Jessica TEng

The anthelmintics #Mebendazole, #Ivermectin, and #Niclosamide inhibit signaling pathways associated with tumor cells (such as PI3K/Akt/mTORC1, Wnt/β-catenin, Hedgehog, PAK-1, NF-κB, and STAT3). They also exhibit antitumor effects by promoting microtubule depolymerization, inhibiting angiogenesis, and suppressing P-glycoprotein (P-gp). When these three anthelmintics are used in combination, they demonstrate synergistic antitumor effects.

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Without a patent, pharmaceutical companies do not pursue drug development.

In Japan, standard treatments are generally limited to medications covered by insurance. The rule states that healthcare providers must not prescribe medications other than those designated by the Minister of Health, Labour and Welfare. Exceptions exist only for clinical trial purposes, but fundamentally, it is prohibited for healthcare institutions or providers to use drugs not covered by insurance for patients.

To receive insurance coverage, pharmaceutical companies must conduct clinical trials to prove the efficacy and safety of a drug, then obtain approval for manufacturing and marketing from the Minister. If a company can secure a patent for a substance, it can sell the drug exclusively, thus gaining profit. However, if a patent cannot be obtained, there is little incentive to invest billions of yen in clinical trials since generic drugs could quickly enter the market, diminishing potential profits. As a result, no pharmaceutical company is likely to pursue approval for such drugs. Without applications, these substances cannot be recognized as standard treatments.

For example, substances like #Dichloroacetate (DCA), #2-Deoxyglucose (2-DG), and #Melatonin have been recognized globally for their alternative cancer treatment potential and have shown efficacy in clinical trials. However, because these substances have been known for decades and cannot be patented, pharmaceutical companies do not conduct costly clinical trials or develop them as drugs. Instead, researchers often conduct small-scale trials using public research funds.

Similarly, substances like Vitamin D3 and Docosahexaenoic acid (DHA), which have demonstrated efficacy in cancer treatment through clinical trials, cannot become insurance-covered drugs. Consequently, standard healthcare providers do not prescribe them for cancer treatment. Patients are left to use these medications or supplements at their own discretion and responsibility..

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Drugs Effective Against Cancer Not Used in Standard Cancer Treatment

There are numerous existing medications, used for purposes other than cancer treatment, that have shown efficacy against cancer. For example, the diabetes medication #Metformin and the cholesterol-lowering drug #Simvastatin have been found in many clinical trials to enhance the effectiveness of cancer therapies and improve survival rates for cancer patients. However, these drugs cannot be used as cancer treatments in insurance-covered medical care because cancer is not included in the list of insured conditions for Metformin and Simvastatin.

If anticancer effects are confirmed in existing medications used for other conditions, new clinical trials can be conducted targeting cancer patients to add cancer as an applicable condition. However, the duration of patent rights is generally 20 years from the date of patent application, and since applications are usually filed before starting clinical trials, only about 10 years remain when the trials conclude and the drug receives approval. Moreover, by the time other clinical trials for cancer treatment are completed, the patent may have expired, making it unlikely that such applications will be pursued.

In addition to Metformin and Simvastatin, other drugs used for different diseases, such as the acid secretion inhibitor #Cimetidine, the COX-2 inhibitor #Celecoxib, and the anthelmintics Ivermectin and Mebendazole, have also demonstrated anticancer activity in clinical trials. However, since these drugs are off-patent, they are unlikely to be developed or approved as cancer treatments in the future.

Among over 2,000 approved drugs for indications other than cancer, at least 235 have demonstrated in vitro, in vivo, or clinically proven antitumor activity. There are reports supporting these findings.

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Repurposing Non-Cancer Drugs in Oncology: How Many Drugs Are Out There?
Among the 235 drugs confirmed to have antitumor activity, 67 (29%) are on the WHO List of Essential Medicines, 176 (75%) are off-patent, and 133 (57%) have clinical data involving cancer patients. Four drugs—#Thalidomide, #All-Trans Retinoic Acid (ATRA), Zoledronic Acid, and non-steroidal anti-inflammatory drugs—already have established guidelines for cancer treatment. Additionally, drugs like Cimetidine (for colorectal cancer), #Progesterone (for breast cancer), and #Itraconazole (for lung cancer) have shown effectiveness in randomized clinical trials as repurposed drugs. In Japan, if a drug is to be used for cancer treatment, it must be prescribed for a condition that is covered by insurance. This means that even if a drug’s effectiveness against cancer is proven, it cannot be used in insurance-covered medical institutions unless it is approved for that specific use. However, in private medical institutions, off-label prescriptions are possible. Many examples of off-label use in cancer treatment exist, and these drugs are often utilized in complementary and alternative medicine. For these reasons, supplements and existing medications used for non-cancer treatments, or known anticancer agents, may never be incorporated into standard cancer treatment despite their proven effectiveness. However, they become important in complementary and alternative medicine, as many of these drugs and supplements have robust evidence of efficacy and safety.

