Mebendazol - antiparasitic substance with antitumor activity

Over the past two decades, scientists have begun to look at bug drugs as potential anti-cancer therapies because they interact with microtubules, which are important for cell division. One of these drugs, Mebendazol (MBZ), has shown potential in stopping the growth of cancer cells. Studies on various cancer cells, animal models and clinical trials have shown that MBZ has the potential to stop the growth and proliferation of cancer cells by affecting their internal structures (microtubule formation) and energy supply (glucose uptake) [1].

MBZ has shown potential against various cancers, including thyroid, gastrointestinal, breast, prostate, pancreatic, ovarian, colorectal, melanoma, head and neck, leukemia and biliary tract cancers [1]. It works by affecting various cancer-related pathways, such as MAPK14, MEK-ERK, C-MYC and several others, depending on the specific cancer.

Mebendazol, along with other similar compounds such as albendazol and fenbendazol, has been safely used for decades to treat a wide range of parasitic infections. It is widely available in doses ranging from 100 to 500 mg, depending on the type of infection. In severe cases, such as echinococcosis, higher doses are recommended for long periods of time, sometimes lasting up to two years. These therapies have proven safe in numerous clinical trials and during widespread use in real-world settings. The safety of MBZ has been well documented, with most side effects being mild in nature, such as abdominal pain and diarrhea. Some rare side effects have been reported at high doses, such as temporary changes in blood cell counts and liver problems, but these are usually reversible. Therefore, Mebendazol's well-known safety and potential new uses make it a promising candidate for renewed use in cancer treatment. It is generally safe for normal cells, but is particularly effective against cancer cells, making it a promising candidate for anti-cancer therapy.

Mebendazol in the treatment of metastatic adrenocortical carcinoma

In 2011. Dobrosotskaya et al. reported the first clinical case of using mebendazol (MBZ) to treat cancer. The patient was a 35-year-old woman with metastatic adrenocortical cancer that had spread from the right adrenal gland to the liver. Despite undergoing multiple surgeries, radiation and chemotherapy, her tumors continued to grow. She then began taking MBZ, 100 mg orally twice a day. After 19 months of treatment, her liver tumors initially shrank and then remained stable throughout the treatment period. Unlike previous therapies, MBZ was well tolerated and significantly improved her quality of life. Although the patient experienced disease progression after 24 months of monotherapy, this case demonstrates that mebendazol can provide long-term tumor control in metastatic adrenocortical cancer with minimal side effects [2].

Mebendazol in the treatment of metastatic colorectal cancer

In addition, Nyger and Larsson documented another successful case with MBZ, this time in a 74-year-old patient with advanced colon cancer. The cancer had spread to multiple sites, including the lungs, abdominal lymph nodes and liver, and had not responded to standard chemotherapy treatment. With no other options, the patient began taking MBZ at a dose of 100 mg twice a day. After six weeks, scans showed almost complete remission of lung and lymph node metastases and a significant reduction in liver tumors. Although the patient developed elevated liver enzymes, which led to temporary discontinuation of MBZ treatment, the enzymes returned to normal and the patient experienced no other side effects. However, after discontinuing MBZ for three months, the patient developed brain metastases, which were treated with radiation therapy, and later showed signs of disease in the lymph nodes.
These cases suggest that MBZ may be an effective and well-tolerated anti-cancer drug, providing significant improvement in patients who have not responded to conventional therapies.

Metastatic colorectal cancer (mCRC)

Metastatic colorectal cancer (mCRC) often leads to cancer-related deaths due to its spread to distant organs. This study investigated the antitumor effect and safety of mebendazol in patients with mCRC. Forty patients were randomized to two groups: one received standard chemotherapy (bevacizumab and FOLFOX4) with placebo, and the other received the same chemotherapy with 500 mg of mebendazol twice daily for 12 weeks. The results showed that the addition of mebendazol significantly improved tumor response (65% versus 10% in the placebo group) and prolonged progression-free survival (9.25 months versus 3 months). In addition, mebendazol reduced VEGF levels, indicating reduced tumor blood supply, and was well tolerated with no significant side effects. These results suggest that
mebendazol may be a safe and effective addition to standard chemotherapy for mCRC, making it a promising candidate for reuse in cancer treatment.

Potential of mebendazol in the treatment of brain cancer: Evidence from animal models and in vivo

Recent studies have shown that mebendazol (MBZ) is a promising drug for the treatment of brain cancer, particularly glioblastoma multiforme (GBM). Ren-Yuan Bai et al [5] demonstrated that MBZ shows significant potential against glioblastoma multiforme (GBM). In vitro and in vivo tests identified MBZ as a potent agent, inducing apoptosis (programmed cell death) in GBM cell lines, with an IC50 of 0.24 μM in mouse glioma line GL261 and 0.1 μM in human GBM line 060919. In addition, MBZ inhibited tubulin polymerization, a process crucial for cell division, at a concentration of 0.1 μM. In mouse models, MBZ significantly prolonged survival to 65 days compared to 48 days in controls and increased the efficacy of temozolomide (TMZ), a common chemotherapeutic drug, in the GL261 mouse model.

