This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zanchi, C. Articles by Zunino, F. Search for Related Content PubMed PubMed Citation Articles by Zanchi, C. Articles by Zunino, F.

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 Receptor Inhibitor ZD1839

Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy

Requests for reprints: Franco Zunino, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy. Phone: 39-02-23902267; Fax: 39-02-23902692; E-mail: franco.zunino{at}istitutotumori.mi.it.

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 ZD1839. 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 -H2AX foci and (b) a complete inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation associated with activation of the proapoptotic protein BAD (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.

Key Words: Atypical retinoids • ZD1839 • apoptosis • survival pathways • ST1926

This article has been cited by other articles:

				V. Benedetti, P. Perego, G. Luca Beretta, E. Corna, S. Tinelli, S. C. Righetti, R. Leone, P. Apostoli, C. Lanzi, and F. Zunino Modulation of survival pathways in ovarian carcinoma cell lines resistant to platinum compounds Mol. Cancer Ther., March 1, 2008; 7(3): 679 - 687. [Abstract] [Full Text] [PDF]

				C Pisano, L Vesci, R Fodera, F. Ferrara, C Rossi, M De Cesare, V Zuco, G Pratesi, R Supino, and F Zunino Antitumor activity of the combination of synthetic retinoid ST1926 and cisplatin in ovarian carcinoma models Ann. Onc., September 1, 2007; 18(9): 1500 - 1505. [Abstract] [Full Text] [PDF]

				G. Petrangolini, R. Supino, G. Pratesi, L. D. Bo, M. Tortoreto, A. C. Croce, P. Misiano, P. Belfiore, C. Farina, and F. Zunino Effect of a Novel Vacuolar-H+-ATPase Inhibitor on Cell and Tumor Response to Camptothecins J. Pharmacol. Exp. Ther., September 1, 2006; 318(3): 939 - 946. [Abstract] [Full Text] [PDF]