Akiyama S, Cornwell M M, Kuwano M, Pastan I, Gottesman M M
Department of Cancer Chemotherapy, Faculty of Medicine, Kagoshima University, Japan.
Mol Pharmacol. 1988 Feb;33(2):144-7.
Multidrug-resistant human KB carcinoma cells express a 170,000-dalton membrane glycoprotein (P-glycoprotein) that can be photoaffinity labeled with the vinblastine analog N-(p-azido-[3-125I]salicyl]-N'-(beta-aminoethyl)vindesine. Several agents that suppress the multidrug-resistant phenotype, including N-solanesyl-N,N'-bis(3,4-dimethylbenzyl)ethylenediamine, cepharanthine, quinidine, and reserpine, were found to inhibit photolabeling of P-glycoprotein at doses comparable to those that reverse multidrug resistance. However, the phenothiazines chlorpromazine and trifluoperazine, which also effectively reverse multidrug resistance, were poor inhibitors of the photoaffinity labeling of P-glycoprotein. Chloroquine, propranolol, or atropine, which only partially reversed the drug resistance, also did not inhibit photolabeling. Naphthalene sulfonamide calmodulin inhibitors, W7 and W5, as well as many other drugs that did not circumvent multidrug resistance, did not inhibit photolabeling. These studies suggest that most, but not all, agents that phenotypically suppress multidrug resistance also inhibit drug binding to a site on P-glycoprotein with which a photoaffinity analog of vinblastine interacts.
多药耐药的人KB癌细胞表达一种170,000道尔顿的膜糖蛋白（P-糖蛋白），该蛋白可用长春碱类似物N-(对叠氮基-[3-¹²⁵I]水杨基)-N'-(β-氨乙基)长春地辛进行光亲和标记。发现几种抑制多药耐药表型的药物，包括N-茄尼基-N,N'-双(3,4-二甲基苄基)乙二胺、千金藤素、奎尼丁和利血平，在与逆转多药耐药的剂量相当的情况下，能抑制P-糖蛋白的光标记。然而，也能有效逆转多药耐药的吩噻嗪类药物氯丙嗪和三氟拉嗪，对P-糖蛋白的光亲和标记抑制作用较弱。仅部分逆转耐药性的氯喹、普萘洛尔或阿托品，也不抑制光标记。萘磺酰胺钙调蛋白抑制剂W7和W5，以及许多其他未克服多药耐药的药物，均不抑制光标记。这些研究表明，大多数（但不是全部）在表型上抑制多药耐药的药物，也能抑制药物与P-糖蛋白上长春碱光亲和类似物相互作用的位点的结合。