Moreover, Ren LW et al [6] suggested that benzimidazole compounds, including MBZ, can inhibit GBM cell proliferation and metastasis by regulating cell migration, cell cycle and programmed cell death. MBZ was found to reduce GBM cell migration and invasion, regulate key markers of epithelial-mesenchymal transition (EMT), and arrest the cell cycle at the G2/M phase, a critical point of cell division, through the P53/P21/cyclin B1 pathway. These findings indicate that MBZ not only stops GBM growth, but also prevents its spread, making it a potential candidate for comprehensive GBM therapy.

In addition, Ren-Yuan Bai et al [7] showed that among the polymorphic forms of mebendazol (A, B and C), MBZ-C had the highest brain penetration and therapeutic efficacy. In particular, combining MBZ-C with elacridar, a P-glycoprotein inhibitor, increased survival in mouse models of GL261 glioma and D425 medulloblastoma. In addition, De Witt M et al [8] showed that both MBZ and vincristine had similar effects on GL261 glioma cells by inhibiting cell viability and microtubule polymerization. MBZ proved more effective than vincristine in prolonging survival in orthotopic GL261-C57BL/6 syngeneic mouse models. Moreover, Dakshanamurthy et al [9] identified MBZ as a potential inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2), a protein that promotes blood vessel growth in tumors. MBZ inhibited VEGFR2 autophosphorylation, suppressing tumor angiogenesis without affecting normal brain vessels, as evidenced by its effect on medulloblastoma models.

In addition, Larsen et al [10] found that Mebendazol (MBZ) can block the Hedgehog (Hh) signaling pathway, which is important for cell growth and development, in human medulloblastoma cell lines. Inhibition of this pathway by MBZ significantly increased the survival of medulloblastoma mice. Bodhinayake et al [11] reported that MBZ treatment prolonged survival in medulloblastoma models, demonstrating its efficacy against tumors associated with the Hedgehog signaling pathway.

Studies have also shown that mebendazol (MBZ) can make cancer cells more sensitive to radiation and chemotherapy. This effect led to longer survival in experimental models of malignant meningioma (a type of brain tumor) and glioma. Studies have shown that combining MBZ with radiation increased survival and slowed tumor growth in meningioma models. One study observed that MBZ increased the efficacy of radiation therapy in glioma cells, suggesting that it could be used in parallel with other treatments [12]. In addition, studies have confirmed that MBZ reduces the viability of glioma cells by inhibiting a specific enzyme, thereby improving the efficacy of chemotherapy against this aggressive brain tumor [13].

A clinical trial is currently underway to study the effects of mebendazol (MBZ) in combination with standard treatments. The trial involves children between the ages of 1 and 21 with medulloblastoma or high-grade glioma (including glioblastoma multiforme, anaplastic staphyloma and diffuse intramedullary glioma) whose tumors continue to grow despite standard treatment (http://clinicaltrials.gov/ct2/show/NCT02644291). Another clinical trial at Cohen Children's Medical Center in New York is testing MBZ with vincristine, carboplatin and temozolomide in the treatment of low-grade gliomas (http://clinicaltrials.gov/ct2/show/NCT01837862).

Potential of mebendazol in the treatment of triple-negative breast cancer

Triple-negative breast cancer (TNBC) is difficult to treat due to the lack of specific molecular targets. Although radiation therapy (RT) is widely used, it can sometimes cause surviving cancer cells to become more resistant. Various studies have analyzed the potential of mebendazol (MBZ) to enhance the effects of RT in the treatment of TNBC. The study evaluated the ability of MBZ to improve the efficacy of RT in both laboratory conditions and animal models. The results showed that MBZ effectively reduced the population of breast cancer initiating cells (BCIC) and prevented radiation-induced resistance of these cells. It also caused cancer cells to stop dividing and
induced cell death through apoptosis. MBZ increased the sensitivity of TNBC cells to radiation, improving tumor control in laboratory and animal models. When combined with radiation, MBZ retarded tumor growth more effectively than radiation alone without additional toxicity. Further studies are needed to confirm these findings and investigate the long-term safety and efficacy of MBZ in combination with radiation therapy [14].

In another study, researchers used mouse models to simulate the spread of triple-negative breast cancer (TNBC) to the brain [15]. Mice were injected with tumor cells and tumor growth was monitored using bioluminescence imaging. Mice were treated with oral doses of MBZ of 50 and 100 mg/kg. The effects of MBZ on tumor growth and survival were then evaluated. The study showed that MBZ effectively slowed TNBC cell migration in laboratory tests. In animal studies, MBZ significantly reduced tumor growth and prolonged survival in mice with TNBC brain metastases. Specifically, MBZ reduced the spread of tumor cells in the brain and prevented the formation of new small metastases. This effect was observed at both 50 mg/kg and 100 mg/kg doses, with no significant difference between the two doses. Importantly, MBZ did not show the same efficacy in a less aggressive type of breast cancer (MCF7-BR). These results suggest that MBZ may be further explored as an alternative therapeutic option for patients with this challenging condition [15, 16].

Mebendazol in preventing colon cancer

Researchers have developed a strategy to prevent colorectal cancer using a combination of the nonsteroidal anti-inflammatory drug (NSAID) sulindac and Mebendazol [17]. The combination was tested on a mouse model of ApcMin/+ familial adenomatous polyposis (FAP), a disease that leads to cancer due to gene mutations. The results showed that Mebendazol, administered orally at a dose of 35 mg/kg per day, reduced the number of intestinal adenomas (a type of benign tumor) by 56%. Sulindac at a dose of 160 ppm reduced the number of adenomas by 74%. Interestingly, the combination of the two drugs reduced the number of adenomas by 90%. This combination treatment also significantly reduced the number and size of polyps in both the small intestine and colon compared to the control group or sulindac alone. It is worth noting that Mebendazol alone was effective in reducing COX2 expression, blood vessel formation and VEGFR2 phosphorylation, all of which are involved in tumor growth. In addition, it acted synergistically with sulindac to reduce the overexpression of cancer-related proteins such as MYC and BCL2 and various pro-inflammatory cytokines.

Given mebendazol's low toxicity, these results support the idea of using it, alone or in combination with sulindac, in clinical trials in people at high risk for cancer. Such combination therapy could potentially reduce the risk of cancer in people with moderate or greater genetic predisposition.

Mebendazol in the treatment of ovarian cancer

A recent study has shown the potential of mebendazol in the treatment of ovarian cancer. Researchers tested mebendazol in a variety of ovarian cancer models, including cell cultures and patient-derived xenograft mice (PDX) of high-grade serous ovarian cancer [18]. These models included various genetic backgrounds, particularly focusing on p53 mutations, which are common in ovarian cancer. In cell cultures, mebendazol effectively inhibited the growth of ovarian cancer cells at very low concentrations, regardless of their p53 mutation status. The drug also prevented tumor formation in an orthotopic mouse model in which tumors are implanted into the tissue from which they originate. In addition, mebendazol was found to induce cell cycle arrest and apoptosis (programmed cell death), which are desirable effects in cancer treatment.

In animal models of PDX, mebendazol significantly slowed tumor growth at doses up to 50 mg/kg [18]. The drug's efficacy was observed in both p53-positive and p53-null tumors, indicating its broad potential. Moreover, the combination of mebendazol with PRIMA-1MET, a drug that reactivates mutant p53, has shown synergistic effects, further reducing tumor growth. Overall, mebendazol showed significant anti-tumor activity in both cell cultures and animal models of ovarian cancer, suggesting that it may be a promising drug for the treatment of this aggressive disease.

Mebendazol for thyroid cancer

Papillary thyroid cancer is the most common type of malignant thyroid cancer, generally responding well to treatment. However, some cases persist and can progress to anaplastic thyroid cancer, a highly aggressive and deadly form. For these patients, the researchers investigated the potential for changing the use of mebendazol to treat thyroid cancer before it metastasizes.

In laboratory studies, mebendazol effectively inhibited the growth of both papillary and anaplastic thyroid cancer cells [19]. It caused tumor cell arrest in the G2/M phase of the cell cycle and induced apoptosis by
activation of the caspase-3 pathway. In aggressive anaplastic thyroid cancer cells, mebendazol significantly reduced their ability to migrate and invade, suggesting that it may prevent the spread of cancer. This was accompanied by a decrease in important signaling proteins involved in cancer progression, such as phosphorylated Akt and Stat3, and a decrease in Gli1 expression.

In animal models, Mebendazolm treatment led to significant tumor regression in papillary thyroid cancer and growth arrest in anaplastic thyroid cancer [19]. Treated tumors showed lower levels of KI67, a marker of cell proliferation, and had reduced blood vessel formation. Most importantly, daily oral doses of mebendazol prevented thyroid tumors from metastasizing to the lungs. These findings underscore the potential of mebendazol as a safe and effective treatment for thyroid cancer, especially in patients with treatment-resistant forms.

Mebendazol in the treatment of malignant meningiomas

Meningiomas are common tumors of the central nervous system, most of them benign, but about 5% of them are atypical or malignant. Treatments such as surgery and radiation therapy can help, but about 33% patients experience recurrences, often with more aggressive tumors. Recent studies suggest that mebendazol may also have anti-cancer properties, especially for brain tumors such as glioma and medulloblastoma

.
In one study, researchers tested the effects of mebendazol on malignant meningiomas [20]. Laboratory tests showed that mebendazol inhibited the growth of meningioma cells, causing significant cell death and preventing colony formation. The drug worked even better when combined with radiation therapy, increasing levels of apoptosis (programmed cell death), as indicated by activation of caspase-3, an enzyme involved in apoptosis.

In addition, in animal models, mice with human meningioma tumors were treated with Mebendazolm alone or in combination with radiation [20]. Both therapies prolonged the survival of the mice, reduced tumor cell proliferation and decreased the density of blood vessels in the tumors. This suggests that mebendazol not only directly kills cancer cells, but also inhibits the growth of new blood vessels that tumors need to grow. These findings underscore mebendazol's potential for treating malignant meningiomas, either alone or in combination with radiation therapy.

