Metabolic targeting of hypoxia and HIF1 in solid tumors can enhance cytotoxic chemotherapy
Metabolic targeting of hypoxia and HIF1 in solid tumors can enhance cytotoxic chemotherapy
复制标题
DOI：
10.1073/pnas.0611662104
复制
发表时间：
2007-05-29
影响因子：
11.1
通讯作者：
Denko, Nicholas C.
中科院分区：
文献类型：
--
作者：
Cairns, Rob A.;Papandreou, Ioanna;Denko, Nicholas C.
实体瘤通常包含低氧浓度的大片区域(缺氧)。低氧微环境诱导肿瘤细胞代谢的适应性变化，这种变化可导致局部微环境的扭曲。这些肿瘤特异性改变的最终结果是微环境抑制了许多标准的细胞毒性抗癌治疗，并预测了糟糕的临床结果。针对实体瘤独特代谢的药物靶向可以改变肿瘤微环境，为抗肿瘤治疗提供更有利的条件。在这里，我们描述了一种策略，通过药物抑制缺氧诱导因子1(HIF1)或其靶基因丙酮酸脱氢酶激酶1(PDK1)来增加肿瘤细胞的线粒体代谢。这种氧气消耗的急剧增加导致了肿瘤氧合的相应减少。虽然氧合减少可能会降低一些传统疗法的有效性，但我们表明，它显著提高了一种低氧特异性细胞毒素的有效性。这种治疗策略应该为提高缺氧细胞毒素的有效性提供高度的肿瘤特异性，因为它依赖于HIF1的激活和缺氧的存在，而这些条件只存在于肿瘤中，而不存在于正常组织中。
Solid tumors frequently contain large regions with low oxygen concentrations (hypoxia). The hypoxic microenvironment induces adaptive changes to tumor cell metabolism, and this alteration can furl:her distort the local microenvironment. The net result of these tumor-specific changes is a microenvironment that inhibits many standard cytotoxic anticancer therapies and predicts for a poor clinical outcome. Pharmacologic targeting of the unique metabolism of solid tumors could alter the tumor microenvironment to provide more favorable conditions for anti-tumor therapy. Here, we describe a strategy in which the mitochondrial metabolism of tumor cells is increased by pharmacologic inhibition of hypoxia-inducible factor 1 (HIF1) or its target gene pyruvate dehydrogenase kinase 1 (PDK1). This acute increase in oxygen consumption leads to a corresponding decrease in tumor oxygenation. Whereas decreased oxygenation could reduce the effectiveness of some traditional therapies, we show that it dramatically increases the effectiveness of a hypoxia-specific cytotoxin. This treatment strategy should provide a high degree of tumor specificity for increasing the effectiveness of hypoxic cytotoxins, as it depends on the activation of HIF1 and the presence of hypoxia, conditions that are present only in the tumor, and not the normal tissue.