Varga A, Sabat R, Mucsi I, Flores V C, Kaiser H E, Molnár J
Department of Molecular Parasitology, Humboldt University, Berlin, Germany.
Anticancer Res. 2001 Jul-Aug;21(4A):2709-12.
The efflux pump of multidrug resistant mdr cells have different sensitivities to some stereoisomeric forms of CNS-active compounds. The ABC transporters of mdr cells were more sensitive to (-)butaclamol than to its stereoisomeric counterpart (8), which may function to alter the membrane structure. We suppose that the drug-accessible membrane structure possesses an important role in the induction (or prevention) of apoptosis. Therefore the apoptosis-inducing effect of three stereoisomeric pairs was studied on mouse lymphoma cells. In these experiments levo- and dextromepromazine had similiar effects. The cis- and trans-clopenthixol were less effective in apoptosis induction than the 12H-benzo(a)-phenothiazine used as a positive control. The effect of stereoisomeric pairs on induced apoptosis was studied when the cells were exposed to the stereoisomers for 60 minutes before subjection apoptosis induction by benzo(a)phenothiazine, a well-known apoptosis inducer. Then the pretreated cells were exposed to 12H-benzo(a)-phenothiazine for 60 minutes. The samples were washed and incubated for 24 hours. The cells were stained with annexin-V-FITC and propidium iodine and investigated by flow cytometry. The mdr cells with increased membrane integrity may result in the preferential killing of multidrug resistant cancer cells in the presence of some stereoisomers.
多药耐药（mdr）细胞的外排泵对某些中枢神经系统活性化合物的立体异构体形式具有不同的敏感性。mdr细胞的ABC转运蛋白对（-）丁酰苯比其立体异构体更敏感（8），这可能起到改变膜结构的作用。我们推测药物可及的膜结构在细胞凋亡的诱导（或预防）中起重要作用。因此，研究了三对立体异构体对小鼠淋巴瘤细胞的凋亡诱导作用。在这些实验中，左旋和右旋丙咪嗪具有相似的作用。顺式和反式氯噻吨在诱导凋亡方面比用作阳性对照的12H-苯并（a）-吩噻嗪效果更差。当细胞在被众所周知的凋亡诱导剂苯并（a）吩噻嗪诱导凋亡之前，先暴露于立体异构体60分钟，研究了立体异构体对诱导凋亡的影响。然后将预处理的细胞暴露于12H-苯并（a）-吩噻嗪60分钟。洗涤样品并孵育24小时。用膜联蛋白-V-异硫氰酸荧光素和碘化丙啶对细胞进行染色，并通过流式细胞术进行研究。在某些立体异构体存在的情况下，膜完整性增加的mdr细胞可能导致多药耐药癌细胞的优先杀伤。
