Dithiolethiones inhibit NF-κB activity via covalent modification in human estrogen receptor-negative breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Nuclear factor-kappa B (NF-κB) signaling is crucial for breast cancer progression, angiogenesis, and metastasis.
• Dithiolethiones are natural compounds with known cancer chemoprevention properties that inhibit NF-κB activity, but their precise mechanism and effects in breast cancer remain unclear.

Purpose of the Study:

• To investigate the chemical and biochemical mechanisms by which dithiolethiones affect the NF-κB pathway in estrogen receptor-negative breast cancer cells.
• To evaluate the impact of dithiolethiones on NF-κB-regulated genes and downstream effector molecules involved in tumor progression.

Main Methods:

• Treatment of estrogen receptor-negative breast cancer cells and murine tumor xenografts with dithiolethiones ACS-1 and ACS-2.
• Assessment of NF-κB transcriptional activity, DNA binding, and expression of downstream genes (IL-6, IL-8, uPA, VEGF).
• Evaluation of ACS-1 effects on matrix metalloproteinase-9 (MMP-9) activity, cell migration, and invasion; assessment of ACS-2 effects on tumor burden and host interactions.

Main Results:

• ACS-1 and ACS-2 effectively inhibited NF-κB transcriptional activity in breast cancer cells.
• Inhibition was achieved through covalent binding to NF-κB p50 and p65 subunits, not via H₂S release or PP2A activation.
• Dithiolethiones suppressed key NF-κB-regulated genes (IL-6, IL-8, VEGF, uPA), reduced MMP-9 activity, inhibited cell migration/invasion, and decreased tumor burden in vivo.

Conclusions:

• Dithiolethiones exert anti-cancer effects in estrogen-negative breast cancer by directly inhibiting NF-κB DNA binding and downstream signaling.
• These compounds demonstrate significant potential as chemotherapeutic or adjuvant agents for treating estrogen-negative breast cancer.