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

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)36461-36473
Number of pages13
JournalOncotarget
Volume7
Issue number24
DOIs
StatePublished - Jan 1 2016

Keywords

  • 2-deoxy-D-glucose
  • EIF2α
  • Energy stress
  • Fenofibrate
  • MTOR

ASJC Scopus subject areas

  • Oncology

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