title: Cytotoxicity of three naturally occurring flavonoid derived compounds (artocarpesin, cycloartocarpesin and isobavachalcone) towards multi-factorial drug-resistant cancer cells.
abstract: BACKGROUND
  Cancer remains an aggressive deadly disease, if drug resistance develops. This problem is aggravated by the fact that multiple rather than single mechanisms are involved in resistance and that multidrug resistance (MDR) phenomena cause inefficacy of many clinical established anticancer drugs. We are seeking for novel cytotoxic phytochemicals to combat drug-resistant tumour cells.
  
  
  METHODS
  In the present study, we investigated the cytotoxicity of three naturally occurring flavonoids including two flavones artocarpesin (1) and cycloartocarpesin (2) and one chalcone, isobavachalcone (3) against 9 drug-sensitive and MDR cancer cell lines. The resazurin reduction assay was used to evaluate the cytotoxicity of these compounds, whilst caspase-Glo assay was used to detect caspase activation. Cell cycle, mitochondrial membrane potential (MMP) and levels of reactive oxygen species (ROS) were all analysed via flow cytometry.
  
  
  RESULTS
  Flavones 1 and 2 as well as chalcone 3 displayed cytotoxic effects at various extent on all the 9 tested cancer cell lines with IC50 values respectively below 106 µM, 50 µM and 25 µM. The IC50 values for the three investigational flavonoids ranged from 23.95 µM (towards hepatocarcinoma HepG2 cells) to 105 µM [towards colon carcinoma HCT116 (p53(-/-)) cells] for 1, from 15.51 µM (towards leukemia CCRF-CEM cells) to 49.83 µM [towards glioblastoma U87MG.ΔEGFR cells] for 2 and from 2.30 µM (towards CCRF-CEM cells) to 23.80 µM [towards colon carcinoma HCT116 (p53(+/+)) cells] for 3 and from 0.20 µM (towards CCRF-CEM cells) to 195.12 µM (towards leukemia CEM/ADR5000 cells) for doxorubicin. Compounds 2 and 3 induced apoptosis in CCRF-CEM leukemia cells, mediated by caspase activation and the disruption of MMP.
  
  
  CONCLUSIONS
  The three tested flavonoids and mostly chalcone 3 are potential cytotoxic natural products that deserve more investigations to develop novel antineoplastic drugs against multifactorial drug-resistant cancers.
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany; Department of Biochemistry, Faculty of Science, University of Dschang, Dschang, Cameroon.
authors.forename: Victor
authors.initials: V
authors.lastname: Kuete
authors.affiliation: Department of Biochemistry, Faculty of Science, University of Dschang, Dschang, Cameroon.
authors.forename: Armelle T
authors.initials: AT
authors.lastname: Mbaveng
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany.
authors.forename: Maen
authors.initials: M
authors.lastname: Zeino
authors.affiliation: Department of Organic Chemistry, Faculty of Science, University of Yaoundé I, Yaoundé, Cameroon.
authors.forename: Christian D
authors.initials: CD
authors.lastname: Fozing
authors.affiliation: Department of Pharmacognosy and Pharmaceutical Chemistry, Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon.
authors.forename: Bathelemy
authors.initials: B
authors.lastname: Ngameni
authors.affiliation: Department of Chemistry, Higher Teachers' Training College, University of Yaoundé I, Yaoundé, Cameroon.
authors.forename: Gilbert Deccaux W F
authors.initials: GD
authors.lastname: Kapche
authors.affiliation: Department of Organic Chemistry, Faculty of Science, University of Yaoundé I, Yaoundé, Cameroon.
authors.forename: Bonaventure T
authors.initials: BT
authors.lastname: Ngadjui
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany. Electronic address: efferth@uni-mainz.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D047188:Chalcones / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D047309:Flavones / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D015394:Molecular Structure; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D047188:Chalcones; D047309:Flavones; D017382:Reactive Oxygen Species; C531017:artocarpesin; C000604029:cycloartocarpesin; C468754:isobavachalcone; D020169:Caspases
keywords: Apoptosis; Cycloartocarpesin; Cytotoxicity; Flavonoids; Isobavachalcone; Multi-drug resistance