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Research Articles: Therapeutics, Targets, and Development

Modulation of survival pathways in ovarian carcinoma cell lines resistant to platinum compounds

¹ Department of Experimental Oncology and Laboratories, Istituto Nazionale Tumori, Milan, Italy; ² Istituto di Farmacologia, Università di Verona, Verona, Italy; and ³ Istituto di Medicina del Lavoro, Università di Brescia, Brescia, Italy

Requests for reprints: Paola Perego, Department of Experimental Oncology and Laboratories, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy. Phone: 39-223902237; Fax: 39-223902692. E-mail: paola.perego{at}istitutotumori.mi.it

Abstract

Because cytotoxic stress elicits various signaling pathways that may be implicated in cell survival or cell death, their alterations may have relevance in the development of platinum-resistant phenotype. Thus, in the present study, we investigated cell response to the epidermal growth factor receptor (EGFR) inhibitor gefitinib of ovarian carcinoma cell lines, including cells selected for resistance to cisplatin (IGROV-1/Pt1) and oxaliplatin (IGROV-1/OHP). Resistant sublines exhibited a marked decrease in sensitivity to gefitinib and resistance to apoptosis. Gefitinib was capable of inhibiting the phosphorylation of EGFR in all the studied cell lines. The Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) kinases, which act downstream of EGFR, were constitutively active in the three cell lines, but phospho-ERK1/2 levels were increased in the two resistant sublines. This feature was associated with reduced sensitivity to the MEK1/2 inhibitor U0126. Pretreatment of resistant cells with U0126 resulted in restoration of sensitivity to gefitinib. Gefitinib was more effective in inhibiting ERK1/2 and Akt phosphorylation in IGROV-1 cells than in IGROV-1/OHP and IGROV-1/Pt1 cells. Phospho-p38 was up-regulated in the resistant sublines, indicating the concomitant activation of distinct mitogen-activated protein kinases. The up-regulation of phospho-p38 was associated with a peculiar localization of EGFR, which, in resistant sublines, was mainly internalized. In conclusion, our results indicate that the development of resistance to platinum drugs is associated with multiple alterations including deregulation of survival pathways activated by EGFR resulting in a reduced cellular response to gefitinib. [Mol Cancer Ther 2008;7(3):679–87]

Grant support: Associazione Italiana Ricerca sul Cancro, Fondazione Cariplo (Milan, Italy) and Ministero della Salute and MIUR (Rome, Italy).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 7/ 4/07; revised 12/10/07; accepted 2/ 1/08.