nifuroxazide and Prostatic-Neoplasms

Fusion of the E-26 transformation-specific (ETS)-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 (NFZ) 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). Poly [ADP-ribose] polymerase 1, the critical mediator of parthanatos, is known to bind ERG and is required for ERG-mediated transcription. NFZ blocked this interaction and overly activated PARP1, leading to cell death that was reduced by olaparib, a PARP1 inhibitor. These results show that NFZ inhibits ERG, leading to parthanatic cell death.

Topics: Cell Line, Tumor; Humans; Male; Nitrofurans; Oncogene Proteins, Fusion; Parthanatos; Prostatic Neoplasms; Serine Endopeptidases; Trans-Activators; Transcriptional Regulator ERG

Reducing polyamine uptake by selecting low polyamine-containing foodstuffs and reducing bacterial gut production can improve performance status and pain control in hormone refractory prostate cancer (HRPC) patients. Long term PRD observance and tolerance were assessed. Cancer specific survival was studied in function of PRD and time of PRD initiation.. Twenty-six volunteers, age: 68+/-10 years with metastatic HRPC accepted a polyamine reduced diet and partial gut decontamination with oral neomycin or nifuroxazide (750 mg daily, one week out of two). Time from HRPC to PRD initiation was 10+/-8 months. WHO performance status, EORTC pain scale, body weight, blood counts and serum proteins were regularly assessed. Sixteen other HRPC patients eating a normal diet served as "controls".. Mean diet observance is 25+/-24 months. Tolerance is good. WHO performance status and EORTC pain scales were significantly improved respectively at 3 months (0.5+/-0.7 vs 0.7+/-0.9: p=0.03) and 6 months (0.5+/-0.8 vs 1+/-1.3, p=0.02) compared to initial values. Median cancer specific survival times after HRPC and PRD initiation are respectively 36 and 21 months. Eleven PRD patients started the diet before a 9 months cut-off period (after HRPC) and 15 patients after. Median cancer specific survival times for these two groups of patients are respectively 44 and 34 months, p=0.014. Median cancer specific survival times (after HRPC) for PRD patients compared to controls are 36 vs 17 months (p=0.004).. Polyamine-reduced diet is well observed and tolerated. It seems to improve and/or maintain quality of life for HRPC patients. Early PRD initiation in HRPC is promising and may impact favorably cancer specific survival. These results open a rationale for PRD in HRPC management and warrant further investigation.

Topics: Aged; Aged, 80 and over; Anti-Infective Agents; Decontamination; Gastrointestinal Tract; Humans; Hydroxybenzoates; Male; Middle Aged; Neomycin; Nitrofurans; Pain; Pain Measurement; Polyamines; Prospective Studies; Prostatic Neoplasms; Quality of Life; Survival; Time Factors; Treatment Outcome

Polyamine contents were assessed by mass spectrometry in 233 current foods and beverages. In order to reduce gut polyamine uptake, a polyamine reduced diet (PRD) and partial intermittent intestinal tract decontamination (PIITD) with neomycin or nifuroxazide was proposed as nutritional therapy to 33 prostate carcinoma patients, 30 of whom with hormone refractory prostate cancer (HRPC). Mean PRD observance was 22 +/- 19 (median: 16; range: 3-72) months. 10, 8 and 3 patients were respectively on PRD for more than 30, 36 and 64 months. No diet toxicity was observed. 8 patients had moderate intestinal intolerance due to PIITD which was interrupted. No significant differences in body weight, blood counts or serum protein levels were observed during the follow-up of patients under PRD. Performance status and pain scores were relatively stable during the trial with improved pain scores at 6 months. A PRD associated with intermittent PIITD is a safe and well observed nutritional regimen and long term observance is possible.

Topics: Aged; Aged, 80 and over; Decontamination; Diet; Food Analysis; Gastrointestinal Tract; Humans; Hydroxybenzoates; Male; Middle Aged; Neomycin; Nitrofurans; Patient Compliance; Polyamines; Prostatic Neoplasms; Quality of Life