Nifuroxazide Activates the Parthanatos to Overcome TMPRSS2:ERG Fusion-Positive Prostate Cancer

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• TMPRSS2:ERG fusion drives approximately 50% of prostate cancers.
• ERG inhibitors are crucial for prostate cancer treatment but none are approved.
• Targeting ERG is a promising strategy for prostate cancer therapy.

Purpose of the Study:

• To identify potential ERG inhibitors using computer-aided drug design (CADD).
• To evaluate the efficacy of identified compounds against prostate cancer cell lines.
• To elucidate the mechanism of action for novel ERG inhibitors.

Main Methods:

• Virtual screening using CADD to identify ERG inhibitors.
• In vitro and in vivo assays to assess anti-proliferative effects.
• Investigating the interaction between nifuroxazide (NFZ), ERG, and PARP1.

Main Results:

• Nifuroxazide (NFZ) demonstrated significant inhibition of TMPRSS2:ERG fusion-positive prostate cancer cell proliferation.
• NFZ exhibited lower IC50 values in fusion-positive cells compared to fusion-negative cell lines.
• NFZ blocked the interaction between ERG and Poly [ADP-ribose] polymerase 1 (PARP1), leading to parthanatic cell death.

Conclusions:

• Nifuroxazide is a potential therapeutic agent for ERG-driven prostate cancer.
• NFZ induces cancer cell death via parthanatos by inhibiting ERG-PARP1 interaction.
• Further research into NFZ as an ERG inhibitor is warranted for clinical application.