Berger Yann, Bernasconi Catherine Chapuis, Juillerat-Jeanneret Lucienne
University Institute of Pathology, University of Lausanne, Bugnon 25, CH1011 Lausanne, Switzerland.
Exp Biol Med (Maywood). 2006 Jun;231(6):1111-9.
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(B)were determined using reverse transcriptase (RT) polymerase chain reaction (PCR) and primers spanning the whole sequence of the ET(B)gene. ET(B)variants 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.
内皮素（ET）-1是人类癌症中的一种自分泌/旁分泌生长因子或抗凋亡因子，阻断ET-1受体可使人类肿瘤细胞对凋亡敏感。在从手术切除标本中获得的五个人类黑色素瘤细胞系中，研究了ET-1轴在黑色素瘤细胞增殖和/或凋亡以及它们对用于人类黑色素瘤临床治疗的烷化剂达卡巴嗪（DTIC）的反应中的作用。黑色素瘤细胞表达ET-1轴各成分的信使核糖核酸（mRNA）。ET-1的结合由ET（B）介导，但在黑色素瘤细胞中不均匀。外源性ET-1不诱导人类黑色素瘤细胞增殖。双重ET（A/B）受体拮抗剂波生坦可降低特定人类黑色素瘤细胞的活力和DNA合成，并诱导黑色素瘤细胞凋亡。波生坦仅在一种黑色素瘤细胞系中增强Fas配体诱导的凋亡。使用逆转录酶（RT）聚合酶链反应（PCR）和跨越ET（B）基因全序列的引物来确定ET（B）的变体。仅在五个细胞系中的一个中检测到ET（B）变体，这与这些细胞中不存在ET-1结合相对应。波生坦不抑制烷化剂的作用，并且波生坦和烷化剂在黑色素瘤细胞中的作用是相加的。总之，外源性ET-1不是人类黑色素瘤细胞的生长因子，但阻断ET受体可降低增殖、诱导凋亡并增强特定黑色素瘤细胞中抗癌药物的作用，这表明ET受体拮抗剂与烷化剂联合治疗可能会提高其疗效。
