title: Cytotoxicity and modes of action of four naturally occuring benzophenones: 2,2',5,6'-tetrahydroxybenzophenone, guttiferone E, isogarcinol and isoxanthochymol.
abstract: BACKGROUND
  The emergence of drug-resistant cancer cells drastically reduces the efficacy of many antineoplasic agents and, consequently, increases the frequency of therapeutic failure. Benzophenones are known to display many pharmacological properties including cytotoxic activities. The present study was aimed at investigating the cytotoxicity and the modes of action of four naturally occurring benzophenones 2,2',5,6'-tetrahydroxybenzophenone (1), isogarcinol (2), isoxanthochymol (3) and guttiferone E (4) on a panel of eleven cancer cell lines including various sensitive and drug-resistant phenotypes.
  
  
  METHODS
  The cytotoxicity of the compounds was determined using a resazurin reduction assay, whereas the caspase-Glo assay was used to detect the activation of caspases 3/7, caspase 8 and caspase 9 in cells treated with compounds 2-4. Flow cytometry was used for cell cycle analysis and detection of apoptotic cells, analysis of mitochondrial membrane potential (MMP) as well as measurement of reactive oxygen species (ROS).
  
  
  RESULTS
  The four tested benzophenones inhibited the proliferation of all tested cancer cell lines including sensitive and drug-resistant phenotypes. Collateral sensitivity of cancer cells to compounds 1-4 was generally better than to doxorubicin. Compound 2 showed the best activity with IC50 values below or around 1 μM against HCT116 colon carcinoma cells (p53+/+) (0.86 μM) and leukemia CCRF-CEM (1.38 μM) cell lines. Compounds 2-4 strongly induced apoptosis in CCRF-CEM cells via caspases 3/7, caspase 8 and caspase 9 activation and disruption of MMP.
  
  
  CONCLUSIONS
  The studied benzophenones are cytotoxic compounds that deserve more detailed exploration in the future, to develop novel anticancer drugs against sensitive and otherwise drug-resistant phenotypes.
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Mainz, Germany.
authors.forename: Victor
authors.initials: V
authors.lastname: Kuete
authors.forename: Patricia D
authors.initials: PD
authors.lastname: Tchakam
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wiench
authors.forename: Bathelemy
authors.initials: B
authors.lastname: Ngameni
authors.forename: Hippolyte K
authors.initials: HK
authors.lastname: Wabo
authors.forename: Michel F
authors.initials: MF
authors.lastname: Tala
authors.forename: Marlyse L
authors.initials: ML
authors.lastname: Moungang
authors.forename: Bonaventure T
authors.initials: BT
authors.lastname: Ngadjui
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Murayama
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001577:Benzophenones / Q000494:pharmacology / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D045325:HCT116 Cells; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010641:Phenotype; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001577:Benzophenones; D010936:Plant Extracts; D017382:Reactive Oxygen Species; C515918:isoxanthochymol; C414433:guttiferone E; D004317:Doxorubicin; D020169:Caspases; D020782:Matrix Metalloproteinases; C035476:2,2',4,4'-tetrahydroxybenzophenone