Dithiolethiones inhibit NF-?B activity via covalent modification in human estrogen receptor-negative breast cancer.

ABSTRACT: The NF-?B 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-?B activity. However, the mechanism of this inhibition has not been identified, and the influence of dithiolethines on NF-?B pathway in breast cancer cells has not been examined. Here, we investigated the chemical and biochemical effects of dithiolethione on NF-?B and downstream effector molecules in estrogen receptor-negative breast cancer cells and murine tumor xenografts. The dithiolethiones ACS-1 and ACS-2 inhibited NF-?B transcriptional activity. Interestingly, this inhibition was not due to H(2)S release or protein phosphatase 2A activation, which are key properties of dithiolethiones, but occurred via a covalent reaction with the NF-?B p50 and p65 subunits to inhibit DNA binding. Dithiolethione-mediated inhibition of NF-?B-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.

SUBMITTER: Switzer CH 

PROVIDER: S-EPMC6548178 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature