Different affinity of nuclear factor-kappa B proteins to DNA modified by antitumor cisplatin and its clinically...

Area of Science:

• Molecular biology
• Cancer research
• Pharmacology

Background:

• Nuclear factor-kappa B (NF-кB) is a transcription factor family regulating cellular processes and cancer drug response.
• Cisplatin is an antineoplastic drug used in cancer treatment, but its precise mechanisms of action are still being investigated.
• Understanding NF-кB's role in drug response is crucial for developing more effective cancer therapies.

Purpose of the Study:

• To investigate how DNA adducts of cisplatin and transplatin affect NF-кB protein binding to DNA.
• To evaluate the synergistic effect of an NF-кB inhibitor (JSH-23) with cisplatin in ovarian cancer cells.

Main Methods:

• Characterization of DNA adducts formed by cisplatin and transplatin.
• Assessment of NF-кB protein-DNA binding affinity in cell-free systems and using a cellular decoy strategy.
• Evaluation of cisplatin cytotoxicity in ovarian cancer cells, with and without the NF-кB inhibitor JSH-23.

Main Results:

• Cisplatin DNA adducts significantly perturbed NF-кB binding to кB sites, while transplatin adducts had a much weaker effect.
• The NF-кB inhibitor JSH-23 demonstrated strong synergy with cisplatin, augmenting its cytotoxicity in ovarian cancer cells.
• Distinct DNA adduct conformations induced by cisplatin likely play a role in inhibiting NF-кB binding.

Conclusions:

• Cisplatin's antitumor efficacy may involve the inhibition of NF-кB binding to DNA, leading to downstream effects like enhanced programmed cell death.
• Targeting NF-кB with inhibitors like JSH-23 represents a promising synergistic strategy to enhance cisplatin's effectiveness against ovarian cancer.