Weaver J L, Szabo G, Pine P S, Gottesman M M, Goldenberg S, Aszalos A
Division of Research and Testing, Food and Drug Administration, Washington, DC 20204.
Int J Cancer. 1993 May 28;54(3):456-61. doi: 10.1002/ijc.2910540317.
The MDRI protein is an energy-dependent transport protein responsible for the multi-drug resistance seen in many tumors. A variety of drugs have been shown to inhibit the function of this pump, including compounds known to block various ion channels. The mouse lymphoma cell line L5178Y has been transduced with the human mdrI gene. Using this cell line, we have tested a number of compounds to determine whether there is a correlation between the ability to block a specific type of ion channel, or shift membrane potential, and the ability to act as an MDR-reversing agent using the fluorescent substrates Rhodamine 123 and daunorubicin as test compounds. Our results show no apparent correlation between the ability to block a specific ion channel and reversal of MDR transport ability. We have found active MDR inhibitors in compounds that affect K+, Na+, Ca++, H+, but not Cl- channels. Our data suggest that Cl- channel activity may be distinct from MDR activity. Several immunosuppressive compounds and analogs were also tested and found to be active reversing agents. Measurements suggest a significant difference in resting membrane potential between the L5178YvMDR line and the L5178Y parental cell line used in these experiments. No correlation was found between the ability of drugs to alter membrane potential and to inhibit MDR transport activity. Our results suggest that MDR transport function may be independent of the physiological movement of ions and show that a wide variety of compounds can inhibit MDR transport.
多药耐药性（MDR）蛋白是一种能量依赖性转运蛋白，与许多肿瘤中出现的多药耐药性有关。多种药物已被证明可抑制该泵的功能，包括已知能阻断各种离子通道的化合物。小鼠淋巴瘤细胞系L5178Y已被转导了人类mdrI基因。利用该细胞系，我们测试了多种化合物，以确定阻断特定类型离子通道或改变膜电位的能力与使用罗丹明123和柔红霉素等荧光底物作为测试化合物作为MDR逆转剂的能力之间是否存在相关性。我们的结果表明，阻断特定离子通道的能力与MDR转运能力的逆转之间没有明显的相关性。我们在影响钾离子、钠离子、钙离子、氢离子但不影响氯离子通道的化合物中发现了活性MDR抑制剂。我们的数据表明，氯离子通道活性可能与MDR活性不同。还测试了几种免疫抑制化合物及其类似物，发现它们是活性逆转剂。测量结果表明，在这些实验中使用的L5178YvMDR细胞系和L5178Y亲本细胞系之间的静息膜电位存在显著差异。未发现药物改变膜电位的能力与抑制MDR转运活性之间存在相关性。我们的结果表明，MDR转运功能可能独立于离子的生理运动，并表明多种化合物可抑制MDR转运。
