Mégalizzi Véronique, Mathieu Véronique, Mijatovic Tatjana, Gailly Philippe, Debeir Olivier, De Neve Nancy, Van Damme Marc, Bontempi Gianluca, Haibe-Kains Benjamin, Decaestecker Christine, Kondo Yasuko, Kiss Robert, Lefranc Florence
Laboratoire de Toxicologie, Institut de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
Neoplasia. 2007 May;9(5):358-69. doi: 10.1593/neo.07130.
Although the molecular function of sigma receptors has not been fully defined and the natural ligand(s) is still not known, there is increasing evidence that these receptors and their ligands might play a significant role in cancer biology. 4-(N-benzylpiperidin-4-yl)-4-iodobenzamide (4-IBP), a selective sigma1 agonist, has been used to investigate whether this compound is able to modify: 1) in vitro the migration and proliferation of human cancer cells; 2) in vitro the sensitivity of human glioblastoma cells to cytotoxic drugs; and 3) in vivo in orthotopic glioblastoma and non-small cell lung carcinoma (NSCLC) models the survival of mice co-administered cytotoxic agents. 4-IBP has revealed weak antiproliferative effects on human U373-MG glioblastoma and C32 melanoma cells but induced marked concentration-dependent decreases in the growth of human A549 NSCLC and PC3 prostate cancer cells. The compound was also significantly antimigratory in all four cancer cell lines. This may result, at least in U373-MG cells, from modifications to the actin cytoskeleton. 4-IBP modified the sensitivity of U373-MG cells in vitro to proapoptotic lomustin and proautophagic temozolomide, and markedly decreased the expression of two proteins involved in drug resistance: glucosylceramide synthase and Rho guanine nucleotide dissociation inhibitor. In vivo, 4-IBP increased the antitumor effects of temozolomide and irinotecan in immunodeficient mice that were orthotopically grafted with invasive cancer cells.
尽管σ受体的分子功能尚未完全明确，其天然配体也仍未可知，但越来越多的证据表明，这些受体及其配体可能在癌症生物学中发挥重要作用。4-(N-苄基哌啶-4-基)-4-碘苯甲酰胺（4-IBP）是一种选择性σ1激动剂，已被用于研究该化合物是否能够改变：1）体外人癌细胞的迁移和增殖；2）体外人胶质母细胞瘤细胞对细胞毒性药物的敏感性；3）在原位胶质母细胞瘤和非小细胞肺癌（NSCLC）模型中，体内联合使用细胞毒性药物的小鼠的生存期。4-IBP对人U373-MG胶质母细胞瘤细胞和C32黑色素瘤细胞显示出较弱的抗增殖作用，但可诱导人A549 NSCLC细胞和PC3前列腺癌细胞的生长出现明显的浓度依赖性降低。该化合物在所有四种癌细胞系中也具有显著的抗迁移作用。至少在U373-MG细胞中，这可能是由于肌动蛋白细胞骨架的改变所致。4-IBP改变了U373-MG细胞在体外对促凋亡药物洛莫司汀和促自噬药物替莫唑胺的敏感性，并显著降低了两种与耐药性相关的蛋白的表达：葡糖神经酰胺合酶和Rho鸟嘌呤核苷酸解离抑制剂。在体内，4-IBP增强了替莫唑胺和伊立替康对原位移植侵袭性癌细胞的免疫缺陷小鼠的抗肿瘤作用。
