Steinfeld R C, Severski M C, Cragoe E J, Knauf P A
Department of Biophysics, University of Rochester School of Medicine and Dentistry, New York 14642.
Exp Hematol. 1990 Aug;18(7):818-23.
Treatment with adriamycin for 8-14 h irreversibly induces K562 human erythroleukemic cells to synthesize hemoglobin. With 16-h exposure, this effect is maximal at concentrations between 180 and 400 nM, yielding 70%-90% benzidine-positive (B+) cells and 24 pg/cell hemoglobin 4 days after the beginning of adriamycin treatment. This induction is accompanied by changes in ouabain-sensitive 86Rb influx opposite to those seen with murine erythroleukemic (MEL) cells. Amiloride and several amiloride analogues strongly inhibit adriamycin induction of hemoglobin synthesis as well as cell growth in the absence of adriamycin. The inhibition of induction is enhanced with the analogues bearing a benzyl or substituted benzyl group on the 5-amino or on a terminal guanidino nitrogen atom. The effect on growth was somewhat greater with the analogue bearing a 2-chlorobenzyl moiety on a terminal guanidino nitrogen atom and with the one bearing a 2-fluorobenzyl group on the 5-amino nitrogen atom. The structural features required for growth inhibition resemble those seen with MEL cells, but the features required for inhibition of induction of hemoglobin synthesis are completely different. These data suggest that different specific binding sites are involved in these two effects of amiloride and its analogues.
用阿霉素处理8 - 14小时可不可逆地诱导K562人红白血病细胞合成血红蛋白。暴露16小时后，在180至400 nM的浓度下这种效应最大，在阿霉素处理开始4天后产生70% - 90%的联苯胺阳性（B +）细胞和24 pg/细胞的血红蛋白。这种诱导伴随着哇巴因敏感的86Rb内流的变化，与鼠红白血病（MEL）细胞所见的变化相反。氨氯吡咪和几种氨氯吡咪类似物在无阿霉素时强烈抑制阿霉素诱导的血红蛋白合成以及细胞生长。在5 - 氨基或末端胍基氮原子上带有苄基或取代苄基的类似物增强了对诱导的抑制作用。在末端胍基氮原子上带有2 - 氯苄基部分的类似物以及在5 - 氨基氮原子上带有2 - 氟苄基的类似物对生长的影响更大。生长抑制所需的结构特征与MEL细胞所见的相似，但抑制血红蛋白合成诱导所需的特征完全不同。这些数据表明，氨氯吡咪及其类似物的这两种效应涉及不同的特异性结合位点。
