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. ©2012 AACR.
CITATION STYLE
Switzer, C. H., Cheng, R. Y. S., Ridnour, L. A., Murray, M. C., Tazzari, V., Sparatore, A., … Wink, D. A. (2012). Dithiolethiones inhibit NF-κB activity via covalent modification in human estrogen receptor-negative breast cancer. Cancer Research, 72(9), 2394–2404. https://doi.org/10.1158/0008-5472.CAN-11-3115
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