title: Glycolysis inhibitor screening identifies the bis-geranylacylphloroglucinol protonophore moronone from Moronobea coccinea.
abstract: Tumor cells exhibit enhanced glucose consumption and lactate production even when supplied with adequate oxygen (a phenomenon known as the Warburg effect, or aerobic glycolysis). Pharmacological inhibition of aerobic glycolysis represents a potential tumor-selective approach that targets the metabolic differences between normal and malignant tissues. Human breast tumor MDA-MB-231 cells were used to develop an assay system to discover natural product-based glycolysis inhibitors. The assay employed was based on hypersensitivity to glycolytic inhibition in tumor cells treated with the mitochondrial electron transport inhibitor rotenone. Under such conditions, ATP supply, and hence cell viability, depends exclusively on glycolysis. This assay system was used to evaluate 10648 plant and marine organism extracts from the U.S. National Cancer Institute's Open Repository. Bioassay-guided isolation of an active Moronobea coccinea extract yielded the new bis-geranylacylphloroglucinol derivative moronone (1). Compound 1 exhibited enhanced antiproliferative/cytotoxic activity in the presence of rotenone-imposed metabolic stress on tumor cells. Surprisingly, mechanistic studies revealed that 1 did not inhibit glycolysis, but rather functions as a protonophore that dissipates the mitochondrial proton gradient. In the presence of rotenone, tumor cells may be hypersensitive to protonophores due to increased ATP utilization by the ATP synthase.
authors.affiliation: Department of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA.
authors.forename: Sandipan
authors.initials: S
authors.lastname: Datta
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Fakhri
authors.initials: F
authors.lastname: Mahdi
authors.forename: Mika B
authors.initials: MB
authors.lastname: Jekabsons
authors.forename: Dale G
authors.initials: DG
authors.lastname: Nagle
authors.forename: Yu-Dong
authors.initials: YD
authors.lastname: Zhou
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D028084:Clusiaceae / Q000737:chemistry*; D005260:Female; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000378:metabolism; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D012402:Rotenone / Q000494:pharmacology
chemical_list: D012402:Rotenone; D010696:Phloroglucinol; D005947:Glucose