Translational Development Department, Celgene Corporation, 1500 Owens St Suite 600, San Francisco, CA 94158, USA.
Cancer Chemother Pharmacol. 2012 Apr;69(4):965-76. doi: 10.1007/s00280-011-1782-x. Epub 2011 Nov 26.
Multi-drug resistance and cumulative cardiotoxicity are major limitations for the clinical use of anthracyclines. Here, we evaluated and compared the cross-resistance of amrubicin, a third-generation synthetic anthracycline and potent topoisomerase (topo)-II inhibitor with little or no observed cardiotoxicity to other anthracyclines and the topo-II inhibitor etoposide in drug-resistant tumor models in order to elucidate its potential mechanisms of action.
Amrubicin activity was assessed in multi-drug-resistant cell lines and human tumor explants using cytotoxicity assays, confocal microscopy, fluorescence time-lapse imaging, flow cytometry, immunoblotting, and gene expression profiling techniques.
We demonstrate that both doxorubicin-resistant tumor cell lines and several drug-resistant human ovarian and breast tumor explants retain sensitivity to amrubicin. In addition, we observed similar levels of amrubicin uptake and accumulation in doxorubicin-sensitive versus doxorubicin-resistant cell lines. Although amrubicin is a weak P-glycoprotein substrate, transport and retention of amrubicin were not solely modulated by P-glycoprotein in the resistant cell lines overexpressing drug efflux pumps. The cellular retention of amrubicin is likely to be a result of rapid influx due to its high intrinsic permeability and lipophilic properties, and this may explain why amrubicin overcomes pleiotropic drug resistance. Consistent with drug accumulation studies, amrubicin induced DNA damage, G(2)-M cell cycle arrest, and apoptosis in both doxorubicin-sensitive and doxorubicin-resistant lines. Using gene expression profiling studies, several classes of genes were significantly and uniquely regulated following amrubicin, but not doxorubicin or etoposide, treatment.
Amrubicin appears to have a distinct mode of action that overcomes typical anthracycline resistance mechanisms. Therefore, amrubicin may be useful in the treatment of anthracycline-refractory or anthracycline-resistant tumors.
多药耐药和累积性心脏毒性是临床应用蒽环类药物的主要限制因素。在这里，我们评估并比较了第三代合成蒽环类药物氨柔比星（amrubicin）与其他蒽环类药物和拓扑异构酶 II 抑制剂依托泊苷（etoposide）的交叉耐药性，该药对拓扑异构酶 II （topo）具有抑制作用，且心脏毒性较小或观察不到，以阐明其潜在的作用机制。
使用细胞毒性测定、共聚焦显微镜、荧光延时成像、流式细胞术、免疫印迹和基因表达谱技术评估氨柔比星在多药耐药细胞系和人肿瘤组织中的活性。
我们证明，多柔比星耐药肿瘤细胞系和几种耐药人卵巢和乳腺癌组织均对氨柔比星敏感。此外，我们观察到在多柔比星敏感细胞系与多柔比星耐药细胞系中，氨柔比星摄取和积累水平相似。尽管氨柔比星是一种弱 P-糖蛋白（P-gp）底物，但在过度表达药物外排泵的耐药细胞系中，氨柔比星的转运和保留并不仅仅受 P-gp 调节。氨柔比星的细胞内保留可能是由于其高内在通透性和亲脂性，导致其快速内流所致，这可能解释了为什么氨柔比星能克服多药耐药性。与药物积累研究一致，氨柔比星在多柔比星敏感和多柔比星耐药细胞系中均诱导 DNA 损伤、G2-M 细胞周期阻滞和细胞凋亡。通过基因表达谱研究，与多柔比星或依托泊苷处理相比，氨柔比星处理后显著且独特地调节了几类基因。
氨柔比星似乎具有一种独特的作用机制，可克服典型的蒽环类药物耐药机制。因此，氨柔比星可能对治疗蒽环类药物难治或蒽环类药物耐药的肿瘤有用。
