title: Overcoming multidrug resistance in human lung cancer with novel benzo[a]quinolizin-4-ones.
abstract: OBJECTIVE
  To investigate the ability of synthetic benzo[a]quinolizin-4-one derivatives to reverse multidrug resistance (MDR) in lung cancer cells.
  
  
  METHODS
  A cell line with MDR, A549RT-eto, was established by exposure to 1.5 μM etoposide. Cytotoxic activity was assayed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromine (MTT) method. The mechanism of drug resistance was studied by real-time PCR, Western blot analysis, and flow cytometry. Benzo[a]quinolizin-4-one derivatives were synthesized and tested for cytotoxic activity and ability to modulate MDR.
  
  
  RESULTS
  A549RT-eto cells had an IC(50) for etoposide of 176 μM, 28-fold higher than parental cells, due to increased levels of MDR1 gene and P-glycoprotein (P-gp), resulting in greater drug efflux. Three benzo[a]quinolizin-4-ones reduced etoposide IC(50) from 176 μM to 22.4 μM -24.7 μM. This resulted from increased drug accumulation without altering P-gp expression at the transcription or translation level.
  
  
  CONCLUSIONS
  Non-toxic concentrations of benzo[a]quinolizin-4-one derivatives can reverse drug resistance of A549RT-eto by increasing the intracellular drug accumulation.
authors.affiliation: Chulabhorn Research Institute, Thailand.
authors.forename: Yodsoi
authors.initials: Y
authors.lastname: Kanintronkul
authors.forename: Rattana
authors.initials: R
authors.lastname: Worayuthakarn
authors.forename: Nopporn
authors.initials: N
authors.lastname: Thasana
authors.forename: Pakorn
authors.initials: P
authors.lastname: Winayanuwattikun
authors.forename: Kovit
authors.initials: K
authors.lastname: Pattanapanyasat
authors.forename: Rudee
authors.initials: R
authors.lastname: Surarit
authors.forename: Somsak
authors.initials: S
authors.lastname: Ruchirawat
authors.forename: Jisnuson
authors.initials: J
authors.lastname: Svasti
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D005047:Etoposide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011807:Quinolizines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011807:Quinolizines; D005047:Etoposide