title: Amorfrutin C Induces Apoptosis and Inhibits Proliferation in Colon Cancer Cells through Targeting Mitochondria.
abstract: A known (1) and a structurally related new natural product (2), both belonging to the amorfrutin benzoic acid class, were isolated from the roots of Glycyrrhiza foetida. Compound 1 (amorfrutin B) is an efficient agonist of the nuclear peroxisome proliferator activated receptor (PPAR) gamma and of other PPAR subtypes. Compound 2 (amorfrutin C) showed comparably lower PPAR activation potential. Amorfrutin C exhibited striking antiproliferative effects for human colorectal cancer cells (HT-29 and T84), prostate cancer (PC-3), and breast cancer (MCF7) cells (IC50 values ranging from 8 to 16 μM in these cancer cell lines). Notably, amorfrutin C (2) showed less potent antiproliferative effects in primary colon cells. For HT-29 cells, compound 2 induced G0/G1 cell cycle arrest and modulated protein expression of key cell cycle modulators. Amorfrutin C further induced apoptotic events in HT-29 cells, including caspase activation, DNA fragmentation, PARP cleavage, phosphatidylserine externalization, and formation of reactive oxygen species. Mechanistic studies revealed that 2 disrupts the mitochondrial integrity by depolarization of the mitochondrial membrane (IC50 0.6 μM) and permanent opening of the mitochondrial permeability transition pore, leading to increased mitochondrial oxygen consumption and extracellular acidification. Structure-activity-relationship experiments revealed the carboxylic acid and the hydroxy group residues of 2 as fundamental structural requirements for inducing these apoptotic effects. Synergy analyses demonstrated stimulation of the death receptor signaling pathway. Taken together, amorfrutin C (2) represents a promising lead for the development of anticancer drugs.
authors.affiliation: Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics , D-14195 Berlin, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Weidner
authors.affiliation: Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics , D-14195 Berlin, Germany.
authors.forename: Morten
authors.initials: M
authors.lastname: Rousseau
authors.affiliation: Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University , Ithaca, New York 14853, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Micikas
authors.affiliation: Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics , D-14195 Berlin, Germany.
authors.forename: Cornelius
authors.initials: C
authors.lastname: Fischer
authors.affiliation: Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics , D-14195 Berlin, Germany.
authors.forename: Annabell
authors.initials: A
authors.lastname: Plauth
authors.affiliation: Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics , D-14195 Berlin, Germany.
authors.forename: Sylvia J
authors.initials: SJ
authors.lastname: Wowro
authors.affiliation: AnalytiCon Discovery GmbH , D-14473 Potsdam, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Siems
authors.affiliation: AnalytiCon Discovery GmbH , D-14473 Potsdam, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Hetterling
authors.affiliation: Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics , D-14195 Berlin, Germany.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kliem
authors.affiliation: Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University , Ithaca, New York 14853, United States.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Schroeder
authors.affiliation: Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics , D-14195 Berlin, Germany.|CU Systems Medicine, University of Würzburg , D-97080 Würzburg, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Sauer
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006035:Glycyrrhiza / Q000737:chemistry*; D019073:HT29 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D015394:Molecular Structure; D009018:Morocco; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists; D018517:Plant Roots / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism; D012459:Salicylates / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D047492:Peroxisome Proliferator-Activated Receptors; D017382:Reactive Oxygen Species; D012459:Salicylates; C582540:amorfrutin B; C000608464:amorfrutin C; D051028:bcl-2-Associated X Protein; D020169:Caspases