Dithiolethiones inhibit NF-κB activity via covalent modification in human estrogen receptor-negative breast cancer
| Autor: | Valerio Tazzari, Lisa A. Ridnour, Harry B. Hines, Christopher H. Switzer, Stefan Ambs, Piero Del Soldato, Anna Sparatore, Robert Y.S. Cheng, David A. Wink, Margaret C. Murray, Sharon A. Glynn |
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| Rok vydání: | 2012 |
| Předmět: |
Transcriptional Activation
Cancer Research medicine.medical_specialty Angiogenesis medicine.drug_class Active Transport Cell Nucleus Nitric Oxide Synthase Type II Antineoplastic Agents Breast Neoplasms Adenocarcinoma Article Metastasis chemistry.chemical_compound Breast cancer Internal medicine Cell Line Tumor medicine Humans Transcription factor Cell Nucleus NF-kappa B Thiones NF-κB Protein phosphatase 2 medicine.disease I-kappa B Kinase Endocrinology Oncology chemistry Receptors Estrogen Tumor progression Estrogen Cancer research Female |
| Zdroj: | Cancer research. 72(9) |
| ISSN: | 1538-7445 |
| Popis: | The NF-κB transcription factor family influences breast cancer outcomes by regulating genes involved in tumor progression, angiogenesis, and metastasis. Dithiolethiones, a class of naturally occurring compounds with cancer chemoprevention effects that have become clinically available, have been found to inhibit NF-κB activity. However, the mechanism of this inhibition has not been identified, and the influence of dithiolethines on NF-κB pathway in breast cancer cells has not been examined. Here, we investigated the chemical and biochemical effects of dithiolethione on NF-κB and downstream effector molecules in estrogen receptor–negative breast cancer cells and murine tumor xenografts. The dithiolethiones ACS-1 and ACS-2 inhibited NF-κB transcriptional activity. Interestingly, this inhibition was not due to H2S release or protein phosphatase 2A activation, which are key properties of dithiolethiones, but occurred via a covalent reaction with the NF-κB p50 and p65 subunits to inhibit DNA binding. Dithiolethione-mediated inhibition of NF-κB–regulated genes resulted in the inhibition of interleukin (IL)-6, IL-8, urokinase-type plasminogen activator, and VEGF production. ACS-1 also inhibited matrix metalloproteinase-9 activity, cellular migration, and invasion, and ACS-2 reduced tumor burden and resulted in increased tumor host interactions. Together, our findings suggest that dithiolethiones show potential clinical use for estrogen negative breast cancer as a chemotherapeutic or adjuvant therapy. Cancer Res; 72(9); 2394–404. ©2012 AACR. |
| Databáze: | OpenAIRE |
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