Mebendazol in the treatment of glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common and aggressive form of brain cancer, with a poor prognosis despite advances in treatment. During a routine study, researchers observed that fenbendazol inhibits brain tumor growth. Further experiments have shown mebendazol to be even more promising in GBM therapy [21]. In laboratory tests, mebendazol showed cytotoxic effects on GBM cell lines, effectively killing tumor cells at low concentrations (0.1 to 0.3 μM). The drug disrupted the formation of microtubules, essential components for cell division, leading to reduced tubulin polymerization in cancer cells. This disruption is key to its anticancer properties.

Moreover, in animal models, mebendazol significantly prolonged survival by as much as 63% in mice implanted with glioblastoma tumors [21]. Given its efficacy in animal models and established safety profile, mebendazol represents a promising new treatment option for brain tumors such as GBM. These findings confirm mebendazol's potential to be tested in clinical trials as a new therapeutic option for brain cancer patients.

Mebendazol in the treatment of prostate cancer

Chemotherapy with docetaxel to treat prostate cancer has a limited chance of improving survival. To improve its efficacy, the researchers investigated the possibility of combining it with other drugs. They tested 857 drugs from repurposing libraries on prostate cancer cell lines to find the right combination. Mebendazol, known to inhibit microtubule folding, emerged as the most promising candidate. When combined with docetaxel, Mebendazol significantly increased cell death both in the laboratory and in animal models [22]. This combination therapy targeted microtubule structure in two different ways, leading to greater G2/M mitotic block and increased apoptosis. The dual treatment caused cancer cells to form abnormal multipolar spindles during division, resulting in aneuploid progenitor cells that contributed to cell death.

In animal studies, liposomes containing both docetaxel and mebendazol effectively inhibited prostate tumor growth and prolonged time to tumor progression [22]. These findings suggest that the combination of docetaxel and mebendazol may be an effective new treatment strategy for chemoresistant prostate cancer.

Mebendazol vs vincristine in the treatment of brain tumors

Vincristine, a microtubule inhibitor, is currently used to treat brain tumors such as low-grade glioma, but it does not penetrate the brain well and causes serious side effects, including nerve damage. Mebendazol, an FDA-approved drug for parasitic infections, has shown promise against brain tumors in animal studies and penetrates the brain more effectively.

Researchers have tested mebendazol on glioma cell lines and found that it inhibits microtubule formation, similar to vincristine, leading to cell death [23]. The efficacy of mebendazol and vincristine was compared in mice with brain tumors. mebendazol significantly prolonged survival time, while vincristine did not. For example, mice treated with Mebendazolm at doses of 50 mg/kg and 100 mg/kg had a mean survival time of 17 and 19 days, respectively, compared to 10.1 days in the control group.

The study also evaluated the toxicity of the drug. Vincristine caused significant nerve pain and weight loss in mice, while mebendazol had less severe side effects. The combination of the two drugs increased toxicity and nerve damage. These results suggest that mebendazol may be a safer and more effective alternative to vincristine in the treatment of brain tumors.

Mebendazol in the treatment of pancreatic cancer

Survival rates for pancreatic cancer are alarmingly low, especially in metastatic cases. Therefore, research studies have looked at the potential of repurposing mebendazol to combat different stages of pancreatic cancer. In one study, researchers tested whether mebendazol could prevent the initiation of precursor lesions, interfere with the tumor lining or inhibit tumor growth and metastasis [24].

Using two mouse models, one for early pancreatitis (KC model) and the other for advanced pancreatic cancer (KPC model), mebendazol was found to significantly reduce pancreatic weight, dysplasia and intraepithelial neoplasia formation compared to the control group [24]. It also reduced connective tissue fibrosis and activation of pancreatic stellate cells, which are markers of fibrogenesis. In an aggressive model of KPC, mebendazol was effective in inhibiting tumor growth as both an early and late intervention [24]. It reduced the overall incidence of pancreatic cancer and the severity of liver metastases. mebendazol-treated mice showed less inflammation, less dysplasia and a lower tumor burden, with fewer advanced tumors and metastases.

Further analysis showed that mice treated with mebendazol had significantly fewer PanIN lesions and desmoplasia of the stroma [24]. In early intervention models, mebendazol led to a significant reduction in markers of tumor progression and less advanced tumor formation. Treated mice had a significantly lower incidence of pancreatic ductal adenocarcinoma (PDAC), suggesting that mebendazol slowed tumor progression. These results suggest that mebendazol significantly reduces tumor growth, decreases fibrosis and limits cancer progression in pancreatic cancer models. Given its low toxicity and promising results, mebendazol warrants further study as a potential adjuvant therapy to slow cancer progression and prevent metastasis.

