Tags

Type your tag names separated by a space and hit enter

Synergy of epidermal growth factor receptor kinase inhibitor AG1478 and ErbB2 kinase inhibitor AG879 in human colon carcinoma cells is associated with induction of apoptosis.
Cancer Res. 2005 Jul 01; 65(13):5848-56.CR

Abstract

Previous studies have shown that constitutive activation of epidermal growth factor receptor (EGFR) and ErbB2 by elevated autocrine transforming growth factor-alpha (TGF-alpha) expression plays an important role in colon cancer progression. Coexpression of EGFR and ErbB2 is found in a subset of colon cancers and may cooperatively promote cancer cell growth and survival, as heterodimerization is known to provide for diversification of signal transduction. In this study, the EGFR-selective tyrosine kinase inhibitor (TKI) AG1478 inhibited cell growth of an aggressive human colon carcinoma cell line, FET6alphaS26X, which harbors constitutively activated EGFR after stable transfection with TGF-alpha cDNA. However, AG1478 failed to induce apoptosis in FET6alphaS26X cells at concentrations sufficient for cell growth inhibition and complete suppression of EGFR phosphorylation. Similarly, AG879, a selective ErbB2 TKI, was incapable of inducing apoptosis in FET6alphaS26X cells at concentrations sufficient to inhibit cell growth and ErbB2 phosphorylation. To test the hypothesis that targeting both ErbB family members would show better efficacy than targeting the single receptors, combinations of inhibitors at fixed ratios of 1:1, 5:1, and 10:1 of AG1478 and AG879, respectively, were compared with single drugs for inhibition of cell growth. All combinations resulted in synergistic effects as indicated by combination index analysis. Synergistic inhibition was associated with induction of apoptosis as reflected by poly(ADP-ribose) polymerase cleavage, caspase-3 activation, and Annexin V staining. Finally, Western blot analysis showed significant inhibition of phosphorylation of both EGFR and ErbB2 by the combination treatment. These data suggest that the strategy to target both EGFR and ErbB2 simultaneously might result in more efficient inhibition of tumor growth than to target single receptor alone.

Authors+Show Affiliations

Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15994962

Citation

Zhou, Yunfei, and Michael G. Brattain. "Synergy of Epidermal Growth Factor Receptor Kinase Inhibitor AG1478 and ErbB2 Kinase Inhibitor AG879 in Human Colon Carcinoma Cells Is Associated With Induction of Apoptosis." Cancer Research, vol. 65, no. 13, 2005, pp. 5848-56.
Zhou Y, Brattain MG. Synergy of epidermal growth factor receptor kinase inhibitor AG1478 and ErbB2 kinase inhibitor AG879 in human colon carcinoma cells is associated with induction of apoptosis. Cancer Res. 2005;65(13):5848-56.
Zhou, Y., & Brattain, M. G. (2005). Synergy of epidermal growth factor receptor kinase inhibitor AG1478 and ErbB2 kinase inhibitor AG879 in human colon carcinoma cells is associated with induction of apoptosis. Cancer Research, 65(13), 5848-56.
Zhou Y, Brattain MG. Synergy of Epidermal Growth Factor Receptor Kinase Inhibitor AG1478 and ErbB2 Kinase Inhibitor AG879 in Human Colon Carcinoma Cells Is Associated With Induction of Apoptosis. Cancer Res. 2005 Jul 1;65(13):5848-56. PubMed PMID: 15994962.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synergy of epidermal growth factor receptor kinase inhibitor AG1478 and ErbB2 kinase inhibitor AG879 in human colon carcinoma cells is associated with induction of apoptosis. AU - Zhou,Yunfei, AU - Brattain,Michael G, PY - 2005/7/5/pubmed PY - 2005/9/8/medline PY - 2005/7/5/entrez SP - 5848 EP - 56 JF - Cancer research JO - Cancer Res VL - 65 IS - 13 N2 - Previous studies have shown that constitutive activation of epidermal growth factor receptor (EGFR) and ErbB2 by elevated autocrine transforming growth factor-alpha (TGF-alpha) expression plays an important role in colon cancer progression. Coexpression of EGFR and ErbB2 is found in a subset of colon cancers and may cooperatively promote cancer cell growth and survival, as heterodimerization is known to provide for diversification of signal transduction. In this study, the EGFR-selective tyrosine kinase inhibitor (TKI) AG1478 inhibited cell growth of an aggressive human colon carcinoma cell line, FET6alphaS26X, which harbors constitutively activated EGFR after stable transfection with TGF-alpha cDNA. However, AG1478 failed to induce apoptosis in FET6alphaS26X cells at concentrations sufficient for cell growth inhibition and complete suppression of EGFR phosphorylation. Similarly, AG879, a selective ErbB2 TKI, was incapable of inducing apoptosis in FET6alphaS26X cells at concentrations sufficient to inhibit cell growth and ErbB2 phosphorylation. To test the hypothesis that targeting both ErbB family members would show better efficacy than targeting the single receptors, combinations of inhibitors at fixed ratios of 1:1, 5:1, and 10:1 of AG1478 and AG879, respectively, were compared with single drugs for inhibition of cell growth. All combinations resulted in synergistic effects as indicated by combination index analysis. Synergistic inhibition was associated with induction of apoptosis as reflected by poly(ADP-ribose) polymerase cleavage, caspase-3 activation, and Annexin V staining. Finally, Western blot analysis showed significant inhibition of phosphorylation of both EGFR and ErbB2 by the combination treatment. These data suggest that the strategy to target both EGFR and ErbB2 simultaneously might result in more efficient inhibition of tumor growth than to target single receptor alone. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/15994962/Synergy_of_epidermal_growth_factor_receptor_kinase_inhibitor_AG1478_and_ErbB2_kinase_inhibitor_AG879_in_human_colon_carcinoma_cells_is_associated_with_induction_of_apoptosis_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=15994962 DB - PRIME DP - Unbound Medicine ER -