title: AEE788 potentiates celecoxib-induced growth inhibition and apoptosis in human colon cancer cells.
abstract: OBJECTIVE
  Combinatorial therapies that target multiple signaling pathways may provide improved therapeutic responses over monotherapies. In the present study, we evaluated the effect of celecoxib and AEE788 alone and in combination on cell proliferation, invasion, migration, angiogenesis, morphological changes, actin filament organization and apoptosis induction in the human colon cancer cell lines.
  
  
  METHODS
  Effect of celecoxib and AEE788 alone and in combination on colon cancer cell lines was evaluated by cell proliferation assay, morphological analysis, cell cycle analysis, scratch-wound healing and chorioallantoic membrane assays, zymography, nuclear fragmentation and western blot analyses.
  
  
  RESULTS
  Either drug alone or in combination inhibited human colonic adenocarcinoma cell lines HCT 15 and HT 29 in a dose-dependent manner. Microscopic analysis revealed inhibition of cell membrane extensions, cell shrinkage, and disorganization of actin filaments. Additionally, either drug alone or in combination inhibited HCT 15 migration, invasion and angiogenesis by suppressing matrix metalloproteinase-2 and -9 activities. Increased reactive oxygen generation, loss of mitochondrial membrane potential, cleavage of PARP, caspase-3 activation and DNA ladder formation characterized the induction of apoptosis by celecoxib and/or AEE788 treatment. Either drug individually induced apoptosis via down-regulation of the anti-apoptotic proteins Bcl(2) and Bcl-x(L), and up-regulation of pro-apoptotic protein Bax, cleavage of PARP, activation of caspase-3 and inhibition of vascular endothelial growth factor receptor signaling pathways.
  
  
  CONCLUSIONS
  Results indicate that AEE788 potentiates celecoxib-mediated inhibition of proliferation and angiogenesis in HCT 15 colon cancer cells and may prove useful for developing a combinatorial therapy for colon cancer.
authors.affiliation: School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, India.
authors.forename: P
authors.initials: P
authors.lastname: Venkatesan
authors.forename: Sujit K
authors.initials: SK
authors.lastname: Bhutia
authors.forename: Abhay K
authors.initials: AK
authors.lastname: Singh
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.forename: Rupesh
authors.initials: R
authors.lastname: Dash
authors.forename: Koel
authors.initials: K
authors.lastname: Chaudhury
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: Mahitosh
authors.initials: M
authors.lastname: Mandal
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000068579:Celecoxib; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002645:Chickens; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D011687:Purines; D011720:Pyrazoles; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C489254:AEE 788; D000068579:Celecoxib