Niclosamide

Niclosamide, an FDA-approved antihelminthic drug traditionally used to treat tapeworm infections, has shown promising preclinical activity against prostate cancer, particularly castration-resistant prostate cancer (CRPC). Its potential as an anticancer agent stems from its ability to target multiple pathways involved in cancer progression, with a focus on androgen receptor variant 7 (AR-V7), a key driver of resistance to standard therapies like enzalutamide and abiraterone. Below is a summary of its role in prostate cancer based on available research:

Mechanisms of Action in Prostate Cancer

1. Inhibition of AR-V7:
   • Niclosamide downregulates AR-V7 expression by promoting its degradation through a proteasome-dependent pathway and inhibiting its transcriptional activity. This reduces AR-V7 recruitment to the prostate-specific antigen (PSA) promoter, curbing cancer cell growth.https://pmc.ncbi.nlm.nih.gov/articles/PMC4058390/https://pubmed.ncbi.nlm.nih.gov/24740322/
   • AR-V7 is a constitutively active splice variant of the androgen receptor that drives resistance to enzalutamide and abiraterone. Niclosamide’s ability to target AR-V7 makes it a candidate for overcoming this resistance.https://www.oncotarget.com/article/8493/
2. Mitochondrial Uncoupling and Pathway Inhibition:
   • Niclosamide acts as an oxidative phosphorylation (OxPhos) uncoupler, disrupting mitochondrial function, which may contribute to its anticancer effects. This is particularly effective in cancer cells with hyperpolarized mitochondria.https://www.sciencedirect.com/science/article/pii/S2468294223000060https://pubmed.ncbi.nlm.nih.gov/36706514/
   • It also inhibits multiple signaling pathways implicated in prostate cancer, including Wnt/β-catenin, mTORC1, STAT3, NF-κB, and Notch, as well as the FOXM1/EXO1 axis involved in DNA damage response.https://www.nature.com/articles/s41598-021-85969-xhttps://pmc.ncbi.nlm.nih.gov/articles/PMC8263667/
3. Synergistic Effects:
   • Niclosamide enhances the efficacy of existing therapies like abiraterone, enzalutamide, and bicalutamide in preclinical models. For example, it resensitizes resistant cells to these drugs, reducing tumor growth by up to 72% when combined with enzalutamide compared to 5% with enzalutamide alone.https://synapse.patsnap.com/article/first-clinical-trial-of-niclosamide-based-metabolic-anticancer-drug-targets-hormone-resistant-prostate-cancerhttps://aacrjournals.org/mct/article/16/8/1521/146117/Niclosamide-and-Bicalutamide-Combination-Treatment
   • Combination therapies with niclosamide have shown reduced cell proliferation, increased apoptosis, and inhibition of tumor growth in vitro and in vivo.https://pmc.ncbi.nlm.nih.gov/articles/PMC4058390/https://www.oncotarget.com/article/8493/

Clinical Trials and Challenges

1. Phase I Trial with Enzalutamide (2018):
   • A phase I study tested niclosamide (500–1500 mg three times daily) with standard-dose enzalutamide in men with metastatic CRPC previously treated with abiraterone. The trial found that the standard oral formulation of niclosamide had poor bioavailability, with plasma concentrations insufficient to inhibit CRPC growth. It concluded that this formulation was not viable for CRPC treatment, recommending the development of analogs with better bioavailability.https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198389https://pmc.ncbi.nlm.nih.gov/articles/PMC5983471/https://pubmed.ncbi.nlm.nih.gov/29856824/
2. Phase Ib Trial with Abiraterone/Prednisone (2021):
   • A reformulated, orally bioavailable niclosamide (PDMX1001) was tested with abiraterone and prednisone in men with progressing CRPC. The trial aimed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). It showed promising preliminary efficacy with low toxicity, suggesting potential for further investigation.https://www.nature.com/articles/s41598-021-85969-xhttps://www.researchgate.net/publication/350173240_Phase_Ib_trial_of_reformulated_niclosamide_with_abirateroneprednisone_in_men_with_castration-resistant_prostate_cancer
3. Ongoing Research:
   • A 2024 clinical trial by ADM Korea is evaluating a niclosamide-based metabolic anticancer drug combined with hormone therapy in prostate cancer patients, monitoring PSA levels over four weeks to assess safety and efficacy.https://synapse.patsnap.com/article/first-clinical-trial-of-niclosamide-based-metabolic-anticancer-drug-targets-hormone-resistant-prostate-cancer

Limitations and Future Directions

• Bioavailability Issues: Niclosamide’s poor water solubility and metabolic instability limit its systemic use. Efforts to overcome this include:
  • Structural Modifications: Analogs like o-alkylamino-tethered derivatives, ethanolamine, and piperazine salts show improved solubility and metabolic stability while retaining anticancer activity.https://www.mdpi.com/2072-6694/16/20/3548https://www.mdpi.com/1424-8247/16/5/735
  • Nanotechnology: Techniques like electrospraying and supercritical fluids aim to enhance drug delivery and tumor targeting.https://www.mdpi.com/2072-6694/16/20/3548
• Resistance Mechanisms: Niclosamide resistance may arise from decreased drug uptake, enhanced efflux, or metabolic changes. Combination therapies with chemotherapies or immune checkpoint inhibitors are being explored to address this.https://www.mdpi.com/2072-6694/16/20/3548
• Mechanistic Complexity: While AR-V7 inhibition is a key mechanism, niclosamide’s broad effects (e.g., OxPhos uncoupling, pathway inhibition) suggest additional mechanisms that require further study to optimize its use.https://www.sciencedirect.com/science/article/pii/S2468294223000060https://pubmed.ncbi.nlm.nih.gov/36706514/

Conclusion

Niclosamide holds significant potential as a repurposed drug for prostate cancer, particularly for overcoming resistance to enzalutamide and abiraterone in CRPC. Its ability to target AR-V7 and multiple cancer-related pathways, combined with its synergistic effects with existing therapies, makes it a compelling candidate. However, its clinical utility is hindered by poor bioavailability, necessitating reformulated versions or analogs. Ongoing trials and research into delivery methods and combination strategies may unlock its full potential, potentially offering a cost-effective treatment option for advanced prostate cancer.