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Old Anticancer Drugs Still in Use After Over 40 Years

The development of pharmaceuticals requires immense costs and long timelines. The challenges of developing new drugs seem to increase each year. For a new drug to receive approval, it must demonstrate superiority in efficacy or safety compared to existing medications. This means that the bar for approval gets higher with newer drugs. Cancer treatments are particularly known to carry high development risks. Data from the U.S. shows that between 2003 and 2011, only 6.7% of substances that began Phase I clinical trials were ultimately approved by the FDA, a success rate reported to be half that of other drug categories.

Of the candidate drugs that have shown promise in preclinical studies as potential cancer treatments, only about one in twenty succeeds in reaching the market. The rest are often discontinued, rendering previous research and development investments futile. Solid tumors, such as lung, stomach, and colorectal cancers, are especially difficult to treat compared to hematological cancers. The challenges in developing new drugs for solid tumors are underscored by the fact that anticancer agents that have been in use for over 40 years remain mainstays in cancer treatment.

For example, the AC regimen for breast cancer combines two different classes of chemotherapy drugs: Adriamycin (doxorubicin) and Cyclophosphamide. Cyclophosphamide (Endoxan) was released in Japan in 1962, while Adriamycin was approved there in 1975.

Methotrexate, a folate antagonist, has been used in the U.S. since the 1950s and was approved in Japan in 1963. The CMF regimen for breast cancer combines Cyclophosphamide, Methotrexate, and Fluorouracil (5-FU), with the latter being approved in Japan in 1981. Cisplatin, a widely used chemotherapy drug, was approved in the U.S. and Canada in 1978—45 years ago.

Thus, many anticancer drugs that have been in use for 40 to 60 years continue to play a central role in cancer treatment today. While targeted therapies aimed at cell receptors and signaling pathways have been developed recently, they have not yielded significant therapeutic benefits. The development of cancer drugs poses high risks for pharmaceutical companies, and for a new drug to be profitable, it must recover many times the costs of its research and development. Consequently, the costs of new cancer drugs continue to rise each year.

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Repurposing Existing Drugs and Off-Label Use

Many cancer patients believe that if a treatment is inexpensive and has minimal side effects—even with only a slight potential for extending life—it may be a preferable option. This perspective necessitates supportive therapies that meet the criteria of being low-cost, having few side effects, and offering some degree of antitumor activity or life extension. Recently, research has gained attention for identifying cancer treatments from existing medications not originally designed for cancer therapy or from substances that have failed clinical trials for other indications. This approach can potentially reduce development costs and timelines.

Existing medications that exhibit antitumor effects often have lower toxicity compared to conventional chemotherapy agents. Therefore, these drugs may align well with the desired criteria of being affordable and having fewer side effects while still providing some therapeutic benefits.

In the context of the substantial financial investments associated with new drug development, "drug repurposing" is gaining attention. This involves evaluating existing medications that may not be approved for other treatments or have been abandoned in development due to a lack of efficacy, to explore their potential as cancer therapies. "Drug Repositioning" or "Drug Repurposing" refers to the practice of finding new uses for established drugs.

The method involves taking medications that have already established safety profiles and pharmacokinetics and testing them for new therapeutic effects. Compared to developing new drugs, this strategy significantly lowers both costs and timelines.

For cancer treatments, if an existing drug or candidate compound demonstrates antitumor activity in cultured cancer cells (in vitro) or animal models (in vivo), it can lead to faster initiation of clinical trials, as its safety and pharmacokinetics are already known. Recently, computational methods (in silico) have also been employed to screen databases of candidate compounds for potential new uses, leveraging various information, such as receptor structures and gene expression patterns affected by anticancer agents. In the U.S., the FDA maintains a database of existing drugs that have been approved or shelved, facilitating research into their potential new uses.

Antiparasitic Drugs and Cancer Treatment

Many diseases, such as heart disease, neurological conditions, and metabolic disorders, arise from the deterioration or damage of organs or tissues. In contrast, cancer occurs through the emergence of new tissues formed by abnormal cell proliferation. Cancer tissue comprises a mass of cells with abnormal proliferative capacities, which absorb normal stromal cells (like fibroblasts and inflammatory cells) and blood vessels to create a new, unified tissue structure. These malignant cells possess autonomous growth capabilities and can invade and metastasize throughout the body, proliferating indefinitely until the host succumbs.

