1652P - Cyclooxygenase-2 inhibition enhances the anti-tumoral activity of the multi-target kinase inhibitor AEE788 in colorectal cancer cells

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Colon Cancer
Rectal Cancer
Translational Research
Presenter Araceli Valverde Estepa
Authors A.M. Valverde Estepa1, A. Cañas2, V. Hernández Nieto3, C. Lopez Pedrera3, J. De La Haba Rodriguez3, A. Rodríguez Ariza3, E. Aranda Aguilar3
  • 1Nuevas Terapias En Cáncer, IMIBIC, Hospital Reina Sofia, 14004 - Córdoba/ES
  • 2Oncology Department, IMIBIC, Hospital Reina Sofia, 14004 - Córdoba/ES
  • 3Oncology Deparment, IMIBIC-Hospital Reina Sofía, 14004 - Córdoba/ES

Abstract

Introduction

KRAS and BRAF mutations are common in colorectal cancer and confer resistance to anti-EGFR therapy. AEE788 is a multiple kinase inhibitor, with a potent inhibitory activity against both EGFR and VEGFR. The aim of this study was to determine the efficacy of AEE788 as anti-tumor treatment in colorectal cancer cells with different RAS/BRAF mutational status.

Material and method

The human colorectal cancer cell lines SW48 (KRAS/BRAF non-mutated), Caco-2 (BRAF V600E) and HCT-116 (KRAS G13D) were treated with AEE788, in the presence or the absence of EGF or VEGF. Cell proliferation was measured using a colorimetric XTT assay, cellular apoptosis was measured using flow-cytometry and VEGF production was analyzed by ELISA. The expression and/or phosphorylation levels of EGFR, VEGFR, Akt, Erk1/2, and COX-2 were determined by western-blot using the corresponding specific antibodies.

Results

Although AEE788 effectively inhibited EGFR phosphorylation in all three cell lines, the more effective inhibition of EGF-dependent growth was observed in Caco-2 cells. In these cells AEE788 inhibited the activation of intracellular kinases Akt and ERK1 / 2, efficiently induced apoptosis and caused cell cycle arrest at G1/M transition. Furthermore, AEE788 reduced in Caco-2 cells both VEGF production and VEGF-dependent growth, effects that were associated with the inhibition of ERK1/2 phosphorylation and the increased expression of COX-2 observed in these cells. Accordingly, the addition of specific inhibitors of COX-2 (celecoxib and NS-398) significantly enhanced the antitumor effect of AEE788 in Caco-2 cells.

Conclusion

Our results support the notion that that AEE788 can be effective in the treatment of colorectal cancer. Besides, its antitumoral efficacy may be potentiated by combination with COX-2 inhibitors.

Disclosure

All authors have declared no conflicts of interest.