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

Abstract

Fusion of the ETS (E-26 transformation-specific)-related gene (ERG) with transmembrane serine protease 2 (TMPRSS2) is a crucial step in the occurrence and progression of approximately 50% of prostate cancers. Despite significant progress in drug discovery, ERG inhibitors have yet to be approved for the clinical treatment of prostate cancer. In this study, we used computer-aided drug design (CADD)-based virtual screening to screen for potential inhibitors of ERG. In vivo and in vitro methods revealed that nifuroxazide inhibited the proliferation of a TMPRSS2:ERG fusion-positive prostate cancer cell line (VCaP) with an IC50 lower than that of ERG-negative prostate cancer cell lines (LNCaP, DU145 and WPMY cells). PARP1, the critical mediator of parthanatos, is known to bind ERG and required for ERG-mediated transcription. Nifuroxazide blocked this interaction, and overly activated PARP1, leading to cell death that was reduced by olaparib, a PARP1 inhibitor. These results show that nifuroxazide inhibits ERG, leading to parthanatic cell death.

Therapeutic strategies of targeting non-apoptotic regulated cell death (RCD) with small-molecule compounds in cancer

“…For instance, the N -methyl- N ′-nitro- N ′-nitrosoguanidine, an alkylating agent, has been reported to produce ROS, leading to DNA damage to abnormally activate PARP-1, triggering parthanotos to inhibit proliferation in HeLa and HCT116 cells 401 . Moreover, nifuroxazide is a nitrofuran agent that has been identified as a novel E-26 transformation-specific-related gene (ERG) inhibitor, which blocked the interaction of ERG with PARP-1, abnormally activating PARP-1 to induce parthanotos with the accumulation of AIF, exerting reliable antiproliferative activity with an IC 50 of 2.56 ± 0.08 μmol/L in TMPRSS2:ERG -positive VCaP cells and slowing tumor growth in the VCaP xenograft model 402 . ZINC253504760 is a MEK inhibitor that has been reported to induce DNA damage and AIF translocation to nuclear with the accumulation of PARP-1 and PAR, inducing parthanotos and inhibiting proliferation with an IC 50 of 0.022 ± 0.002 μmol/L in CCRF-CEM cells 403 .…”

Synthesis of New Nifuroxazide Derivatives Based on Nitropyrrole Skeleton with Good Antitumor Activity in Vitro

“…[7] Nifuroxazide has antitumor activity [8] by downregulating JAK kinase self-phosphorylation, blocking STAT3 constitutive phosphorylation, inhibiting STAT transcription factor signal transduction, and reducing tumor cell viability. [9] Nifuroxazide has been reported to have antitumor activity against melanoma, [10] breast cancer, [11] prostate cancer, [12] colorectal cancer, [13] hepatocellular carcinoma, [14] etc. In recent decades, tremendous developments have been made in this field.…”