MAPK and PI3K inhibition reduces proliferation of Barrett's adenocarcinoma in vitro.
BACKGROUND
Esophageal adenocarcinoma often arises from Barrett's esophagus. Mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) play critical roles in cell survival. We hypothesized that inhibition of these pathways in Barrett's adenocarcinoma would decrease cell proliferation and alter apoptosis in vitro.


METHODS
Two Barrett's-associated adenocarcinoma cell lines, SEG-1 (wild-type p53) and BIC-1 (mutant p53), were treated with MAPK (U0126) and PI3K (LY294002) inhibitors at 20 microm concentrations. After 24 and 72 h, cell viability was measured by MTT assay. Apoptosis and necrosis were evaluated by the Annexin V-FITC assay. Statistical analysis was performed by ANOVA.


RESULTS
LY294002 and U0126 treatment produced significant reductions (range 15.7 to 62.0%, P < 0.05) in cellular proliferation at both 24 and 72 h in the SEG-1 cells. BIC-1 cell viability was reduced (39.3 to 56.4%, P < 0.05) at 72 h. Both early and late apoptotic activity were significantly increased (P < 0.05) in the SEG-1 cells using both inhibitors. Necrosis was significantly reduced (P < 0.05) using both inhibitors. No changes in either early or late apoptosis or necrosis were observed in the BIC-1 cells.


CONCLUSIONS
Herein, we report significant antiproliferative effects against Barrett's adenocarcinoma by MAPK and PI3K inhibition in vitro. Pro-apoptotic mechanisms prevail in the wild-type p53 cells. Further investigation is warranted to advance the clinical treatment of this devastating disease.
Vona-Davis
Linda
L
Department of Surgery, West Virginia University, Morgantown, West Virginia 26506-9238, USA.
Frankenberry
Krista
K
Cunningham
Cynthia
C
Riggs
Dale R
DR
Jackson
Barbara J
BJ
Szwerc
Michael F
MF
McFadden
David W
DW
D000230:Adenocarcinoma; D017209:Apoptosis / Q000187:drug effects; D001471:Barrett Esophagus / Q000473:pathology*; D002070:Butadienes / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004938:Esophageal Neoplasms; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009025:Morpholines / Q000494:pharmacology*; D009336:Necrosis; D009570:Nitriles / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors
D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D009570:Nitriles; D000081082:Phosphoinositide-3 Kinase Inhibitors; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D020928:Mitogen-Activated Protein Kinases