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CANCER

Targeting the Endothelin Axis in Human Melanoma: Combination of Endothelin Receptor Antagonism and Alkylating Agents

University Institute of Pathology, University of Lausanne, Bugnon 25, CH1011 Lausanne, Switzerland

To whom requests for reprints should be addressed at ¹ University Institute of Pathology, CHUV, Bugnon 25, CH1011 Lausanne, Switzerland. E-mail: lucienne.juillerat{at}chuv.ch

Abstract

Endothelin (ET)-1 is an autocrine/paracrine growth factor or an antiapoptotic factor in human cancers, and blockade of ET-1 receptors can sensitize human tumor cells to apoptosis. The role of the ET-1 axis in the proliferation and/or apoptosis of melanoma cells and in their response to the alkylating agent, dacarbazine (DTIC), used in clinical treatment of human melanoma were investigated in five human melanoma cell lines obtained form surgical resection specimens. Melanoma cells expressed the messenger RNAs (mRNAs) for the components of the ET-1 axis. ET-1 binding was mediated by ET_B but was inhomogeneous among melanoma cells. Exogenous ET-1 did not induce human melanoma cell proliferation. Bosentan, a dual ET_A/B-receptor antagonist, decreased melanoma cell viability and DNA synthesis and induced melanoma cell apoptosis in defined human melanoma cells. Bosentan potentiated Fas ligand–induced apoptosis only in one melanoma cell line. Variants of ET_Bwere determined using reverse transcriptase (RT) polymerase chain reaction (PCR) and primers spanning the whole sequence of the ET_Bgene. ET_Bvariants were demonstrated only in one of the five cell lines, corresponding to the absence of ET-1 binding by these cells. Bosentan did not inhibit the effects of alkylating agents, and the effects of bosentan and alkylating agents were additive in melanoma cells. In conclusion, exogenous ET-1 is not a growth factor for human melanoma cells, but blockade of ET receptors decreases proliferation, induces apoptosis, and potentiates the effects of anticancer agents in defined melanoma cells, suggesting that combination therapy of ET-receptor antagonists with alkylating agents may improve their efficacy.

Key Words: endothelin axis • bosentan • melanoma • apoptosis • Fas ligand • alkylating agents

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