Majumder S, Dutta P, Mookerjee A, Choudhuri S K
Department of Environmental Carcinogenesis and Toxicology, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Calcutta 700026, India.
Chem Biol Interact. 2006 Feb 1;159(2):90-103. doi: 10.1016/j.cbi.2005.10.044. Epub 2005 Nov 10.
One of the important pathways of resistance to anthracyclines is governed by elevated levels of glutathione (GSH) in cancer cells. Resistant cells having elevated levels of GSH show higher expression of multidrug-resistant protein (MRP); the activity of glutathione S-transferases (GSTs) group of enzymes have also been found to be higher in some drug-resistant cells. The general mechanism in this type of resistance seems to be the formation of conjugates enzymatically by GSTs, and subsequent efflux by active transport through MRP (MRP1-MRP9). MRPs act as drug efflux pump and can also co-transport drugs like doxorubicin (Dox) with GSH. Depletion of GSH in resistant neoplastic cells may possibly sensitize such cells, and thus overcome multidrug resistance (MDR). A number of resistance modifying agents (RMA) like DL-buthionine (S, R) sulfoxamine (BSO) and ethacrynic acid (EA) moderately modulate resistance by acting as a GSH-depleting agent. As most of the GSH-depleting agents have dose-related toxicity, development of non-toxic GSH-depleting agent has immense importance in overcoming MDR. The present study describes the resistance reversal potentiality of novel copper complex, viz., copper N-(2-hydroxy acetophenone) glycinate (CuNG) developed by us in Dox-resistant Ehrlich ascites carcinoma (EAC/Dox) cells. CuNG depletes GSH in resistant (EAC/Dox) cells possibly by forming conjugate with it. Depletion of GSH results in higher Dox accumulation that may lead to enhanced rate of apoptosis in EAC/Dox cells. In vivo studies with male Swiss albino mice bearing ascitic growth of EAC/Dox showed tremendous increase in life span (treated/control, T/C = 453%) for the treated group with apparent regression of tumor. Resistance to Dox in EAC/Dox cells is associated with over expression of GST-P1, GST-M1 (enzymes involved in phase II detoxification) and MRP1 (a transmembrane ATPase efflux pump for monoglutathionyl conjugates of xenobiotics). CuNG causes down regulation of all these three proteins in EAC/Dox cells. The effect of CuNG as RMA is better than BSO in many aspects.
对蒽环类药物产生耐药性的重要途径之一是癌细胞中谷胱甘肽（GSH）水平升高。GSH水平升高的耐药细胞显示多药耐药蛋白（MRP）表达更高；在一些耐药细胞中还发现谷胱甘肽S-转移酶（GSTs）组酶的活性也更高。这种耐药类型的一般机制似乎是GSTs通过酶促作用形成共轭物，随后通过MRP（MRP1-MRP9）的主动转运进行外排。MRP作为药物外排泵，还可以与GSH共同转运阿霉素（Dox）等药物。耐药肿瘤细胞中GSH的消耗可能会使此类细胞敏感化，从而克服多药耐药性（MDR）。许多耐药修饰剂（RMA），如DL-丁硫氨酸（S，R）亚砜胺（BSO）和依他尼酸（EA），通过作为GSH消耗剂来适度调节耐药性。由于大多数GSH消耗剂具有剂量相关的毒性，开发无毒的GSH消耗剂对于克服MDR具有极其重要的意义。本研究描述了我们开发的新型铜配合物，即N-（2-羟基苯乙酮）甘氨酸铜（CuNG）对耐阿霉素艾氏腹水癌（EAC/Dox）细胞的耐药逆转潜力。CuNG可能通过与耐药（EAC/Dox）细胞中的GSH形成共轭物来消耗GSH。GSH的消耗导致更高的阿霉素积累，这可能导致EAC/Dox细胞中凋亡率增加。对携带EAC/Dox腹水生长的雄性瑞士白化小鼠进行的体内研究表明，治疗组的寿命显著延长（治疗/对照，T/C = 453%），肿瘤明显消退。EAC/Dox细胞对阿霉素的耐药性与GST-P1、GST-M1（参与II期解毒的酶）和MRP1（一种用于外源性物质单谷胱甘肽共轭物的跨膜ATP酶外排泵）的过度表达有关。CuNG导致EAC/Dox细胞中所有这三种蛋白质的下调。在许多方面，CuNG作为RMA的效果优于BSO。
