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Research Articles: Therapeutics, Targets, and Development

Nordihydroguaiaretic acid, a cytotoxic insulin-like growth factor-I receptor/HER2 inhibitor in trastuzumab-resistant breast cancer

Departments of ¹ Pharmacology and ² Hematology/Oncology, School of Medicine, ³ Winship Cancer Institute, and ⁴ Molecular and Systems Pharmacology Program, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, Georgia

Requests for reprints: Rita Nahta, Department of Pharmacology, School of Medicine, Emory University, Suite 5001, 1510 Clifton Road, Atlanta, GA 30322. Phone: 404-778-3097; Fax: 404-778-5530. E-mail: rnahta{at}emory.edu

Abstract

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. [Mol Cancer Ther 2008;7(7):1900–8]

Grant support: National Cancer Institute grant K01CA118174 and Georgia Cancer Coalition Distinguished Cancer Scholar Award (R. Nahta).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: D.L. Rowe and T. Ozbay contributed equally to this article.

Received 1/ 4/08; revised 3/31/08; accepted 4/ 2/08.