Mebendazole

Mebendazole's current off-label status for cancer treatment highlights the ongoing need for rigorous, large-scale clinical trials to definitively establish its efficacy, optimal dosing, and long-term safety. The overall picture is one of cautious optimism, emphasizing the need for continued research to fully realize its therapeutic potential. Preclinical studies have demonstrated its efficacy across a broad spectrum of cancer types, often showing synergistic effects when combined with conventional chemotherapies and radiotherapy.

Synergy with Conventional Chemotherapeutics

Numerous cell-line studies have demonstrated significant synergy between mebendazole and standard chemotherapeutics. For instance, mebendazole effectively overcomes cisplatin resistance in human ovarian cancer cells and synergizes with cisplatin to suppress cell proliferation, induce apoptosis, and blunt tumor growth in xenograft models. It also potentiates the effect of temozolomide in resistant gliomas, and a triple combination of Temozolomide, Vinblastine, and Mebendazole (TVM) has been suggested as a therapeutic alternative for temozolomide-tolerant gliomas. In head and neck squamous cell carcinoma cell lines, mebendazole demonstrated a more potent antiproliferative effect than cisplatin in vitro and a synergistic effect when combined with cisplatin. Synergy has also been observed with paclitaxel and docetaxel.

Synergy with Radiotherapy

Mebendazole has shown significant potential in enhancing radiation sensitivity and preventing metastasis, partly by reducing cancer stemness. It exhibits radiosensitizing properties in breast cancer and glioma cells, hindering DNA repair mechanisms and preventing the radiation-induced conversion of triple-negative breast cancer (TNBC) cells into cancer stem cells. A synergistic effect was observed when combining mebendazole with radiation in an intracranial mouse model of malignant meningioma, leading to increased median survival and delayed tumor growth.

Mechanism	Description	Key Molecular Targets / Pathways	Cancer Types Studied
Microtubule Disruption	Binds to β-tubulin, prevents polymerization, causes mitotic arrest, and spindle collapse	β-tubulin, mitotic spindle	Glioblastoma, colorectal, melanoma, lung, breast
Apoptosis Induction	Triggers programmed cell death through the intrinsic pathway	Caspase-3/7/9, cytochrome c, PARP cleavage, Bcl-2 downregulation	Melanoma, lung, AML, glioblastoma
Anti-Angiogenesis	Inhibits tumor blood vessel formation	VEGFR2, HIF-1α, VEGF	Lung, glioblastoma, colon, melanoma
MAPK Pathway Inhibition	Synergizes with MEK inhibitors to suppress ERK signaling	MEK, ERK	NRAS-mutant melanoma
Wnt/β-catenin Pathway Inhibition	Blocks β-catenin/TCF4 transcriptional activity via TNIK inhibition	TNIK, β-catenin, c-Myc, Cyclin D	Colorectal cancer, polyposis models
Hedgehog Pathway Inhibition	Suppresses GLI1 expression and cilia-dependent SHH signaling	GLI1, Smoothened (via cilia disruption)	Medulloblastoma, basal cell carcinoma
Cancer Stem Cell Targeting	Inhibits self-renewal of leukemic and possibly solid tumor stem cells	c-Myb, colony-forming potential	AML, colorectal, breast
Immune Modulation	Activates M1 macrophages, enhances NK and T cell cytotoxicity	CD80/CD86, IL-1β, granzyme B, perforin	Breast, glioblastoma, lung
Autophagy Modulation	Induces protective autophagy that can be exploited by combining with autophagy inhibitors	LC3B, Beclin-1, p62	Melanoma, glioblastoma
Metastasis Suppression	Reduces migration, invasion, and formation of metastatic lesions	Matrix metalloproteinases (MMPs), VEGFR, tubulin	Lung, melanoma

	Specific Adverse Event/Interacting Drug	Description/Clinical Implication
Common Side Effects	Stomach pain, discomfort, bloating, wind	Generally mild, can be managed with dietary adjustments or symptomatic relief.
	Nausea, vomiting, diarrhea	Common gastrointestinal upset; hydration is important for diarrhea.
	Loss of appetite, rash, headache, fatigue	General systemic symptoms; fatigue and headache are common at higher doses.
Severe Side Effects	Neutropenia, Marrow Aplasia	Low white blood cell count, bone marrow failure; rare, but risk is higher with high/long-term doses. Usually reversible.
	Elevated Liver Enzymes (ALT, AST)	Signs of liver problems; reversible with dose adjustment/discontinuation. Monitor LFTs.
	Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN)	Severe, life-threatening skin reactions. Strictly contraindicated with metronidazole.
	Serious Allergic Reactions	Breathing problems, wheezing, swelling of face/lips/throat, hives, dizziness. Requires immediate medical attention.
Drug Interaction	Metronidazole	Severe skin reactions (SJS/TEN), contraindicated.
	Nitroglycerin + Metformin	Interference with antitumor effects, leading to more tumor progression in animal studies.
	Disulfiram + Metformin Diclofenac + Metformin	Blocked anticancer activity in animal studies.
	Carbamazepine, Cimetidine, Phenytoin, Phenobarbital, Primidone, Ritonavir, Sodium Iodide (I-123, I-131)	Moderate interactions; typically require caution, monitoring, or alternative drugs.