj Kumar1, Anatoliy V. Popov1, Harish Poptani1,2, Edward J. Delikatny1

1Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States

2Department of Cellular and Molecular Physiology, Institute of Regenerative Medicine, University of Liverpool, Liverpool, United Kingdom

Correspondence to:

Edward J. Delikatny, email: delikatn@mail.med.upenn.edu

Keywords: choline kinase, breast cancer, fluorescence optical imaging, chemotherapy

Received: November 18, 2016     Accepted: January 16, 2017     Published: February 01, 2017

ABSTRACT

Choline kinase alpha (ChoKα) overexpression is associated with an aggressive tumor phenotype. ChoKα inhibitors induce apoptosis in tumors, however validation of their specificity is difficult in vivo. We report the use of optical imaging to assess ChoKα status in cells and in vivo using JAS239, a carbocyanine-based ChoKα inhibitor with inherent near infrared fluorescence. JAS239 attenuated choline phosphorylation and viability in a panel of human breast cancer cell lines. Antibody blockade prevented cellular retention of JAS239 indicating direct interaction with ChoKα independent of the choline transporters and catabolic choline pathways. In mice bearing orthotopic MCF7 breast xenografts, optical imaging with JAS239 distinguished tumors overexpressing ChoKα from their empty vector counterparts and delineated tumor margins. Pharmacological inhibition of ChoK by the established inhibitor MN58b led to a growth inhibition in 4175-Luc+ tumors that was accompanied by concomitant reduction in JAS239 uptake and decreased total choline metabolite levels as measured using magnetic resonance spectroscopy. At higher therapeutic doses, JAS239 was as effective as MN58b at arresting tumor growth and inducing apoptosis in MDA-MB-231 tumors, significantly reducing tumor choline below baseline levels without observable systemic toxicity. These data introduce a new method to monitor therapeutically effective inhibitors of choline metabolism in breast cancer using a small molecule companion diagnostic.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 14965