van Vlerken Lilian E, Duan Zhenfeng, Seiden Michael V, Amiji Mansoor M
Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, Massachusetts, USA.
Cancer Res. 2007 May 15;67(10):4843-50. doi: 10.1158/0008-5472.CAN-06-1648.
Although multidrug resistance (MDR) is known to develop through a variety of molecular mechanisms within the tumor cell, many tend to converge toward the alteration of apoptotic signaling. The enzyme glucosylceramide synthase (GCS), responsible for bioactivation of the proapoptotic mediator ceramide to a nonfunctional moiety glucosylceramide, is overexpressed in many MDR tumor types and has been implicated in cell survival in the presence of chemotherapy. The purpose of this study was to investigate the therapeutic strategy of coadministering ceramide with paclitaxel, a commonly used chemotherapeutic agent, in an attempt to restore apoptotic signaling and overcome MDR in the human ovarian cancer cell line SKOV3. Poly(ethylene oxide)-modified poly(epsilon-caprolactone) (PEO-PCL) nanoparticles were used to encapsulate and deliver the therapeutic agents for enhanced efficacy. Results show that indeed the cotherapy eradicates the complete population of MDR cancer cells when they are treated at their IC(50) dose of paclitaxel. More interestingly, when the cotherapy was combined with the properties of nanoparticle drug delivery, the MDR cells can be resensitized to a dose of paclitaxel near the IC(50) of non-MDR (drug sensitive) cells, indicating a 100-fold increase in chemosensitization via this approach. Molecular analysis of activity verified the hypothesis that the efficacy of this therapeutic approach is indeed due to a restoration in apoptotic signaling, although the beneficial properties of PEO-PCL nanoparticle delivery seemed to enhance the therapeutic success even further, showing the promising potential for the clinical use of this therapeutic strategy to overcome MDR.
尽管已知多药耐药性（MDR）是通过肿瘤细胞内多种分子机制产生的，但许多机制往往趋向于凋亡信号的改变。葡糖神经酰胺合酶（GCS）负责将促凋亡介质神经酰胺生物活化为无功能的部分葡糖神经酰胺，在许多多药耐药肿瘤类型中过度表达，并与化疗存在时的细胞存活有关。本研究的目的是研究将神经酰胺与常用化疗药物紫杉醇联合给药的治疗策略，试图恢复凋亡信号并克服人卵巢癌细胞系SKOV3中的多药耐药性。聚（环氧乙烷）修饰的聚（ε-己内酯）（PEO-PCL）纳米颗粒用于包裹和递送治疗剂以提高疗效。结果表明，当以其IC（50）剂量的紫杉醇治疗时，联合治疗确实根除了全部多药耐药癌细胞群体。更有趣的是，当联合治疗与纳米颗粒药物递送特性相结合时，多药耐药细胞可对接近非多药耐药（药物敏感）细胞IC（50）的紫杉醇剂量重新敏感，表明通过这种方法化学增敏增加了100倍。活性分子分析证实了这一假设，即这种治疗方法的疗效确实归因于凋亡信号的恢复，尽管PEO-PCL纳米颗粒递送的有益特性似乎进一步提高了治疗成功率，显示出这种治疗策略临床应用克服多药耐药性的潜在前景。
