Rowe Danica L, Ozbay Tuba, Bender Laura M, Nahta Rita
Department of Pharmacology, School of Medicine, Emory University, Suite 5001, 1510 Clifton Road, Atlanta, GA 30322, USA.
Mol Cancer Ther. 2008 Jul;7(7):1900-8. doi: 10.1158/1535-7163.MCT-08-0012.
The majority of patients with HER2-overexpressing metastatic breast cancer who initially respond to the HER2-targeted antibody trastuzumab show disease progression within 1 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 show that the phenolic compound nordihydroguaiaretic acid (NDGA) promoted cell death of trastuzumab-naive and trastuzumab-refractory HER2-overexpressing breast cancer cells. NDGA induced DNA fragmentation, cleavage of poly(ADP-ribose) polymerase and caspase-3, and inhibition of colony formation. In addition, NDGA inhibited insulin-like growth factor-I and HER2 signaling in trastuzumab-refractory cells, with reduced downstream phosphatidylinositol-3 kinase/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.
大多数最初对HER2靶向抗体曲妥珠单抗有反应的HER2过表达转移性乳腺癌患者在1年内会出现疾病进展。识别能有效抑制在曲妥珠单抗治疗后进展的癌细胞存活的新型药物对于改善这一患者群体的预后至关重要。在当前研究中，我们表明酚类化合物去甲二氢愈创木酸（NDGA）可促进未接受过曲妥珠单抗治疗以及对曲妥珠单抗耐药的HER2过表达乳腺癌细胞的死亡。NDGA诱导DNA片段化、聚（ADP-核糖）聚合酶和半胱天冬酶-3的裂解，并抑制集落形成。此外，NDGA在对曲妥珠单抗耐药的细胞中抑制胰岛素样生长因子-I和HER2信号传导，同时降低下游磷脂酰肌醇-3激酶/蛋白激酶B信号传导。重要的是，NDGA与曲妥珠单抗联合治疗比单独使用任何一种药物都能更大程度地抑制对曲妥珠单抗耐药细胞的增殖和存活，这表明NDGA可增加耐药细胞对曲妥珠单抗的敏感性。NDGA的衍生物目前正在针对其他实体瘤进行临床试验。我们的数据有力地支持进一步研究将NDGA作为治疗在曲妥珠单抗治疗后进展的乳腺癌的潜在疗法。