This behavior resembles infections caused by parasites, fungi, or bacteria. Cancer cells can be seen as parasitic entities that invade the body and consume its resources. While the exact reasons for this relationship are unclear, numerous studies suggest that medications used to treat infections or parasites also exhibit anticancer properties. These medications tend to have low side effects and high safety profiles, making combinations of antiparasitic drugs a promising avenue for cancer treatment.

Mebendazole is a broad-spectrum anthelmintic drug that acts against various parasites, including nematodes, tapeworms, and roundworms. It has demonstrated strong anticancer activity in in vitro and in vivo studies, as well as through computational analyses.

The mechanism by which mebendazole kills parasites involves the inhibition of tubulin polymerization, which is crucial for cell division as it affects microtubule function. This mechanism is similar to that of paclitaxel (Taxol) and vincristine, which stabilize microtubules by promoting tubulin polymerization to inhibit cancer cell division. In contrast, mebendazole binds to tubulin and inhibits microtubule polymerization by targeting the colchicine binding domain of tubulin. Additionally, mebendazole exhibits various anticancer mechanisms, including angiogenesis inhibition and suppression of signaling pathways like Wnt/β-catenin and Hedgehog signaling.

In summary, repurposing existing drugs, particularly those with antiparasitic properties, holds promise as a cost-effective and safe strategy for cancer treatment.

Cell Division and the Role of Microtubules

During cell division, replicated DNA (chromosomes) is separated into two daughter cells by microtubules. Microtubules are composed of heterodimers formed by α-tubulin and β-tubulin, which assemble into protofilaments. Thirteen protofilaments group together to form the hollow structure known as a microtubule, with a diameter of 25 nm. Mebendazole binds to tubulin, inhibiting microtubule polymerization and halting the M phase of the cell cycle, which induces apoptosis.

When vascular endothelial growth factor (VEGF) binds to the vascular endothelial growth factor receptor-2 (VEGFR-2), it forms a dimer and undergoes autophosphorylation at tyrosine residues within the receptor’s tyrosine kinase domain. This activates intracellular signaling pathways that promote endothelial cell proliferation and angiogenesis. Mebendazole inhibits the activation of VEGFR-2, thereby blocking angiogenesis.

Wnt signaling activates when Wnt binds to the Frizzled receptor and low-density lipoprotein receptor-related proteins 5/6 (LRP5/6). This leads to an increase in β-catenin levels in the cytoplasm, which translocates to the nucleus and binds to the transcription factor TCF, activating the transcription of target genes like c-Myc and cyclin D1, thus promoting cell proliferation. Mebendazole suppresses the activity of the kinase TNIK (Traf2- and Nck-interacting kinase), which is essential for TCF activation, thereby inhibiting TCF-mediated transcriptional activity. Through these various mechanisms, mebendazole inhibits cancer cell proliferation and induces apoptosis.

Ivermectin: Mechanism and Anticancer Potential

Ivermectin is derived from avermectins, which are fermentation products isolated from the soil bacterium Streptomyces avermitilis. It is approved in Japan for the treatment of intestinal strongyloidiasis and scabies.

Ivermectin is particularly effective against onchocerciasis (river blindness), a parasitic disease prevalent in regions such as Central America and Nigeria. This condition leads to severe itching, skin changes, and can result in permanent blindness. Ivermectin is also effective against various other parasitic diseases, including lymphatic filariasis, and is widely used for treating both human and animal infections.

Ivermectin selectively binds to glutamate-gated chloride channels present in the nervous and muscular systems of invertebrates. This binding increases the permeability of the cell membrane to chloride ions, causing hyperpolarization of the nerve or muscle cells, leading to paralysis and death of the parasites. Since glutamate-gated chloride channels are not reported in mammals, ivermectin is considered to have a high safety profile.

As a result, ivermectin is known to have minimal side effects in humans infected with parasites, aside from symptoms related to immune or inflammatory responses during the parasitic die-off. Numerous preclinical studies have confirmed its anticancer effects. In vitro experiments have demonstrated antitumor activity against various cancers, including breast, ovarian, prostate, head and neck, colorectal, pancreatic cancers, and malignant melanoma. Ivermectin has been shown to inhibit cancer cell proliferation and induce apoptosis, as well as exert anti-angiogenic effects.

Animal studies have also confirmed its antitumor efficacy. Mechanisms of action include mitochondrial respiration inhibition, induction of oxidative stress, inhibition of the Akt/mTOR pathway, suppression of the WNT-TCF pathway, PAK-1 inhibition, and anti-angiogenesis. Like mebendazole, ivermectin has also been reported to bind to tubulin, inhibiting microtubule function. Its in vitro and in vivo antitumor activity has been shown to be achievable at clinically relevant concentrations based on pharmacokinetic studies conducted in healthy humans and patients infected with parasites.

