INTRODUCTION:

Cancer is among the leading causes of death globally.¹ After cardiovascular disease , cancer is the second most common disease.² Cancer disease that results from very rapid and abnormal cell growth.^3,4,5 Cancer occurs because of a number of factors, such as chemical exposure, environmental, nutritional, and unhealthy lifestyle.⁶ Cancer is serious health threat that causes enormous social and financial obstacles to the healthcare system.⁷ All cancers are classified into 4 categories such as carcinoma, lymphoma , leukaemia , sarcoma.⁸ Novel medication discoveries to lower cancer mortality are made possible by technological advancements and growing understanding of human neoplastic sickness.⁹

Cancer therapies include chemotherapy, targeted treatment, surgery, immunotherapy, radiation and endocrine treatment, which can be used alone or in combined form based on the diagnosis, phase and form of the tumor.^10,11 Chemotherapy is most significant treatment used.¹² In 1971, the FDA approved Mebendazole (MBZ) as an anthelmintic medication for treating parasitic infections.¹³Mebendazole is an accepted benzimidazole applied in medical treatment to treat a variety of helminths through interfering with tubulin polymerization.¹⁴Currently, MBZ has demonstrated preclinical effectiveness in treating pancreatic¹⁵, lung¹⁶, thyroid¹⁷, breast¹⁸, colorectal^19,20,21, and brain^22,23,24 melanoma²⁵,meningioma cancer²⁶, ovarian cancer²⁷ prostate cancer²⁸. The drug repurposing or repositioning is the trending technology used in drug development which was mentioned in Figure 1.

Figure 1: On-target and Off-target drug repurposing

(Source: https://www.intechopen.com/chapters/72744)

MECHANISM:

Mechanism of action has also been shown to have anticancer effects, as disruption of microtubules can result in stopping the cell cycle, inducing apoptosis, and preventing angiogenesis.²⁹The decrease in cancer cell angiogenesis caused by mebendazole has also been shown to contribute to its anti-tumor effects, as angiogenesis is crucial for tumor development and spread.³⁰It blocks the angiogenesis-mediating vascular endothelial growth factor receptor 2 (VEGFR2) which disrupts the formation of new blood vessels.³¹Earlier research have shown that mebendazole is capable of causing apoptosis and G2/M cell cycle arrest in cellular models from colon, breast, glioblastoma, and thyroidcancers.³²Alsoby promoting the expression of caspase-3 and preventing cell division, mebendazole induces apoptosis .Therefore the impact of mebendazole treatment on proteins is related to apoptosis and cell cycle arrest.³³Essential elements of the cytoskeleton, microtubules are involved in intracellular transport, cell shape, and division. In cancer cells, microtubules are often overexpressed and are more dynamic compared to normal cells, making them a target for cancer therapy, mebendazole disrupts microtubule assembly by binding to and depolymerizing microtubules, thereby inhibiting cancer cell proliferation.³⁴Mebendazole specifically prevents the intestinal cells of parasitic worms from synthesizing microtubules, preventing them from absorbing sugar and other nutrients. This results in paralysis and the removal of helminths from the human body. In a number of cancer models, mebendazole has been demonstrated to cause tubulin to depolymerize³⁵. Research has demonstrated that mebendazole exhibits radio sensitizing properties in breast cancer. It also reduced the proportion of stem-like cells by activating the hedgehog mechanism, which is likely responsible for controlling the response of glioma-associated oncogene homolog 1 to DNA damage.⁹Depending on the particular cancer model, mebendazole can modify a number of cancer-related pathways including, MEK/ERK, AP1, ELK1/SRF, MYC/MAX and STAT1/2.³⁶Of all the MAPK pathways, RAS-RAF-MEK-ERK mechanism is the extensively thoroughly researched and is essential for survival of cell, proliferation, and differentiation.³⁷In many mammalian cell types, the ERK pathway is crucial in facilitating the integration of extrinsic signals from mitogens like epidermal growth factor (EGF) into directing cascades which encourage cell growth and division. Canonical receptor tyrosine kinases, like EGFR, are activated in the existence of growth factors and mitogens. This causes the kinases to dimerize, which in turn activates the small GTPase Ras.³⁸This ultimately causes the phosphorylation and activation of ERK through a sequence of phosphorylation activities downstream in the MAPK cascade (Raf-MEK-ERK). The kinase activity of ERK is activated upon phosphorylation, which also phosphorylates several of its downstream targets that are requiring in the control of cell division. ³⁹Uncontrolled growth is caused by defects in the MAP/ERK pathway in many cancers, including melanoma. Numerous substances have the ability to inhibit MAP/ERK pathway steps.^{40, 41} Cell division, transformation, and death are mediated by the transcription factor AP-1. ⁴² Through the transduction of signals from metabolites, cytokines, growth factors, and their receptors, STAT proteins can frame specific metabolic processes that control tumour progression and resistance to therapy. Many cellular activities, such as cell growth, cell differentiation and programmed cell death have been associated with the AP-1 transcription factor.⁴³ The composition of DNA binding dimers, interactions with different binding partners, and post-translational modifications are common ways to control AP-1 mechanism. Additionally, Activator protein-1 transcription factors are linked to a variety of physiological processes, particularly those that determine an organism's lifespan and capacity for tissue regeneration. Numerous interactions related to apoptosis are linked to the Activator protein-1 transcription factor. Several extracellular matrix and genotoxic agents cause AP-1 activity, which may be related to program cell death. ⁴³ Numerous stimuli phosphorylate Jun proteins and raise the transcriptional function of genes dependent on AP-1 by activating c-Jun N-terminal kinases (JNKs) ⁴³. In situations where cells undergo apoptosis, there have been reports of rise in the levels of the proteins Fos and Jun as well as JNK activity.⁴⁴ There is rapidly increasing evidence linking a number of cancers to down reguslation of the JAK/STAT pathway.⁴⁵The process of dimerization occurs when different ligands, typically cytokines like interleukins and interferons, attach to cell-surface receptors, bringing the receptor-associated JAKs closer together. Subsequently, through a process known as transphosphorylation, the JAKs phosphorylate one another on tyrosine residues found in areas known as activation loops, increasing the activity of their kinase domains. Subsequently, the tyrosine residues of the receptor are phosphorylated by the activated JAKs, creating receptor sites for proteins that have SH2 domains. ⁴⁶ STATs attach to the phosphorylated tyrosines on the receptor using their SH2 domains. The JAKs phosphorylate the tyrosines afterwards, leading to the detachment of the STATs from the receptor. These activated STATs initiate transcription of the target gene by forming hetero- or homodimers and moving towards the cell nucleus after binding the phosphorylated tyrosine of the opposing STAT with their SH2 domains.⁴⁷ Elevated STAT activation has been connected to cancer; specifically, elevated STAT5 and STAT3 activation is primarily associated with more severe tumours.⁴⁸ Excessive STAT3 function is linked to a greater likelihood of melanoma recurrence post-treatment, and unusually elevated functions of STAT5 is linked to higher risk of patient death in prostate cancer.^{48, 49} the development of breast cancer may also be influenced by altered JAK-STAT signalling. During pregnancy and puberty, when JAK-STAT mechanism is over activated, cancer may result because it can promote apoptotic cell death division and decrease in the mammary glands, which are located inside the breasts. ⁵⁰

PRECLINICAL STUDIES:

Numerous preclinical models have proved the anticancer result of mebendazole in several cancer types. For example, Studies have shown that mebendazole can hinder the growth of lung cancer cells in laboratory experiments and in living organisms. A study demonstrated that mebendazole can hinder the growth of non-small cell lung cancer cells by inducing cell death and stopping the cell cycle in the G2/M phase.⁵¹In research, mebendazole was also found to reduce the improvement and metastasis in breast cancer cells.³³ Due to apoptosis and preventing angiogenesis, mebendazole was observed to prevent triple-negative breast cancer cells from growing in a study. ³²Additionally, mebendazole has been demonstrated to have anticancer effects in gastric cancer. The anthelmintic medication mebendazole hinders the development, movement, and infiltration in stomach cancer cell model.⁵³Mebendazole provides an ideal effective therapy for brain tumours.⁵⁴By targeting signalling pathways linked to cell division, cell death, invasion/migration, or both, mebendazole has capability to pass the blood-brain barrier and inhibit the malignant progression of gliomas. Furthermore, mebendazole can make glioma cells more susceptible to radiation or conventional chemotherapy.¹⁰Mebendazole has been shown to have anticancer properties in colon and pancreatic cancer. Mebendazole was also found to control the development of pancreatic cancer cells in laboratory studies and in animal by causing apoptosis and inhibiting angiogenesis. The dose of mebendazole used for mouse pancreatitis study is 35 mg/kg. ¹⁵Mebendazole may inhibit tumour growth and liver metastasis, as well as the onset of pancreatic cancer precursor lesions, stromal desmoplastic reaction, and other activities.¹⁵

PHARMACOKINETICS:

Mebendazole has a quick first pass metabolism and is poorly absorbed, most likely as a result of its insolubility in conventional solid dosage tablet formulations.⁵⁵Only 20% of the oral dosage forms enters into bloodstream because of mebendazole's first-pass metabolism, which reaches its maximum plasma concentration 2-4 hours after administration. It is well known that dosing with a high-fat meal will somewhat enhance bioavailability. When mebendazole is taken continuously, compared to a single dose, the plasma concentration rises by a factor of two to three .⁵⁶Rapid metabolism involving decarbamylation and keto-reduction, followed by conjugation, inactivates it.⁵⁵ This drug mainly undergoes hepatic metabolism, with 5–10% of its bioavailability occurring in urine. Its biological half-life is 3-6 hours.³⁶Cimetidine interacts with albendazole and mebendazole to prevent metabolism and has been shown to raise mebendazole plasma levels. The fact that this interaction offers a method crucial to enhance bioavailability in the event that it's the anti-cancer effect makes it potentially significant and clinically relevant. Considering that cimetidine might also possess some anti-tumour properties. ⁵⁶

CLINICAL TRIALS:

Studies on patients with advanced cancer have demonstrated mebendazole's anticancer effects in both case studies and experimental cancer models. In this study eleven patients with gastrointestinal cancer were included. Blood sampling, clinical monitoring, and CT scans were used to analyze safety and potency of the treatment. There were no very adverse effects noted .⁵⁷In human toxicity studies, mebendazole has demonstrated efficacy against a variety of cancer models, including colon, pancreatic, thyroid, glioblastoma multiforme, breast, and medulloblastoma. During phase 1 clinical study involving individuals newly detected glioma, MBZ was well tolerated .³³A different phase 1 and 2 study looked at the effectiveness and safety of mebendazole when used with chemotherapy medications such as carboplatin, vincristine and temozolomide in paediatric patients with gliomas. The study found that for patients with low-grade gliomas, especially those with pilomyxoidastrocytoma’s, mebendazole in combination with carboplatin, vincristine and temozolomide may offer an extra therapeutic benefit with better progression-free and overall existence .⁵⁸The 48-year-old male patient had adrenocortical carcinoma with metastases to his liver. Conventional treatments included radiation therapy, bevacizumab, streptozotocin, 5-fluorouracil, and mitotane, but they were ineffective and intolerable. During the treatment of mebendazole, patient experienced a satisfactory quality of life and no clinically adverse effects. Hepatic metastatic lesions were reduced by mebendazole (200 mg daily) for 19 months, and the lesions stabilized for an additional 19 months.³⁰

SAFETY:

Mebendazole has been utilized as an anthelmintic drug for over 44 years and has a well-established safety profile.¹⁹The safety and tolerability of mebendazole was shown in a phase 1 clinical study involving individuals along high-grade glioma. ¹³In 39 clinical trials involving 6276 participants and years of post-marketing surveillance, the safety of mebendazole has been documented .²⁹ it is not recommended to use mebendazole while pregnant. It is advisable to proceed with caution when treating infants under the age of two, mainly because there is insufficient data in these cases. ⁵⁶ It is safe to give mebendazole in high doses for prolonged periods of time to both adults and children.¹⁰

TOXICITY:

Mebendazole is safe with minimal adverse effects.³⁰ The most frequently reported side effects included nausea, vomiting, decreased appetite, and abdominal pain.⁵⁷In some conditions, liver toxicity, severe myelosuppression may observe.²²Mebendazole has minimal toxicity, however in cases of severe infection and parasite excretion, patients may experience temporary symptoms like diarrhoea and pain in abdomen. Rarely, hypersensitivity reactions have been documented, including angioedema, rash and urticaria .⁵⁶Because of low toxicity profile and capability to pass the blood brain barrier, mebendazole is a desirable anticancer therapy.²When differentiated with other microtubule inhibitors like paclitaxel and vincristine the level of toxicity in children is especially low.¹

DISCUSSION:

Mebendazole is an anthelmintic drug that has shown anticancer effects in preclinical assessment and clinical trials. These above studies presented in this article suggest that mebendazole may have a promising contribution in the treatment of different classification of cancer.⁵⁷ Research conducted in laboratories and in live organisms has demonstrated that mebendazole inhibits tumour cell development by initiating a halt in the cell cycle and triggering death of cell. Mebendazole appears to have an effect on microtubules, leading to disruption of the cytoskeleton and interference with the transport of nutrients and other molecules within cells.³⁴ Furthermore, it has been discovered that mebendazole prevents vasculogenesis, that is necessary during the development and metastasis of tumours.²⁹Mebendazole also act on various cancer related pathways such as MEK/ERK, STAT1/2, AP1, ELK1/SRF, and MYC/MAX in which mebendazole inhibit growth of cancer cells.³⁶Mebendazole shows anticancer effect with low toxicity profile.¹⁰ additionally its direct anticancer activity, mebendazole has also been demonstrated to enhance the potency of another anticancer drug. Mebendazole in combination with cisplatin, this could potentially lead to the development of combination therapies that could improve the overall efficacy of cancer treatment.⁵⁹Also, in case of mebendazole in combination with sulindac which is decrease the occurrence of a tumour in a colon cancer.¹⁹ In cancer therapy, mebendazole in combination with radiation therapy reduces cell viability and triggers apoptosis.²⁶ Because mebendazole has anti-tubulin characteristics that have been demonstrated to prevent tubulin polymerization in different cancerous cell lines, it is being considered as a replacement for vincristine in brain tumour treatment. Mebendazole has been shown in several preclinical studies to be effective as a preventor of several procedures responsible for resistance of tuomor.²⁹Mebendazole has anticancer properties against a variety of cancer types, as shown by numerous preclinical investigations. Mebendazole effective in case of gastric cancer, brain tumour, lung cancer, colon, pancreatic cancer according to various preclinical studies. ¹⁰In combination with other drugs, mebendazole shows its safety and efficacy in phase 1 and 2 clinical trials in glioma patients. ⁵⁸Minimal side effects with safety profile are seen in case of mebendazole.³⁰ Abdominal pain, nausea, decrease appetite and hypersensitivity have been documented .^56,57Overall, the preclinical and clinical data presented in this article suggest that mebendazole has potential as a safe and effective anticancer drug. However, further research is needed to fully establish its role in cancer treatment and to optimize its use in combination with other therapies.⁵⁷

CONCLUSION:

Mebendazole is an anthelmintic drug that has shown promising action as a potential anticancer drug. Its ability to disrupt microtubule assembly results in halt in cell division process, apoptosis, and prevention of angiogenesis in cancerous cells. Numerous preclinical researches have demonstrated anticancer properties of mebendazole in numerous cancer types, and early-phase clinical trials have shown that mebendazole is well-tolerated and has some efficacy in individual with advanced solid tumours. Mebendazole is used in treatment of different cancers like pancreatic, colon, brain, breast, thyroid, ovarian cancer. The capacity of mebendazole to approach several targets can therefore enhance the effectiveness of anticancer treatment and aid in overcoming obtained resistance to traditional chemotherapy. Current clinical studies will ascertain more information on effectiveness of mebendazole as a cancer therapy. Mebendazole has a well-established safety profile, pharmacokinetics, low cost and a low toxicity profile in preclinical assessment, indicating it a potential candidate as an anticancer agent in future. Further study is required for optimized understanding of mechanism of action of mebendazole in cancer cells as well as to optimize its usage as a cancer therapy.

LIST OF ABBREVATIONS:

ERK- Extracellular signal regulated kinase; AP 1- Activated protein 1; STAT – Signal transducer and activator of transcription; ELK 1- ETS Like-1 protein; SRF – Serum response factor; MYC-Myelocytomatosis oncogene; MAX-MYC-associated factor X; RAF-Rapidly Accelerated Fibrosarcoma; RAS – Rat sarcoma; MAPK- Mitogen activated protein kinase; EGFR-Epidermal growth factor rate; JAK-Janus tyrosine kinase

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Received on 18.03.2024 Revised on 16.07.2024

Accepted on 05.10.2024 Published on 10.04.2025

Available online from April 12, 2025

Research J. Pharmacy and Technology. 2025;18(4):1619-1624.

DOI: 10.52711/0974-360X.2025.00232

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.