Inhibition of Lysyl Oxidases Improves Drug Diffusion and Increases Efficacy of Cytotoxic Treatment in 3D Tumor Models
Inhibition of Lysyl Oxidases Improves Drug Diffusion and Increases Efficacy of Cytotoxic Treatment in 3D Tumor Models
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赖氨酰氧化酶的抑制可改善药物扩散并提高 3D 肿瘤模型中细胞毒性治疗的功效
DOI：
10.1038/srep17576
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发表时间：
2015
影响因子：
4.6
通讯作者：
E. Henke
中科院分区：
文献类型：
--
作者：
Schütze;F. Röhrig;S. Vorlova;S. Gätzner;A. Kuhn;S. Ergün;E. Henke
肿瘤的特点是刚性、高度交联的细胞外基质 (ECM)，它阻碍药物均匀分布，并可能保护恶性细胞免受治疗药物的影响。赖氨酰氧化酶是组织僵硬的主要贡献者，在大多数癌症中观察到的这些酶的表达升高可能会影响药物的分布和功效。我们在 3D 体外测定系统中检查了赖氨酰氧化酶对药物分布和功效的影响。在我们的实验中，赖氨酰氧化酶活性升高导致缺氧条件下药物扩散减少，从而损害各种化疗药物的细胞毒性。这种效应仅在 3D 环境中观察到，但在 2D 细胞培养中未观察到，证实赖氨酰氧化酶通过修改 ECM 影响药物功效，并且不会产生直接脱敏作用。通过抑制赖氨酰氧化酶，药物扩散和功效均得到强烈增强。体外实验的结果与体内肿瘤药物分布相关，并预测小鼠肿瘤模型中对治疗的反应。我们的结果表明，赖氨酰氧化酶活性调节 ECM 对小分子药物的物理屏障功能，影响其治疗效果。针对这一过程有可能显着提高恶性疾病的治疗效果。
Tumors are characterized by a rigid, highly cross-linked extracellular matrix (ECM), which impedes homogeneous drug distribution and potentially protects malignant cells from exposure to therapeutics. Lysyl oxidases are major contributors to tissue stiffness and the elevated expression of these enzymes observed in most cancers might influence drug distribution and efficacy. We examined the effect of lysyl oxidases on drug distribution and efficacy in 3Din vitroassay systems. In our experiments elevated lysyl oxidase activity was responsible for reduced drug diffusion under hypoxic conditions and consequently impaired cytotoxicity of various chemotherapeutics. This effect was only observed in 3D settings but not in 2D-cell culture, confirming that lysyl oxidases affect drug efficacy by modification of the ECM and do not confer a direct desensitizing effect. Both drug diffusion and efficacy were strongly enhanced by inhibition of lysyl oxidases. The results from thein vitroexperiments correlated with tumor drug distributionin vivoand predicted response to therapeutics in murine tumor models. Our results demonstrate that lysyl oxidase activity modulates the physical barrier function of ECM for small molecule drugs influencing their therapeutic efficacy. Targeting this process has the potential to significantly enhance therapeutic efficacy in the treatment of malignant diseases.
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影响因子：
4.1
作者：
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通讯作者：
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DOI：
10.1016/s1570-9639(03)00053-0
发表时间：
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DOI：
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发表时间：
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期刊：
影响因子：
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作者：
通讯作者：
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影响因子：
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作者：
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通讯作者：
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