Mebendazol in the treatment of biliary tract cancer

Based on the anticancer potential of mebendazol (MBZ), its effects on biliary tract cancer (CCA) cells have been studied both in laboratory conditions and in animal models [25]. In vitro experiments with the KKU-M213 cell line showed that MBZ significantly reduced cell proliferation. This reduction was associated with a significant increase in the expression and activity of caspase-3, an enzyme crucial to the process of apoptosis.

In vivo, oral administration of MBZ to nude mice with subcutaneously xenografted KKU-M213 tumors resulted in a slight reduction in tumor growth [25]. The TUNEL assay, which detects apoptotic cells, showed an increased number of apoptotic cells in the tumor tissues of MBZ-treated mice. These results suggest that MBZ can effectively inhibit CCA cell proliferation through caspase-3-activated apoptosis. Further studies are needed to ascertain the potential of MBZ as an alternative treatment for biliary tract cancer.

Cytotoxic and immunomodulatory effects

Mebendazol (Mbz) is showing potential as an anti-cancer drug. It was initially thought to fight cancer by inhibiting microtubule formation, but recent studies have shown that it also helps switch macrophages from a type that promotes tumors (M2) to one that suppresses them (M1). The scientific study was designed to examine the effects of Mbz on cancer cells, alone and in combination with other cancer treatments such as cytotoxic drugs and PD-1 antibodies [26]. The researchers tested tumor samples from patients with solid tumors and blood cancers and observed that while Mbz alone had modest effects, it worked well with other therapies. In particular, combining Mbz with a PD-1 antibody significantly enhanced the immune response against cancer in a mouse model, increasing the number of M1 macrophages and reducing the number of M2 macrophages in tumors. These results suggest that Mbz, especially when combined with therapies such as PD-1 antibodies, may be a promising new approach to cancer treatment.

Mebendazol in acute myeloid leukemia

Acute myeloid leukemia (AML) is a common and aggressive form of leukemia in adults, with a low survival rate. The main problem is resistance to current chemotherapy treatments. Researchers analyzed more than 1,000 FDA-approved drugs and found that mebendazol (MBZ) effectively inhibited the growth of AML cells in the laboratory [27-29]. MBZ was found to inhibit the growth of various AML cell lines and bone marrow cells from AML patients at concentrations achievable in the human body. Importantly, MBZ had minimal effect on the growth of normal blood cells and endothelial cells, indicating its potential in selectively targeting cancer cells. MBZ induced mitotic arrest and mitotic catastrophe in AML cells, leading to the death of these cancer cells.

The drug also inhibited key signaling pathways (Akt and Erk) involved in AML cell survival and proliferation. In animal models, MBZ treatment slowed leukemia progression and significantly prolonged survival [27-29]. These findings suggest that MBZ could be used as a novel therapeutic agent for AML, offering a potential new treatment option with minimal side effects.

Mebendazol in the treatment of head and neck cancer

Head and neck squamous cell carcinoma (HNSCC) is a common and aggressive cancer with a high rate of recurrence and resistance to chemotherapy. Given the need for new treatments, researchers investigated the potential of repurposing mebendazol (MBZ) as an anti-cancer agent for HNSCC.

In studies using two human HNSCC cell lines, CAL27 and SCC15, MBZ showed more potent antiproliferative effects than cisplatin, a standard chemotherapeutic drug [30]. MBZ effectively inhibited cell growth, arrested cell cycle progression, reduced cell migration and induced apoptosis (programmed
cell death) in HNSCC cells. It also modulated cancer-related pathways such as ELK1/SRF, AP1, STAT1/2 and MYC/MAX, according to the context.

MBZ was found to act synergistically with cisplatin, enhancing its ability to inhibit cell proliferation and induce apoptosis [30]. Moreover, MBZ promoted terminal differentiation of CAL27 cells and keratinization (a form of cell maturation) of CAL27-derived tumors in animal models. These findings suggest that MBZ can be used as a safe and effective treatment for HNSCC, especially in combination with existing chemotherapeutic drugs such as cisplatin.

Mebendazol as treatment for chemoresistant hepatocellular carcinoma

Patients with hepatoblastoma, a type of liver cancer, often have poor outcomes when tumors fail to respond to preoperative chemotherapy, leading to incomplete surgical removal. Researchers have identified mebendazol as a potential treatment for chemotherapy-resistant liver cancer. In hepatoblastoma cell culture models, mebendazol significantly inhibited both short- and long-term growth of tumor cells [31]. The drug was found to arrest cell division and induce programmed cell death by interfering with genes involved in the unwindosome complex.

To test the efficacy of mebendazol under preclinical conditions, mice with tumors were orally administered mebendazol at a dose of 40 mg/kg body weight five days a week for 16 days. The results showed a significant decrease in tumor growth in Mebendazolm-treated mice compared to vehicle-treated mice. Importantly, the mice maintained a stable body weight and showed no changes in physical appearance or behavior.

Further analysis of treated tumors showed a reduction in the number of proliferating cells and an increase in areas of cell death, characterized by the presence of apoptotic cells and the apoptosis marker cleaved caspase-3. These results indicate that mebendazol is both effective and safe for use in the treatment of chemoresistant and aggressive liver cancer.

