Meng Zhaowei, Mitsutake Norisato, Nakashima Masahiro, Starenki Dmytro, Matsuse Michiko, Takakura Shu, Namba Hiroyuki, Saenko Vladimir, Umezawa Kazuo, Ohtsuru Akira, Yamashita Shunichi
Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin, Japan.
Endocrinology. 2008 Nov;149(11):5357-65. doi: 10.1210/en.2008-0279. Epub 2008 Jul 24.
Nuclear factor kappaB (NF-kappaB), as an antiapoptotic factor, crucially affects the outcomes of cancer treatments, being one of the major culprits of resistance to chemotherapy. In this study, we investigated whether dehydroxymethylepoxyquinomicin (DHMEQ), a novel NF-kappaB inhibitor, can enhance antitumor activities of taxanes in anaplastic thyroid cancer (ATC) cells. Taxanes induced NF-kappaB activation in ATC cells, which could compromise the therapeutic effect of the drugs. However, DHMEQ, by inhibiting the nuclear translocation of NF-kappaB, completely suppressed the DNA binding capacities of NF-kappaB and lowered the levels of nuclear NF-kappaB protein. Compared with single treatment (either taxane or DHMEQ), the combined treatment strongly potentiated apoptosis, confirmed by cell survival assay; Western blotting for poly (ADP-ribose) polymerase, caspase 3, X-linked inhibitor of apoptosis, and survivin; and flow cytometry for annexin V. Furthermore, we also demonstrate for the first time that the combined treatment showed significantly greater inhibitory effect on tumor growth in a nude mice xenograft model. These findings suggest that taxanes are able to induce NF-kappaB activation in ATC cells, which could attenuate antitumor activities of the drugs, but inhibition of NF-kappaB by DHMEQ creates a chemosensitive environment and greatly enhances apoptosis in taxanes-treated ATC cells in vitro and in vivo. Thus, DHMEQ may emerge as an attractive therapeutic strategy to enhance the response to taxanes in ATCs.
核因子κB（NF-κB）作为一种抗凋亡因子，对癌症治疗结果有着至关重要的影响，是化疗耐药的主要元凶之一。在本研究中，我们调查了新型NF-κB抑制剂去羟甲基环氧喹霉素（DHMEQ）是否能增强紫杉烷类药物对间变性甲状腺癌（ATC）细胞的抗肿瘤活性。紫杉烷类药物可诱导ATC细胞中的NF-κB激活，这可能会损害药物的治疗效果。然而，DHMEQ通过抑制NF-κB的核转位，完全抑制了NF-κB的DNA结合能力，并降低了核内NF-κB蛋白的水平。与单一治疗（紫杉烷或DHMEQ）相比，联合治疗显著增强了细胞凋亡，这通过细胞存活试验得到证实；对聚（ADP-核糖）聚合酶、半胱天冬酶3、凋亡抑制蛋白X连锁抑制因子和生存素进行蛋白质免疫印迹分析；以及用膜联蛋白V进行流式细胞术检测。此外，我们还首次证明，在裸鼠异种移植模型中，联合治疗对肿瘤生长的抑制作用明显更强。这些发现表明，紫杉烷类药物能够诱导ATC细胞中的NF-κB激活，这可能会减弱药物的抗肿瘤活性，但DHMEQ对NF-κB的抑制作用营造了一个化学敏感环境，并在体外和体内极大地增强了紫杉烷类药物处理的ATC细胞中的细胞凋亡。因此，DHMEQ可能成为一种有吸引力的治疗策略，以增强ATC对紫杉烷类药物的反应。
