title: Broad Anti-tumor Activity of a Small Molecule that Selectively Targets the Warburg Effect and Lipogenesis.
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.
authors.affiliation: Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA. Electronic address: flavenyca@slu.edu.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Flaveny
authors.affiliation: Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
authors.forename: Kristine
authors.initials: K
authors.lastname: Griffett
authors.affiliation: Chemistry Department, Faculty of Science, Benha University, Benha 13518, Egypt.
authors.forename: Bahaa El-Dien M
authors.initials: Bel-D
authors.lastname: El-Gendy
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Kazantzis
authors.affiliation: Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
authors.forename: Monideepa
authors.initials: M
authors.lastname: Sengupta
authors.affiliation: Lineberger Comprehensive Cancer Center, Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Antonio L
authors.initials: AL
authors.lastname: Amelio
authors.affiliation: Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
authors.forename: Arindam
authors.initials: A
authors.lastname: Chatterjee
authors.affiliation: Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
authors.forename: John
authors.initials: J
authors.lastname: Walker
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Solt
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
authors.affiliation: 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.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Burris
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D006019:Glycolysis / Q000187:drug effects; D019073:HT29 Cells; D056945:Hep G2 Cells; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects*; D000071518:Liver X Receptors; D051379:Mice; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009928:Organ Specificity; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D054852:Small Molecule Libraries / Q000008:administration & dosage* / Q000494:pharmacology; D013449:Sulfonamides / Q000008:administration & dosage* / Q000494:pharmacology; D015431:Weight Loss / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; C000602007:SR9243; D054852:Small Molecule Libraries; D013449:Sulfonamides