Nordihydroguaiaretic acid, a cytotoxic insulin-like growth factor-I receptor/HER2 inhibitor in trastuzumab-resistant breast cancer.
Nordihydroguaiaretic acid, a cytotoxic insulin-like growth factor-I receptor/HER2 inhibitor in trastuzumab-resistant breast cancer.
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DOI：
10.1158/1535-7163.mct-08-0012
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发表时间：
2008-07
影响因子：
5.7
通讯作者：
Nahta R
中科院分区：
文献类型：
--
作者：
Rowe DL;Ozbay T;Bender LM;Nahta R
大多数her2过表达的转移性乳腺癌患者最初对her2靶向抗体曲妥珠单抗有反应，在一年内病情进展。在曲妥珠单抗治疗下，有效抑制癌细胞存活的新药物的鉴定对于改善这一患者群体的预后至关重要。在目前的研究中，我们证明了酚类化合物北二氢愈创木酸（NDGA）促进trastuzumab-naïve和曲妥珠单抗难治性her2过表达乳腺癌细胞的细胞死亡。NDGA诱导DNA断裂，PARP和caspase 3的裂解，抑制菌落形成。此外，NDGA抑制曲妥珠单抗难治性细胞中的IGF-I和HER2信号通路，降低下游PI3K/Akt信号通路。重要的是，与单独使用任何一种药物相比，NDGA和曲妥珠单抗联合治疗在更大程度上抑制了曲妥珠单抗难治性细胞的增殖和存活，这表明NDGA增加了难治性细胞对曲妥珠单抗的敏感性。NDGA衍生物目前正在其他实体肿瘤的临床试验中。我们的数据强烈支持进一步研究NDGA作为曲妥珠单抗治疗进展的乳腺癌的潜在治疗方法。
The majority of patients with HER2-overexpressing metastatic breast cancer who initially respond to the HER2-targeted antibody trastuzumab demonstrate disease progression within one year. The identification of novel agents that effectively inhibit survival of cancer cells that have progressed on trastuzumab is critical for improving outcome for this patient population. In the current study, we demonstrate that the phenolic compound nordihydroguaiaretic acid (NDGA) promoted cell death of trastuzumab-naïve and trastuzumab-refractory HER2-overexpressing breast cancer cells. NDGA induced DNA fragmentation, cleavage of PARP and caspase 3, and inhibition of colony formation. In addition, NDGA inhibited IGF-I and HER2 signaling in trastuzumab-refractory cells, with reduced downstream PI3K/Akt signaling. Importantly, combination treatment with NDGA and trastuzumab suppressed proliferation and survival of trastuzumab-refractory cells to a greater degree than either agent alone, suggesting that NDGA increases the sensitivity of refractory cells to trastuzumab. Derivatives of NDGA are currently in clinical trial for other solid tumors. Our data strongly support further study of NDGA as a potential therapeutic against breast cancers that have progressed on trastuzumab.