Targeting the Wnt/β-Catenin Pathway in Colorectal Cancer (CRC)
One of niclosamide's primary mechanisms in cancer involves inhibiting the Wnt/β-catenin pathway, an oncogenic driver in various cancers, particularly colorectal cancer. The study in CRC showed that niclosamide reduces the expression of S100A4, a metastasis-promoting protein driven by Wnt/β-catenin. This reduction in S100A4 levels suppresses metastatic potential, indicating that niclosamide could improve outcomes for metastatic CRC patients with high Wnt/β-catenin activity.
STAT3 Inhibition and Radiosensitization in Lung Cancer
Another study highlighted niclosamide’s ability to inhibit STAT3, a transcription factor linked to tumor growth and immune evasion, especially in non-small cell lung cancer (NSCLC). The drug blocks STAT3 activation, reversing radioresistance and improving radiotherapy outcomes. Additionally, niclosamide downregulates PD-L1 expression, enhancing the efficacy of immune checkpoint inhibitors like PD-1/PD-L1 antibodies. This dual inhibition of STAT3 and PD-L1 can improve T-cell infiltration and tumor cell lysis, thus presenting a promising combination strategy with immunotherapy for NSCLC.
CREB-Dependent Pathway Suppression in Acute Myeloid Leukemia (AML)
In AML, niclosamide disrupts CREB, a critical cancer cell survival and proliferation regulator. By inhibiting CREB-dependent signaling, niclosamide induces apoptosis and cell cycle arrest in AML cells while sparing normal hematopoietic cells. Preclinical studies further demonstrate niclosamide's potential to synergize with traditional chemotherapeutics, enhancing cytotoxicity and improving treatment response. The effectiveness of niclosamide in targeting CREB suggests its applicability in other CREB-overexpressing cancers as well.
Inducing Oxidative Stress and Ferroptosis in Triple-Negative Breast Cancer (TNBC)
Niclosamide’s ability to induce ferroptosis—a form of programmed cell death reliant on iron and lipid peroxidation—was observed in triple-negative breast cancer cells. By inhibiting the transporters SLC38A5 and SLC7A11, which modulate glutathione levels and antioxidant defenses, niclosamide depletes cellular glutathione, disrupts redox balance, and enhances lipid peroxidation. This oxidative stress-mediated cell death pathway offers a novel therapeutic angle for targeting resistant breast cancer subtypes.
Mitochondrial Uncoupling and Metabolic Reprogramming in Solid Tumors
Niclosamide also acts as a mitochondrial uncoupler, disrupting cancer cell metabolism. This uncoupling effect reverses the Warburg effect—a phenomenon in which cancer cells preferentially utilize glycolysis over oxidative phosphorylation—by enhancing mitochondrial respiration and decreasing glycolysis dependence. This metabolic reprogramming impairs tumor growth and inhibits pathways like NF-κB, mTORC1, and Notch, often upregulated in aggressive cancers. The metabolic disruption induced by niclosamide contributes to its broad-spectrum anticancer effects.
Enhancing PD-1/PD-L1 Immunotherapy in NSCLC
Research in NSCLC suggests that combining niclosamide with PD-1/PD-L1 inhibitors augments immune response by increasing T-cell infiltration and activity. Niclosamide decreases PD-L1 expression in tumor cells via STAT3 inhibition, thus sensitizing tumors to immunotherapy. This combination therapy prolongs survival in preclinical models, indicating the potential for broader clinical application in immune checkpoint inhibitor-resistant cancers.
Table: Primary Mechanisms of Niclosamide in Cancer Therapy
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