Oncotarget

Research Papers:

Combining 2-deoxy-D-glucose with fenofibrate leads to tumor cell death mediated by simultaneous induction of energy and ER stress

Huaping Liu, Metin Kurtoglu, Clara Lucia León-Annicchiarico, Cristina Munoz-Pinedo, Julio Barredo, Guy Leclerc, Jaime Merchan, Xiongfei Liu, Theodore J. Lampidis _

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Oncotarget. 2016; 7:36461-36473. https://doi.org/10.18632/oncotarget.9263

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Abstract

Huaping Liu1, Metin Kurtoglu2, Clara Lucia León-Annicchiarico3, Cristina Munoz-Pinedo3, Julio Barredo4, Guy Leclerc4, Jaime Merchan5, Xiongfei Liu1, Theodore J. Lampidis1

1Department of Cell Biology, University of Miami, Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL, USA

2National Institutes of Health, Bethesda, MD, USA

3Cell Death Regulation Group, Bellvitage Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain

4Department of Pediatrics, University of Miami, Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL, USA

5Department of Medicine, University of Miami, Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL, USA

Correspondence to:

Theodore J. Lampidis, email: tlampidi@miami.edu

Keywords: 2-deoxy-D-glucose, fenofibrate, energy stress, mTOR, eIF2α

Received: February 24, 2016     Accepted: April 16, 2016     Published: May 10, 2016

ABSTRACT

Unregulated growth and replication as well as an abnormal microenvironment, leads to elevated levels of stress which is a common trait of cancer. By inducing both energy and endoplasmic reticulum (ER) stress, 2-Deoxy-glucose (2-DG) is particularly well-suited to take advantage of the therapeutic window that heightened stress in tumors provides. Under hypoxia, blocking glycolysis with 2-DG leads to significant lowering of ATP resulting in energy stress and cell death in numerous carcinoma cell types. In contrast, under normoxia, 2-DG at a low-concentration is not toxic in most carcinomas tested, but induces growth inhibition, which is primarily due to ER stress. Here we find a synergistic toxic effect in several tumor cell lines in vitro combining 2-DG with fenofibrate (FF), a drug that has been safely used for over 40 years to lower cholesterol in patients. This combination induces much greater energy stress than either agent alone, as measured by ATP reduction, increased p-AMPK and downregulation of mTOR. Inhibition of mTOR results in blockage of GRP78 a critical component of the unfolded protein response which we speculate leads to greater ER stress as observed by increased p-eIF2α. Moreover, to avoid an insulin response and adsorption by the liver, 2-DG is delivered by slow-release pump yielding significant anti-tumor control when combined with FF. Our results provide promise for developing this combination clinically and others that combine 2-DG with agents that act synergistically to selectively increase energy and ER stress to a level that is toxic to numerous tumor cell types.

Author Information

Huaping Liu

Metin Kurtoglu

Clara Lucia León-Annicchiarico

Cristina Munoz-Pinedo

Julio Barredo

Guy Leclerc

Jaime Merchan

Xiongfei Liu

Theodore J. Lampidis
Primary Contact  _


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