Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China.
Hepatology. 2013 May;57(5):1847-57. doi: 10.1002/hep.26224. Epub 2013 Mar 14.
The increasing incidence of hepatocellular carcinoma (HCC) is of great concern not only in the United States but throughout the world. Although sorafenib, a multikinase inhibitor with antiangiogenic and antiproliferative effects, currently sets the new standard for advanced HCC, tumor response rates are usually quite low. An understanding of the underlying mechanisms for sorafenib resistance is critical if outcomes are to be improved. In this study we tested the hypothesis that hypoxia caused by the antiangiogenic effects of sustained sorafenib therapy could induce sorafenib resistance as a cytoprotective adaptive response, thereby limiting sorafenib efficiency. We found that HCCs, clinically resistant to sorafenib, exhibit increased intratumor hypoxia compared with HCCs before treatment or HCCs sensitive to sorafenib. Hypoxia protected HCC cells against sorafenib and hypoxia-inducible factor 1 (HIF-1α) was required for the process. HCC cells acquired increased P-gp expression, enhanced glycolytic metabolism, and increased nuclear factor kappa B (NF-κB) activity under hypoxia. EF24, a molecule having structural similarity to curcumin, could synergistically enhance the antitumor effects of sorafenib and overcome sorafenib resistance through inhibiting HIF-1α by sequestering it in cytoplasm and promoting degradation by way of up-regulating Von Hippel-Lindau tumor suppressor (VHL). Furthermore, we found that sustained sorafenib therapy led to increased intratumor hypoxia, which was associated with sorafenib sensitivity in HCC subcutaneous mice tumor models. The combination of EF24 and sorafenib showed synergistically effects against metastasis both in vivo and in vitro. Synergistic tumor growth inhibition effects were also observed in subcutaneous and orthotopic hepatic tumors.
Hypoxia induced by sustained sorafenib treatment confers sorafenib resistance to HCC through HIF-1α and NF-κB activation. EF24 overcomes sorafenib resistance through VHL-dependent HIF-1α degradation and NF-κB inactivation. EF24 in combination with sorafenib represents a promising strategy for HCC.
肝细胞癌（HCC）的发病率不断上升，不仅在美国，而且在全世界都引起了极大关注。尽管索拉非尼是一种具有抗血管生成和抗增殖作用的多激酶抑制剂，目前为晚期 HCC 设定了新标准，但肿瘤反应率通常相当低。如果要改善结果，则必须深入了解索拉非尼耐药的潜在机制。在这项研究中，我们检验了这样一个假设，即持续索拉非尼治疗的抗血管生成作用引起的缺氧会导致索拉非尼耐药，作为一种细胞保护适应性反应，从而限制索拉非尼的效率。我们发现，与治疗前的 HCC 或对索拉非尼敏感的 HCC 相比，临床上对索拉非尼耐药的 HCC 表现出肿瘤内缺氧增加。缺氧可保护 HCC 细胞免受索拉非尼的影响，并且缺氧诱导因子 1（HIF-1α）是该过程所必需的。在缺氧条件下，HCC 细胞获得了增加的 P-糖蛋白表达，增强的糖酵解代谢和增加的核因子 kappa B（NF-κB）活性。EF24 是一种与姜黄素结构相似的分子，通过将其隔离在细胞质中并通过上调 Von Hippel-Lindau 肿瘤抑制因子（VHL）促进其降解，从而协同增强索拉非尼的抗肿瘤作用并克服索拉非尼耐药性。此外，我们发现持续的索拉非尼治疗导致肿瘤内缺氧增加，这与 HCC 皮下小鼠肿瘤模型中的索拉非尼敏感性相关。EF24 与索拉非尼联合使用在体内和体外均表现出对转移的协同作用。在皮下和原位肝肿瘤中也观察到协同的肿瘤生长抑制作用。
持续索拉非尼治疗引起的缺氧通过 HIF-1α 和 NF-κB 的激活赋予 HCC 对索拉非尼的耐药性。EF24 通过 VHL 依赖性 HIF-1α 降解和 NF-κB 失活克服索拉非尼耐药性。EF24 联合索拉非尼代表了 HCC 的一种有前途的策略。
