title: Combination of CYP inhibitor with MEK/ERK inhibitor enhances the inhibitory effect on ERK in BRAF mutant colon cancer cells.
abstract: OBJECTIVE
  To investigate mechanisms of discrepancy in response to a MEK/ERK inhibitor, U0126, in KRAS- and BRAF-mutant colorectal cancer cells.
  
  
  METHODS
  Multiparametric flow cytometry was performed on two colon cancer cell lines, HCT116 and HT29. Cells were treated with U0126, and phospho-specific antibodies were used to monitor ERK signaling.
  
  
  RESULTS
  HCT116 and HT29 cells were treated with increasing amounts of U0126. The western blot analysis revealed that by increasing the amount of U0126 resulted in inhibition of phospho-ERK, in HCT116 and to a lesser degree in HT29 cells. Microarray profiling identified CYP1A1 and 1A2 overexpression in HT29 cells and that inhibition of CYP1A1 with α-naphthoflavone and furanfylline restored sensitivity to U0126 in HT29 cells.
  
  
  CONCLUSIONS
  Combination of a CYP inhibitor with MEK/ERK inhibitor enhances the inhibitory effect on ERK in BRAF-mutant colon cancer cells.
authors.affiliation: Department of Obstetrics and Gynecology, LMU, University of Munich, Munich, Germany.
authors.forename: Sun Min
authors.initials: SM
authors.lastname: Lim
authors.forename: Jee Won
authors.initials: JW
authors.lastname: Hwang
authors.forename: Joong Bae
authors.initials: JB
authors.lastname: Ahn
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Bae
authors.forename: Chan Hee
authors.initials: CH
authors.lastname: Park
authors.forename: Ki-Yeol
authors.initials: KY
authors.lastname: Kim
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Rha
authors.forename: Hyun Cheol
authors.initials: HC
authors.lastname: Chung
authors.forename: Jae Kyung
authors.initials: JK
authors.lastname: Roh
authors.forename: Sang Joon
authors.initials: SJ
authors.lastname: Shin
mesh_terms: D001571:Benzoflavones / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*
chemical_list: D001571:Benzoflavones; D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; C113580:U 0126; C011512:alpha-naphthoflavone; C569463:CYP1A1 protein, human; C504573:CYP1A2 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: CYP inhibitor; Cell signaling; ERK; HCT116; HT29; MEK/ERK inhibitor; U0126; colorectal cancer