title: Dithiolethiones inhibit NF-κB activity via covalent modification in human estrogen receptor-negative breast cancer.
abstract: 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 H(2)S 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.
authors.affiliation: Radiation Biology Branch, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Switzer
authors.forename: Robert Y-S
authors.initials: RY
authors.lastname: Cheng
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Ridnour
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Murray
authors.forename: Valerio
authors.initials: V
authors.lastname: Tazzari
authors.forename: Anna
authors.initials: A
authors.lastname: Sparatore
authors.forename: Piero
authors.initials: P
authors.lastname: Del Soldato
authors.forename: Harry B
authors.initials: HB
authors.lastname: Hines
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Glynn
authors.forename: Stefan
authors.initials: S
authors.lastname: Ambs
authors.forename: David A
authors.initials: DA
authors.lastname: Wink
mesh_terms: D021581:Active Transport, Cell Nucleus; D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D011960:Receptors, Estrogen / Q000096:biosynthesis; D013871:Thiones / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D011960:Receptors, Estrogen; D013871:Thiones; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D051550:I-kappa B Kinase