Modulation of survival signaling pathways and persistence of the genotoxic stress as a basis for the synergistic interaction between the atypical retinoid ST1926 and the epidermal growth factor inhibitor ZD1839

Chiara Zanchi, Valentina Zuco, Cinzia Lanzi, Rosanna Supino, Franco Zunino

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Strategies targeting apoptotic pathways may have relevance to improve the efficacy of antitumor therapy. Because synthetic atypical retinoids are potent inducers of apoptosis, there is an increasing interest in exploiting their potential in novel therapeutic approaches. In the present study, we have investigated the cellular effects of the combination of a novel atypical retinoid, ST1926, and the epidermal growth factor receptor inhibitor ZB1839. The results indicated a synergistic interaction between the two drugs associated with a dramatic enhancement of apoptotic response, up-regulation of the cell death receptor DR5, and caspase 8 activation. Other molecular events induced by the cotreatment included (a) a stabilization of the ST1926-induced genotoxic stress detected by formation of phosphorylated γ-H2AX foci and (b) a complete inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation associated with activation of the proapoptotic protein BAB (i.e., inhibition of phosphorylation on Ser112). In addition, ZD1839 itself inhibited survival pathways by causing a partial dephosphorylation of Akt and a marked down-regulation of survivin. The role of ERK-mediated survival pathways in the cellular response to the drug combination was further supported by the counteracting effect of stimulation of survival pathways by an alternative receptor tyrosine kinase and by the use of a specific inhibitor of the ERK pathway. In conclusion, the results support that the survival pathways activated by epidermal growth factor receptor are determinants of the cell susceptibility to ST1926-induced apoptosis and lowering survival signals may increase the cellular sensitivity to the atypical retinoid. The favorable pharmacologic profiles of both ST1926 and ZD1839 suggest that the combination of these well-tolerated agents may have therapeutic potential.

Original languageEnglish
Pages (from-to)2364-2372
Number of pages9
JournalCancer Research
Volume65
Issue number6
DOIs
Publication statusPublished - Mar 15 2005

Fingerprint

Retinoids
Epidermal Growth Factor
DNA Damage
Epidermal Growth Factor Receptor
Phosphorylation
Apoptosis
Death Domain Receptors
Mitogen-Activated Protein Kinase 3
Caspase 8
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase 1
Receptor Protein-Tyrosine Kinases
Drug Combinations
Cell Death
Up-Regulation
Therapeutics
Down-Regulation
gefitinib
3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Modulation of survival signaling pathways and persistence of the genotoxic stress as a basis for the synergistic interaction between the atypical retinoid ST1926 and the epidermal growth factor inhibitor ZD1839. / Zanchi, Chiara; Zuco, Valentina; Lanzi, Cinzia; Supino, Rosanna; Zunino, Franco.

In: Cancer Research, Vol. 65, No. 6, 15.03.2005, p. 2364-2372.

Research output: Contribution to journalArticle

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