Ivermectin and Its Anticancer Mechanisms

Ivermectin consists mainly of 22,23-Dihydroavermectin B1a (H2B1a), making up over 80% of its composition, and 22,23-Dihydroavermectin B (H2B1b) at less than 20%. It is widely used for the treatment of various parasitic diseases, including intestinal strongyloidiasis, onchocerciasis, and scabies. Recent studies indicate that ivermectin exerts anticancer effects through multiple mechanisms.

Niclosamide: Inhibiting Multiple Signaling Pathways in Cancer Stem Cells

Niclosamide was discovered in 1953 by Bayer’s chemotherapy research institute as a molluscicide to kill the intermediate host of schistosomiasis. In 1960, it was found to be effective against human tapeworm infections and was marketed as Yomesan in 1962. The FDA approved its use for tapeworm infections in humans in 1982, and it is included in the World Health Organization's list of essential medicines.

While millions of patients have been treated safely with niclosamide, its mechanisms of action remain insufficiently understood. Recent evidence suggests that niclosamide is a multifunctional drug capable of inhibiting or modulating various signaling pathways and biological processes, indicating its potential as a novel treatment beyond helminthiasis, including in cancer therapy. Relevant studies include:

• Niclosamide's Antitumor Activity: A 2012 study found that niclosamide demonstrates antitumor activity by blocking multiple signaling pathways involved in cancer stem cell regulation, including NF-κB, Wnt/β-catenin, Notch, mTORC1, and Stat3.

Key Findings:

• Niclosamide has been shown to inhibit the β-catenin/c-Myc axis, which is crucial for maintaining cancer stem cell characteristics. This suggests its potential in targeting cancer stem cells.

A subsequent study in 2018 reported that niclosamide inhibits cancer stemness, extracellular matrix remodeling, and metastasis through dysregulation of the nuclear β-catenin/c-Myc axis in oral squamous cell carcinoma (OSCC).

Research Highlights:

• Niclosamide effectively reduced the formation of tumor spheroids and modulated expression levels of key proteins involved in the Wnt/β-catenin pathway, thereby inhibiting epithelial-to-mesenchymal transition (EMT), migration, and colony formation in OSCC.

Role of ALDH in Cancer Stem Cells

ALDH (aldehyde dehydrogenase) is highly expressed in cancer stem cells, serving as a marker for their identification. High ALDH activity is associated with cells that possess stem cell-like properties. Genes necessary for the maintenance of cancer stem cells include Nanog, Oct-4, Sox2, Klf4, and c-Myc.

By inhibiting the Wnt/β-catenin signaling pathway, niclosamide reduces the expression of pluripotency transcription factors such as OCT4, Nanog, and Sox2, thereby impairing tumor formation and metastasis.

Antitumor Activity in Various Cancers

Recent research has explored the antitumor effects of niclosamide across various cancers, including prostate cancer, breast cancer, osteosarcoma, and colorectal cancer. Niclosamide is shown to effectively inhibit several cancer stem cell-related signaling pathways, including Hedgehog, JAK/STAT3, NF-κB, and Akt/mTORC pathways, highlighting its potential as a therapeutic agent in cancer treatment.

In conclusion, niclosamide’s broad-spectrum anticancer activity, mediated through the inhibition of multiple signaling pathways associated with cancer stemness and tumor progression, warrants further clinical investigation to assess its efficacy in cancer therapy.

Wnt Signaling Pathway and Its Mechanism

In the OFF state of the Wnt signaling pathway, β-catenin is degraded by a "destruction complex" composed of casein kinase 1α (CK1α), glycogen synthase kinase 3 β (GSK-3β), axis inhibition (Axin), and adenomatous polyposis coli (APC). When Wnt ligands bind to the Frizzled receptor and low-density lipoprotein receptor-related proteins 5/6 (LRP5/6), Disheveled (DVL) inhibits the phosphorylation of β-catenin. This prevents its degradation by the proteasome, allowing β-catenin to accumulate in the cytoplasm and translocate to the nucleus.

Once in the nucleus, β-catenin forms a complex with the transcription factors Tcf/Lef (T-cell factor/lymphoid enhancer factor), promoting the expression of target genes such as c-Myc and cyclin D1, which in turn stimulates cell proliferation.

Combining Anticancer Effects of Anthelmintics

As demonstrated, the anthelmintics mebendazole, ivermectin, and niclosamide exert anticancer effects through various mechanisms. Combining these three anthelmintics could potentially enhance their overall anticancer efficacy. Importantly, these drugs are already in use and have been reported to have minimal side effects.