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

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...

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Vydáno v:Molecular cancer therapeutics Ročník 7; číslo 7; s. 1900
Hlavní autoři: Rowe, Danica L, Ozbay, Tuba, Bender, Laura M, Nahta, Rita
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 01.07.2008
Témata:
Antibodies, Monoclonal - pharmacology
Antibodies, Monoclonal, Humanized
Antineoplastic Agents - pharmacology
Breast Neoplasms - pathology
Cell Death - drug effects
Cell Line, Tumor
Cell Proliferation - drug effects
Cell Survival - drug effects
Drug Resistance, Neoplasm - drug effects
Drug Screening Assays, Antitumor
Drug Synergism
Humans
Insulin-Like Growth Factor I - metabolism
Masoprocol - pharmacology
Receptor, ErbB-2 - antagonists & inhibitors
Receptor, IGF Type 1 - antagonists & inhibitors
Signal Transduction - drug effects
Trastuzumab
Treatment Outcome
ISSN:1535-7163
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Popis
Shrnutí: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.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1535-7163
DOI:10.1158/1535-7163.MCT-08-0012