1, 9-Pyrazoloanthrones downregulate HIF-1α and sensitize cancer cells to cetuximab-mediated anti-EGFR therapy.
1, 9-Pyrazoloanthrones downregulate HIF-1α and sensitize cancer cells to cetuximab-mediated anti-EGFR therapy.
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DOI：
10.1371/journal.pone.0015823
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发表时间：
2010-12-29
期刊：
影响因子：
3.7
通讯作者：
Fan Z
中科院分区：
文献类型：
--
作者：
Lu Y;Li X;Lu H;Fan Z
西妥昔单抗是一种阻断表皮生长因子受体（EGFR）的单克隆抗体，目前已被批准用于治疗几种类型的实体瘤。我们之前研究表明，西妥昔单抗可以通过抑制EGFR下游信号通路（包括Erk、Akt和mTOR）的激活来抑制缺氧诱导因子-1 α（HIF-1α）蛋白的合成。1，9-吡唑并蒽酮（1，9 PA）是一种蒽吡唑啉酮化合物，最好称为SP 600125，其特异性抑制c-jun N-末端激酶（JNK）。本文报道了1，9-PA可下调HIF-1α的表达，而不依赖于其对JNK的抑制。当HIF-1α的氧依赖性结构域（ODD）（HIF-1α-ΔODD，负责HIF-1α降解的结构域）被实验性删除或当HIF-1α脯氨酰羟化酶（PHD）或26 S蛋白酶体复合物的活性被抑制时，这种下调作用被消除，表明1，9 PA通过促进PHD依赖的HIF-1α降解来下调HIF-1α。我们发现，1，9 PA和西妥昔单抗的组合协同作用，以诱导癌细胞的凋亡，其中西妥昔单抗或1，9 PA单独没有或只有弱的凋亡活性。这种协同作用在转染HIF-1α-ΔODD的癌细胞中显著降低，表明HIF-1α的下调是这种协同作用的机制。更重要的是，1，9 PA可下调癌细胞中的HIF-1α，所述癌细胞由于致癌Ras（RasG 12 V）过表达而对西妥昔单抗诱导的HIF-1α表达抑制不敏感。我们的研究结果表明，1，9 PA是一类新型药物的先导化合物，可用于通过对HIF-1α下调的互补作用来增强癌细胞对西妥昔单抗的反应。
Cetuximab, a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR), is currently approved for the treatment of several types of solid tumors. We previously showed that cetuximab can inhibit hypoxia-inducible factor-1 alpha (HIF-1α) protein synthesis by inhibiting the activation of EGFR downstream signaling pathways including Erk, Akt, and mTOR. 1, 9-pyrazoloanthrone (1, 9 PA) is an anthrapyrazolone compound best known as SP600125 that specifically inhibits c-jun N-terminal kinase (JNK). Here, we report 1, 9 PA can downregulate HIF-1α independently of its inhibition of JNK. This downregulatory effect was abolished when the oxygen-dependent domain (ODD) of HIF-1α (HIF-1α-ΔODD, the domain responsible for HIF-1α degradation) was experimentally deleted or when the activity of HIF-1α prolyl hydroxylase (PHD) or the 26S proteasomal complex was inhibited, indicating that the 1, 9 PA downregulates HIF-1α by promoting PHD-dependent HIF-1α degradation. We found that the combination of 1, 9 PA and cetuximab worked synergistically to induce apoptosis in cancer cells in which cetuximab or 1, 9 PA alone had no or only weak apoptotic activity. This synergistic effect was substantially decreased in cancer cells transfected with HIF-1α-ΔODD, indicating that downregulation of HIF-1α was the mechanism of this synergistic effect. More importantly, 1, 9 PA can downregulate HIF-1α in cancer cells that are insensitive to cetuximab-induced inhibition of HIF-1α expression due to overexpression of oncogenic Ras (RasG12V). Our findings suggest that 1, 9 PA is a lead compound of a novel class of drugs that may be used to enhance the response of cancer cells to cetuximab through a complementary effect on the downregulation of HIF-1α.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
45.3
作者：
Jimeno, Antonio;Messersmith, Wells A.;Eckhardt, S. Gail
通讯作者：
Eckhardt, S. Gail
影响因子：
45.3
作者：
Khambata-Ford, Shirin;Garrett, Christopher R.;Mauro, David J.
通讯作者：
Mauro, David J.
影响因子：
45.3
作者：
Baselga, J;Trigo, JM;Eckardt, A
通讯作者：
Eckardt, A