Mebendazol: Potential antitumor and anti-tumor mechanisms

Based on various studies, the following are some of the potential antitumor and anti-tumor mechanisms of mebendazol [32].

Tubulin depolymerization:

Mebendazol (MBZ) was first tested against cancer in 2002, where it was shown to disrupt tubulin in human lung cancer cells,
causing cell division to stop and leading to cell death. A study on mice with lung cancer tumors showed a significant reduction in tumor growth within 14 days of MBZ treatment. Another study showed that MBZ effectively inhibited tumor growth in glioma (a type of brain cancer) in both cell cultures and mice, significantly improving survival rates.

Inhibition of angiogenesis:

Angiogenesis, or the formation of new blood vessels, is important for tumor growth. MBZ was found to inhibit this process in various cancer models. It significantly reduced blood vessel formation and tumor growth in lung, breast, ovarian, colon and melanoma cancers without showing toxicity in treated animals. The drug also inhibited the formation of lung metastases (spread of cancer to the lungs) in mouse models of lung cancer.

Inhibition of cancer pathways:

MBZ affects several key signaling pathways involved in cancer progression. For example, it inhibited the Hedgehog signaling pathway in medulloblastoma, a common brain tumor in children, leading to increased survival in mice. It also affected protein kinase-related pathways involved in various cancers, including colon and melanoma, inhibiting the growth of cancer cells and promoting their death.

Sensitization to chemotherapy and radiation therapy:

MBZ increases the effectiveness of chemotherapy and radiation therapy by sensitizing cancer cells to these treatments. Studies have shown that MBZ combined with radiation therapy increases the effectiveness of triple-negative breast cancer and glioblastoma treatment by making cancer cells more susceptible to damage and death.

Induction of apoptosis:

MBZ has been shown to induce apoptosis (programmed cell death) in various cancer cells, including melanoma and adrenocortical cancer. It activates pathways leading to cell death, such as the mitochondrial pathway, contributing to its effectiveness against cancer.

Kinase inhibition:

Kinases are enzymes that play a role in the growth and survival of cancer cells. MBZ inhibits several key kinases, including those involved in colorectal cancer and melanoma, reducing the proliferation and survival of cancer cells.

Modulation of the immune response:

MBZ also modulates the immune response against tumors. It promotes the activity of immune cells that attack cancer cells and reduces factors that promote tumor growth. Studies have shown that MBZ can stimulate the anti-tumor immune response, making it a promising candidate for immunotherapy.

Overall, mebendazol shows potential as an anticancer agent through various mechanisms, including interfering with cancer cell division, inhibiting blood vessel formation in tumors, affecting tumor growth pathways, enhancing the efficacy of chemotherapy and radiotherapy, inducing cancer cell death, inhibiting key enzymes and modulating the immune response against cancer cells. These discoveries suggest that MBZ could be used again in cancer treatment, giving new hope to patients with various types of cancer.

Links

1. Chai, J.Y., Jung, B.K. and Hong, S.J., 2021. Albendazole and mebendazol as anti-parasitic and anti-cancer agents: an update. The Korean Journal of Parasitology, 59(3), p.189.
2. Dobrosotskaya I.Y., Hammer G.D., Schteingart D.E., Maturen K.E., Worden F.P. Mebendazol monotherapy and long-term disease control in metastatic adrenocortical carcinoma.  Pract. 2011;17:59-62. doi: 10.4158/EP10390.CR. https://www.sciencedirect.com/science/article/abs/pii/S1530891X20404434
3. Nygren P., Larsson R. Drug repositioning from bench to bedside: Tumour remission by the antihelminthic drug mebendazol in refractory metastatic colon cancer. Acta Oncol. 2014;53:427-428. doi: 10.3109/0284186X.2013.844359. https://pubmed.ncbi.nlm.nih.gov/24160353
4. Hegazy SK, El-Azab GA, Zakaria F, Mostafa MF, El-Ghoneimy RA. Mebendazol; from an anti-parasitic drug to a promising candidate for drug repurposing in colorectal cancer. Life Sci. 2022 Jun 15;299:120536. doi: 10.1016/j.lfs.2022.120536. epub 2022 Apr 3. PMID: 35385794. https://pubmed.ncbi.nlm.nih.gov/35385794/
5. Bai R.Y., Staedtke V., Aprhys C.M., Gallia G.L., Riggins G.J. Antiparasitic Mebendazol shows survival benefit in 2 preclinical models of glioblastoma multiforme. Neuro-Oncol. 2011;13:974-982. doi: 10.1093/neuonc/nor077. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3158014/
6. Ren L.W., Li W., Zheng X.J., Liu J.Y., Yang Y.H., Li S., Zhang S., Fu W.Q., Xiao B., Wang J.H., et al. Author Correction: Benzimidazoles induce concurrent apoptosis and pyroptosis of human glioblastoma cells via arresting cell cycle. Acta Pharmacol. Sin. 2022;15:194-208. doi: 10.1038/s41401-021-00752-y. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8724275/
7. Bai R.Y., Staedtke V., Wanjiku T., Rudek M.A., Joshi A., Gallia G.L., Riggins G.J. Brain Penetration and Efficacy of Different Mebendazol Polymorphs in a Mouse Brain Tumor Model.  Cancer Res. 2015;21:3462-3470. doi: 10.1158/1078-0432.CCR-14-2681. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526400/
8. De Witt M., Gamble A., Hanson D., Markowitz D., Powell C., Al Dimassi S., Atlas M., Boockvar J., Ruggieri R., Symons M. Repurposing mebendazol as a replacement for vincristine for the treatment of brain tumors.  Med. 2017;23:50-56. doi: 10.2119/molmed.2017.00011. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5403762/
9. Dakshanamurthy S., Issa N.T., Assefnia S., Seshasayee A., Peters O.J., Madhavan S., Uren A., Brown M.L., Byers S.W. Predicting new indications for approved drugs using a proteochemometric method.  Med. Chem. 2012;55:6832-6848. doi: 10.1021/jm300576q. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419493/
10. Larsen A.R., Bai R.-Y., Chung J.H., Borodovsky A., Rudin C.M., Riggins G.J., Bunz F. Repurposing the antihelminthic Mebendazol as a hedgehog inhibitor.  Cancer Ther. 2015;14:3-13. doi: 10.1158/1535-7163.MCT-14-0755-T. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297232/
11. Bodhinayake I., Symons M., Boockvar J.A.. Repurposing mebendazol for the treatment of medulloblastoma. 2015;76:N15-N16. doi: 10.1227/01.neu.0000460594.93803.cb. https://pubmed.ncbi.nlm.nih.gov/25594199
12. Markowitz D., Ha G., Ruggieri R., Symons M. Microtubule-targeting agents can sensitize cancer cells to ionizing radiation by an interphase-based mechanism. Onco Targets Ther. 2017;24:5633-5642. doi: 10.2147/OTT.S143096. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703169/
13. Ariey-Bonnet J., Carrasco K., Le Grand M., Hoffer L., Betzi S., Feracci M., Tsvetkov P., Devred F., Collette Y., Morelli X., et al. In silico molecular target prediction unveils mebendazol as a potent MAPK14 inhibitor.  Oncol. 2020;14:3083-3099. doi: 10.1002/1878-0261.12810. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718943/
14. Zhang, Le; Bochkur Dratver, Milana; Yazal, Taha; Dong, Kevin; Nguyen, Andrea; Yu, Garrett; Dao, Amy; Bochkur Dratver, Michael; Duhachek-Muggy, Sara; Bhat, Kruttika; Alli, Claudia; Pajonk, Frank; Vlashi, Erina . (2019). Mebendazol Potentiates Radiation Therapy in Triple-Negative Breast Cancer. International Journal of Radiation Oncology*Biology*Physics, 103(1), 195-207. doi:10.1016/j.ijrobp.2018.08.046 https://pismin.com/10.1016/j.ijrobp.2018.08.046
15. Rodrigues, A., Chernikova, S.B., Wang, Y., Trinh, T.T., Solow-Cordero, D.E., Alexandrova, L., Casey, K.M., Alli, E., Aggarwal, A., Quill, T. and Koegel, A., 2024. Repurposing mebendazol against triple-negative breast cancer leptomeningeal disease. https://www.researchsquare.com/article/rs-3915392/latest
16. Choi, H.S., Ko, Y.S., Jin, H., Kang, K.M., Ha, I.B., Jeong, H., Song, H.N., Kim, H.J. and Jeong, B.K., 2021. Anticancer effect of benzimidazole derivatives, especially mebendazol, on triple-negative breast cancer (TNBC) and radiotherapy-resistant TNBC in vivo and in vitro. Molecules, 26(17), p.5118. https://www.mdpi.com/1420-3049/26/17/5118
