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Cancer Cell. 2015 Jul 13;28(1):42-56. doi: 10.1016/j.ccell.2015.05.007. Epub 2015 Jun 25.

Broad Anti-tumor Activity of a Small Molecule that Selectively Targets the Warburg Effect and Lipogenesis.

Author information

1
Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA. Electronic address: flavenyca@slu.edu.
2
Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
3
Chemistry Department, Faculty of Science, Benha University, Benha 13518, Egypt.
4
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
5
Lineberger Comprehensive Cancer Center, Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA.
6
Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63310, USA. Electronic address: burristp@slu.edu.

Abstract

Malignant cells exhibit aerobic glycolysis (the Warburg effect) and become dependent on de novo lipogenesis, which sustains rapid proliferation and resistance to cellular stress. The nuclear receptor liver-X-receptor (LXR) directly regulates expression of key glycolytic and lipogenic genes. To disrupt these oncogenic metabolism pathways, we designed an LXR inverse agonist SR9243 that induces LXR-corepressor interaction. In cancer cells, SR9243 significantly inhibited the Warburg effect and lipogenesis by reducing glycolytic and lipogenic gene expression. SR9243 induced apoptosis in tumors without inducing weight loss, hepatotoxicity, or inflammation. Our results suggest that LXR inverse agonists may be an effective cancer treatment approach.

PMID:
26120082
PMCID:
PMC4965273
DOI:
10.1016/j.ccell.2015.05.007
[Indexed for MEDLINE]
Free PMC Article

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