Niclosamide is a medication used for decades to treat parasitic tapeworm infections. Scientists are now investigating it for a new purpose in a practice known as drug repurposing, which leverages the known safety profiles of existing drugs to speed up development. Niclosamide has become a significant candidate in this field, attracting attention for its potential as an anti-cancer agent.
The Original Purpose of Niclosamide
For nearly half a century, niclosamide has been an established anthelmintic agent, a class of drugs that acts against parasitic worms. Its primary and approved application is for treating infections caused by various species of tapeworms, including beef, fish, and pork tapeworms. The drug is taken orally and functions by directly targeting the parasite’s metabolism.
Niclosamide disrupts the tapeworm’s ability to generate energy. It achieves this by uncoupling oxidative phosphorylation, a process within the parasite’s mitochondria that produces the main energy molecule for cellular functions. This metabolic disruption is fatal to the tapeworms, causing them to detach from the intestinal wall and be passed from the body through the stool.
Uncovering Anti-Cancer Properties
High-throughput screening studies identified niclosamide as a compound with potent anti-cancer activity. Unlike many targeted therapies that inhibit a single molecular target, niclosamide’s effectiveness appears to stem from its ability to interfere with multiple signaling pathways that cancer cells use to grow and survive. This multi-targeted approach is a subject of research.
One of the main pathways niclosamide disrupts is the Wnt/β-catenin pathway, which is often overactive in cancers and contributes to tumor initiation and metastasis. Niclosamide promotes the degradation of proteins in this pathway, effectively shutting down the signals that tell cancer cells to proliferate. It also interferes with several other cellular communication networks hijacked by tumors.
The drug inhibits the STAT3 pathway by preventing the phosphorylation and nuclear translocation of the STAT3 protein, a step for activating genes involved in cell survival and growth. Similarly, it blocks the NF-κB pathway, which protects cancer cells from self-destruction (apoptosis) and promotes inflammation that can fuel tumor progression. Niclosamide has also been found to disrupt the mTOR pathway, a regulator of cell growth and metabolism, by causing lysosomal dysfunction.
Research and Clinical Trial Status
Promising laboratory results have spurred preclinical studies on cancer cell lines and in animal models. These studies have shown its activity against a range of malignancies, including:
- Colorectal cancer
- Prostate cancer
- Breast cancer
- Ovarian cancer
In some animal studies, niclosamide not only inhibited tumor growth but also reduced the formation of metastases, the spread of cancer to distant organs.
Human clinical trials are conducted in phases to assess safety and effectiveness. Most research on niclosamide for cancer remains in the preclinical stage or in early-phase (Phase I and II) clinical trials, which focus on determining safe dosages and gathering preliminary data on effectiveness.
Several Phase I and II trials have been initiated to test niclosamide, often in combination with other cancer drugs, for cancers like metastatic colorectal cancer and castration-resistant prostate cancer. These studies aim to determine the drug’s safety in cancer patients and its ability to enhance standard therapies. Niclosamide is not currently an approved standard treatment for any cancer.
Challenges in Repurposing for Cancer Treatment
A significant hurdle in repurposing niclosamide for systemic cancer treatment is its physicochemical properties. The drug has very low water solubility and poor oral bioavailability, meaning only a small fraction is absorbed into the bloodstream when taken orally. While this is acceptable for treating tapeworms in the gut, it is a major limitation for treating tumors elsewhere in the body.
For an anti-cancer drug to be effective systemically, it must achieve a high concentration in the blood to reach tumor cells. The low absorption of standard niclosamide makes this difficult without administering potentially toxic doses. The portion of the drug that is absorbed is also rapidly broken down by liver enzymes before it can circulate widely.
To overcome these bioavailability issues, researchers are developing new formulations of the drug. One approach involves creating salt forms which have better water solubility. Another area of research is nanotechnology, where scientists encapsulate niclosamide into nanoparticles. These advanced formulations are designed to protect the drug from degradation and enhance its absorption into the bloodstream.