title: Lower antioxidative capacity of multidrug-resistant cancer cells confers collateral sensitivity to protoflavone derivatives.
abstract: OBJECTIVE
  Multidrug resistance (MDR) may develop due to a series of adaptive responses under a new stress conditions, such as chemotherapy. Novel strategies are urgently needed to fight MDR in cancer, and chemotherapeutics that are selective for MDR cancer cells offer a promising approach. Certain protoflavones were previously found to have potential in this regard.
  
  
  METHODS
  Cytotoxicity of six protoflavones was assessed in different P-glycoprotein overexpressing MDR cancer cell lines and in their non-MDR counterparts. The impacts of compound 5, 6-methylprotoflavone previously published and a new derivative, 6-bromoprotoflavone (compound 6), on the cell cycle distribution were evaluated, and 6 was also studied for its potential to regulate the intracellular antioxidative capacity.
  
  
  RESULTS
  Protoflavones showed a significant cytotoxicity against all cancer cell lines and selectivity toward MDR cancer cells adapted to conventional chemotherapeutics. Inverse sensitivity versus MDR selectivity pattern was observed. Treatment with H₂O₂ showed that MDR cancer cells are more vulnerable to oxidative stress. Compounds 5 and 6 significantly decreased the portion of MDR cells in the G1 phase. The levels of reactive oxygen and nitrogen species (ROS/RNS) between MDR and non-MDR cells significantly differed upon exposure to 6, accompanied by changes in the glutathione (GSH) levels and in the expression of manganese superoxide dismutase (MnSOD), glutathione-S-transferase π (GST π) and hypoxia-inducible factor-1α (HIF-1α).
  
  
  CONCLUSIONS
  Our results suggest that MDR cancer cells can be more vulnerable to the pro-oxidative activity of protoflavones due to an impaired antioxidative defense that might arise during the adaptation processes provoked by chemotherapy.
authors.affiliation: Institute for Biological Research, Department of Neurobiology, University of Belgrade, Bulevar Despota Stefana 142, 11060, Belgrade, Serbia.
authors.forename: Tijana
authors.initials: T
authors.lastname: Stanković
authors.forename: Balázs
authors.initials: B
authors.lastname: Dankó
authors.forename: Ana
authors.initials: A
authors.lastname: Martins
authors.forename: Miodrag
authors.initials: M
authors.lastname: Dragoj
authors.forename: Sonja
authors.initials: S
authors.lastname: Stojković
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Isaković
authors.forename: Hui-Chun
authors.initials: HC
authors.lastname: Wang
authors.forename: Yang-Chang
authors.initials: YC
authors.lastname: Wu
authors.forename: Attila
authors.initials: A
authors.lastname: Hunyadi
authors.forename: Milica
authors.initials: M
authors.lastname: Pešić
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D047309:Flavones / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000975:Antioxidants; D047309:Flavones; D017382:Reactive Oxygen Species