AEE788 potentiates celecoxib-induced growth inhibition and apoptosis in human colon cancer cells

P. Venkatesan, Sujit K. Bhutia, Abhay K. Singh, Swadesh K. Das, Rupesh Dash, Koel Chaudhury, Devanand Sarkar, Paul B. Fisher, Mahitosh Mandal

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Aims: 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. Main 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. Key findings: 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 Bcl2 and Bcl-xL, 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. Significance: 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.

Original languageEnglish (US)
Pages (from-to)789-799
Number of pages11
JournalLife Sciences
Volume91
Issue number15-16
DOIs
StatePublished - Oct 22 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Keywords

  • AEE788
  • Angiogenesis
  • Apoptosis
  • Celecoxib
  • Chemotherapy
  • Colon cancer
  • Inhibition
  • Potentiation

Fingerprint Dive into the research topics of 'AEE788 potentiates celecoxib-induced growth inhibition and apoptosis in human colon cancer cells'. Together they form a unique fingerprint.

Cite this