title: Cytotoxicity and modes of action of 4'-hydroxy-2',6'-dimethoxychalcone and other flavonoids toward drug-sensitive and multidrug-resistant cancer cell lines.
abstract: BACKGROUND
  Resistance of cancer to chemotherapy is a main cause in treatment failure. Naturally occurring chalcones possess a wide range of biological activities including anti-cancer effects. In this work, we evaluated the antiproliferative activity of three chalcones [4'-hydroxy-2',6'-dimethoxychalcone (1), cardamomin (2), 2',4'-dihydroxy-3',6'-dimethoxychalcone (3)], and four flavanones [(S)-(-)-pinostrobin (4), (S)-(-)-onysilin (5) and alpinetin (6)] toward nine cancer cell lines amongst which were multidrug resistant (MDR) types.
  
  
  METHODS
  The resazurin reduction assay was used to detect the antiproliferative activity of the studied samples whilst flow cytometry for the mechanistic studies of the most active molecule (1).
  
  
  RESULTS
  IC50 values in a range of 2.54 μM against CEM/ADR5000 leukemia cells to 58.63 μM toward hepatocarcinoma HepG2 cells were obtained with 1. The lowest IC50 values of 8.59 μM for 2 and 10.67 μM for 3 were found against CCRF-CEM cells leukemia cells, whilst the corresponding values were above 80 μM for 4 and 6. P-glycoprotein-expressing and multidrug-resistant CEM/ADR5000 cells were much more sensitive toward compound 1 than toward doxorubicin and low cross-resistance or even collateral sensitivity was observed in other drug-resistent cell lines to this compound. Normal liver AML12 cells were more resistant to the studied compounds than HepG2 liver cancer cells, indicating tumor specificity at least to some extent. Compound 1 arrested the cell cycle between Go/G1 phase, strongly induced apoptosis via disrupted mitochondrial membrane potential (MMP) and increased production of reactive oxygen species (ROS) in the studied leukemia cell line.
  
  
  CONCLUSIONS
  Chalcone 1 was the best tested cytotoxic molecule and further studies will be performed in order to envisage its possible use in the fight against multifactorial resistant cancer cells.
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, P.O. Box 67, Dschang, Cameroon.
authors.forename: Victor
authors.initials: V
authors.lastname: Kuete
authors.affiliation: Department of Chemistry, Faculty of Science, University of Dschang, P.O. Box 67, Dschang, Cameroon.
authors.forename: Antoine H L
authors.initials: AH
authors.lastname: Nkuete
authors.affiliation: Department of Biochemistry, Faculty of Science, University of Dschang, P.O. Box 67, 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: Benjamin
authors.initials: B
authors.lastname: Wiench
authors.affiliation: Department of Chemistry, Faculty of Science, University of Dschang, P.O. Box 67, Dschang, Cameroon.
authors.forename: Hippolyte K
authors.initials: HK
authors.lastname: Wabo
authors.affiliation: Department of Chemistry, Faculty of Science, University of Dschang, P.O. Box 67, Dschang, Cameroon.
authors.forename: Pierre
authors.initials: P
authors.lastname: Tane
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*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D047188:Chalcones / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005419:Flavonoids / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D015394:Molecular Structure; D010936:Plant Extracts / Q000737:chemistry; D028502:Polygonum / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C000596251:4'-hydroxy-2',6'-dimethoxychalcone; D000972:Antineoplastic Agents, Phytogenic; D047188:Chalcones; D005419:Flavonoids; D010936:Plant Extracts; D017382:Reactive Oxygen Species; C436747:cardamonin
keywords: Anticancer; Apoptosis; Chalcones; Flavanones; Mode of action; Resistance