硼替佐米与多药转运体的相互作用：对晚期多发性骨髓瘤和其他肿瘤治疗应用的影响。
The interaction of bortezomib with multidrug transporters: implications for therapeutic applications in advanced multiple myeloma and other neoplasias.
机构信息
School of Nursing and Human Sciences, Dublin City University, Dublin 9, Ireland.
出版信息
Cancer Chemother Pharmacol. 2013 May;71(5):1357-68. doi: 10.1007/s00280-013-2136-7. Epub 2013 Apr 16.
PURPOSE
Bortezomib is an important agent in multiple myeloma treatment, but resistance in cell lines and patients has been described. The main mechanisms of resistance described in cancer fall into one of two categories, pharmacokinetic resistance (PK), e.g. over expression of drug efflux pumps and pharmacodynamic resistance, e.g. apoptosis resistance or altered survival pathways, where the agent reaches an appropriate concentration, but this fails to propagate an appropriate cell death response. Of the known pump mechanisms, P-glycoprotein (P-gp) is the best studied and considered to be the most important in contributing to general PK drug resistance. Resistance to bortezomib is multifactorial and there are conflicting indications that cellular overexpression of P-gp may contribute to resistance agent. Hence, better characterization of the interactions of this drug with classical resistance mechanisms should identify improved treatment applications.
METHODS
Cell lines with different P-gp expression levels were used to determine the relationship between bortezomib and P-gp. Coculture system with stromal cells was used to determine the effect of the local microenvironment on the bortezomib-elacridar combination. To further assess P-gp function, intracellular accumulation of P-gp probe rhodamine-123 was utilised.
RESULTS
In the present study, we show that bortezomib is a substrate for P-gp, but not for the other drug efflux transporters. Bortezomib activity is affected by P-gp expression and conversely, the expression of P-gp affect bortezomib's ability to act as a P-gp substrate. The local microenvironment did not alter the cellular response to bortezomib. We also demonstrate that bortezomib directly affects the expression and function of P-gp.
CONCLUSIONS
Our findings strongly support a role for P-gp in bortezomib resistance and, therefore, suggest that combination of a P-gp inhibitor and bortezomib in P-gp positive myeloma would be a reasonable treatment combination to extend efficacy of this important drug.
目的
硼替佐米是多发性骨髓瘤治疗中的一种重要药物，但已描述了细胞系和患者的耐药性。癌症中描述的主要耐药机制可归入两类之一，即药代动力学耐药（PK），例如药物外排泵的过度表达和药效动力学耐药，例如凋亡耐药或改变的存活途径，其中药物达到适当浓度，但这不能引起适当的细胞死亡反应。在已知的泵机制中，P-糖蛋白（P-gp）研究最多，被认为是导致一般 PK 药物耐药性的最重要因素。硼替佐米耐药是多因素的，有矛盾的迹象表明，细胞 P-gp 的过度表达可能有助于耐药剂。因此，更好地描述该药物与经典耐药机制的相互作用应能确定改善的治疗应用。
方法
使用具有不同 P-gp 表达水平的细胞系来确定硼替佐米与 P-gp 之间的关系。使用基质细胞共培养系统来确定局部微环境对硼替佐米-埃拉西达组合的影响。为了进一步评估 P-gp 的功能，利用 P-gp 探针罗丹明 123 的细胞内积累来评估 P-gp 的功能。
结果
在本研究中，我们表明硼替佐米是 P-gp 的底物，但不是其他药物外排转运体的底物。P-gp 的表达影响硼替佐米的活性，反之，P-gp 的表达也影响硼替佐米作为 P-gp 底物的能力。局部微环境不会改变细胞对硼替佐米的反应。我们还证明硼替佐米直接影响 P-gp 的表达和功能。
结论
我们的研究结果强烈支持 P-gp 在硼替佐米耐药中的作用，因此，建议在 P-gp 阳性骨髓瘤中将 P-gp 抑制剂与硼替佐米联合使用是一种合理的治疗组合，可以延长这种重要药物的疗效。
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