Combining repurposed anthelmintics like fenbendazole with complementary metabolic agents or standard chemotherapeutics significantly enhances anti-tumor activity, modulates cell death pathways, and mitigates treatment-related toxicities.
Drug Repurposing in Oncology: Fenbendazole & Combination Therapies 1. Fenbendazole + Diisopropylamine Dichloroacetate (DADA)
The combination of fenbendazole with diisopropylamine dichloroacetate (DADA) represents a dual-action metabolic and cytotoxic strategy, evaluated in A549 non-small cell lung cancer (NSCLC) models.
Complementary Mechanisms: DADA functions as a pyruvate dehydrogenase kinase (PDK) inhibitor—targeting tumor glycolysis—while also acting as a hepatoprotective agent that counteracts potential drug-induced liver injury from fenbendazole.
Apoptotic & Cell Cycle Cascades:
ROS Generation: The combination stimulates intracellular reactive oxygen species (ROS) accumulation.
Pro-Apoptotic Shift: It alters Bcl-2 family dynamics by downregulating anti-apoptotic Bcl-2 and upregulating pro-apoptotic BAX.
Caspase & PARP Activation: This shift initiates an apoptotic cascade marked by the cleavage and activation of caspase-3, caspase-7, and PARP.
Cycle Suppression: It inhibits Cyclin A and Cyclin E protein expression, blocking cell cycle progression.
In Vivo Efficacy & Tumor Regression: In immunodeficient BALB/c nude mouse xenograft models, combined oral treatment (40 mg/kg fenbendazole + 100 mg/kg DADA) achieved a 50% complete tumor regression rate by Day 60, compared to 11.1% for fenbendazolSource:
Vlachou, I., Parsonidis, P., Mamagkaki, A., Bouris, I., & Papasotiriou, I. (2022). Teaching an old dog new tricks: The case of Fenbendazole. Cancer Treatment and Research Communications, 32, 100601. https://doi.org/10.1016/j.ctarc.2022.100601e alone, 10.0% for DADA alone, and 0% in untreated/cisplatin controls. It also significantly extended overall survival duration.
Safety & Hepatoprotection: After 60 days of daily oral administration, combination therapy maintained normal body weight, blood glucose, hematological counts (RBC, WBC, hemoglobin), kidney markers (urea and creatinine), and liver enzymes (ALT and AST), showing no systemic or tissue toxicity.
2. Synergies with Standard Chemotherapeutics & Radiation
Microtubule Co-Targeting (Paclitaxel): Combining fenbendazole with paclitaxel in HL-60 leukemia cells produces enhanced anti-cancer cytotoxicity by simultaneously targeting distinct aspects of microtubule dynamics and spindle integrity.
Docetaxel & Radiosensitization: Fenbendazole acts as a radiosensitizing and chemo-sensitizing agent, significantly enhancing the anti-tumor cytotoxicity of radiation and docetaxSource:
Vlachou, I., Parsonidis, P., Mamagkaki, A., Bouris, I., & Papasotiriou, I. (2022). Teaching an old dog new tricks: The case of Fenbendazole. Cancer Treatment and Research Communications, 32, 100601. https://doi.org/10.1016/j.ctarc.2022.100601el in mammary tumor models.
Tumor Regression
3. Verification of Caspase-Dependent Execution (Z-VAD-FMK)
To confirm whether caspase activation is strictly required for fenbendazole-mediated cell death across solid tumors, researchers tested the pan-caspase inhibitor Z-VAD-FMK in human epithelial ovarian cancer cells (A2780 and SKOV3):
Pretreatment with Z-VAD-FMK significantly restored cell viability and blocked apoptotic cell death, reducing the apoptosis rate in SKOV3 cells from 54.28% (fenbendazole alone) down to 8.11% (combination).
This confirms that while auxiliary cell death mechanisms like ferroptosis or mitotic catastrophe may occur, the mitochondrial caspase-3 execution pathway remains the indispensable backbone of fenbendazole-induced apoptosis.
Source:
Vlachou, I., Parsonidis, P., Mamagkaki, A., Bouris, I., & Papasotiriou, I. (2022). Teaching an old dog new tricks: The case of Fenbendazole. Cancer Treatment and Research Communications, 32, 100601. https://doi.org/10.1016/j.ctarc.2022.100601