17. Williamson, T., Bai, R. Y., Staedtke, V., Huso, D., & Riggins, G. J. (2016). Mebendazol and a non-steroidal anti-inflammatory combination to reduce tumor initiation in a colon cancer preclinical model. Oncotarget, 7(42), 68571-68584. https://doi.org/10.18632/oncotarget.11851 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356574/
18. Elayapillai, Suganthapriya; Ramraj, Satishkumar; Benbrook, Doris Mangiaracina; Bieniasz, Magdalena; Wang, Lin; Pathuri, Gopal; Isingizwe, Zitha Redempta; Kennedy, Amy L.; Zhao, Yan D.; Lightfoot, Stanley; Hunsucker, Lauri A.; Gunderson, Camille C. . (2020). Potential and mechanism of mebendazol for treatment and maintenance of ovarian cancer. Gynecologic Oncology, (), S009082582034018X-. doi:10.1016/j.ygyno.2020.10.010  https://pismin.com/10.1016/j.ygyno.2020.10.010
19. Williamson, T., Mendes, T.B., Joe, N., Cerutti, J.M. and Riggins, G.J., 2020. Mebendazol inhibits tumor growth and prevents lung metastasis in models of advanced thyroid cancer. Endocrine-related cancer, 27(3), pp.123-136. https://erc.bioscientifica.com/view/journals/erc/27/3/ERC-19-0341.xml
20. Skibinski, C.G., Williamson, T., and Riggins, G.J., 2018. Mebendazol and radiation in combination increase survival through anticancer mechanisms in an intracranial rodent model of malignant meningioma. Journal of neuro-oncology, 140, pp.529-538. https://link.springer.com/article/10.1007/s11060-018-03009-7
21. Bai, R.Y., Staedtke, V., Aprhys, C.M., Gallia, G.L. and Riggins, G.J., 2011. antiparasitic mebendazol shows survival benefit in 2 preclinical models of glioblastoma multiforme. Neuro-oncology, 13(9), pp.974-982. https://academic.oup.com/neuro-oncology/article/13/9/974/1096119
22. Rushworth, L.K., Hewit, K., Munnings-Tomes, S. et al.Repurposing screen identifies mebendazol as a clinical candidate to synergize with docetaxel for prostate cancer treatment. Br J Cancer 122, 517-527 (2020). https://doi.org/10.1038/s41416-019-0681-5 https://www.nature.com/articles/s41416-019-0681-5#
23. De Witt, M., Gamble, A., Hanson, D. et al.Repurposing Mebendazol as a Replacement for Vincristine for the Treatment of Brain Tumors. Mol Med 23, 50-56 (2017). https://doi.org/10.2119/molmed.2017.00011 https://link.springer.com/article/10.2119/molmed.2017.00011#
24. Williamson, T., de Abreu, M. C., Trembath, D. G., Brayton, C., Kang, B., Mendes, T. B., de Assumpção, P. P., Cerutti, J. M., & Riggins, G. J. (2021). Mebendazol disrupts stromal desmoplasia and tumorigenesis in two models of pancreatic cancer. Oncotarget, 12(14), 1326-1338. https://doi.org/10.18632/oncotarget.28014 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274724/
25. Sawanyawisuth K, Williamson T, Wongkham S, Riggins GJ. EFFECT OF THE ANTIPARASITIC DRUG mebendazol ON CHOLANGIOCARCINOMA GROWTH. Southeast Asian J Trop Med Public Health. 2014 Nov;45(6):1264-70. PMID: 26466412. https://pubmed.ncbi.nlm.nih.gov/26466412/
26. Mansoori, S., Blom, K., Andersson, C., Fryknäs, M. and Nygren, H.P., 2023. 2299P Mebendazol enhances the anticancer effect of irinotecan and check-point inhibitor in vitro and in vivo. Annals of Oncology, 34, p.S1176. https://www.annalsofoncology.org/article/S0923-7534(23)02163-4/fulltext
27. He, L., Shi, L., Du, Z., Huang, H., Gong, R., Ma, L., Chen, L., Gao, S., Lyu, J. and Gu, H., 2018. Mebendazol exhibits potent anti-leukemia activity on acute myeloid leukemia. Experimental cell research, 369(1), pp.61-68. https://www.sciencedirect.com/science/article/pii/S0014482718302684
28. Wang, X., Lou, K., Song, X., Ma, H., Zhou, X., Xu, H. and Wang, W., 2020. Mebendazol is a potent inhibitor to chemoresistant T cell acute lymphoblastic leukemia cells. Toxicology and Applied Pharmacology, 396, p.115001. https://www.sciencedirect.com/science/article/abs/pii/S0041008X20301253
29. Maali, A., Ferdosi-Shahandashti, E., Sadeghi, F. and Aali, E., 2020. The anti-helminthic drug, mebendazol, induces apoptosis in adult T-cell leukemia/lymphoma cancer cells: an in-vitro trial. International Journal of Hematology-Oncology and Stem Cell Research, 14(4), p.257. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876428/
30. Zhang, F., Li, Y., Zhang, H., Huang, E., Gao, L., Luo, W., Wei, Q., Fan, J., Song, D., Liao, J. and Zou, Y., 2017. Anthelmintic mebendazol enhances cisplatin's effect on suppressing cell proliferation and promotes differentiation of head and neck squamous cell carcinoma (HNSCC). Oncotarget, 8(8), p.12968. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355070/
31. Li, Q., Demir, S., Del Río-Álvarez, Á., Maxwell, R., Wagner, A., Carrillo-Reixach, J., Armengol, C., Vokuhl, C., Häberle, B., von Schweinitz, D. and Schmid, I., 2022. Targeting the unwindosome by mebendazol is a vulnerability of chemoresistant hepatoblastoma. Cancers, 14(17), p.4196. https://www.mdpi.com/2072-6694/14/17/4196
32. Guerini, A.E., Triggiani, L., Maddalo, M., Bonù, M.L., Frassine, F., Baiguini, A., Alghisi, A., Tomasini, D., Borghetti, P., Pasinetti, N. and Bresciani, R., 2019. Mebendazol as a candidate for drug repurposing in oncology: An extensive review of current literature. Cancers, 11(9), p.1284. https://www.mdpi.com/2072-6694/11/9/1284