Cell-selective inhibition of NF-κB signaling improves therapeutic index in a melanoma chemotherapy model.
Cell-selective inhibition of NF-κB signaling improves therapeutic index in a melanoma chemotherapy model.
复制标题
细胞选择性抑制 NF-κB 信号传导可提高黑色素瘤化疗模型的治疗指数。
DOI：
10.1158/2159-8290.cd-11-0143
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发表时间：
2011-11
期刊：
影响因子：
28.2
通讯作者：
Park JM
中科院分区：
文献类型：
--
作者：
Enzler T;Sano Y;Choo MK;Cottam HB;Karin M;Tsao H;Park JM
转录因子NF-κB促进暴露于阿霉素和其他化疗药物的癌细胞存活。I-κB激酶是化疗诱导的核因子-κB活化所必需的，被认为是抗癌治疗的主要靶点。一种IκB激酶抑制剂使小鼠体内的人黑色素瘤移植瘤对阿霉素致敏，但也加剧了宿主动物的治疗毒性。使用模拟细胞选择性靶向的小鼠模型，我们发现黑色素瘤和宿主髓系细胞中NF-κB活性受损分别是治疗和不良反应的原因。在阿霉素治疗后，肿瘤固有的NF-κB活性的消融导致了细胞凋亡驱动的肿瘤消退。相比之下，在髓系特异性丧失NF-κB活性的小鼠中，化疗导致产生白细胞介素1β的中性粒细胞在肿瘤内大量募集，并导致肿瘤坏死损害，这种情况与宿主死亡率增加有关，但不伴随肿瘤消退。因此，基于分子靶向的治疗可能会根据药物的细胞特异性效应而产生不同的临床结果。
The transcription factor NF-κB promotes survival of cancer cells exposed to doxorubicin and other chemotherapeutic agents. IκB kinase is essential for chemotherapy-induced NF-κB activation and considered a prime target for anticancer treatment. An IκB kinase inhibitor sensitized human melanoma xenografts in mice to killing by doxorubicin, yet also exacerbated treatment toxicity in the host animals. Using mouse models that simulate cell-selective targeting, we found that impaired NF-κB activation in melanoma and host myeloid cells accounts for the therapeutic and the adverse effects, respectively. Ablation of tumor-intrinsic NF-κB activity resulted in apoptosis-driven tumor regression following doxorubicin treatment. By contrast, chemotherapy in mice with myeloid-specific loss of NF-κB activation led to a massive intratumoral recruitment of interleukin-1β-producing neutrophils and necrotic tumor lesions, a condition associated with increased host mortality but not accompanied by tumor regression. Therefore, a molecular target-based therapy may be steered toward different clinical outcomes depending on the drug’s cell-specific effects.