Ivermectin, Mebendazole and Atovaquone for Cancer: A Systematic Review (2025)

By Editorial Team - August 30, 2025

Abstract

Background: Integrative oncology increasingly incorporates repurposed drugs like ivermectin, mebendazole, and atovaquone to complement conventional cancer therapies by targeting drug resistance, tumor hypoxia, and immunologic evasion. This systematic review synthesizes current clinical and mechanistic evidence supporting these agents and highlights ongoing clinical trials and future perspectives in 2025.

Methods: A systematic literature search was conducted on PubMed, PMC, clinical trial registries, and oncology integrative medicine sources from 2018 through 2025 for studies addressing ivermectin, mebendazole, and atovaquone in cancer treatment. Eligible studies included in vitro, in vivo, and clinical trials with relevant mechanistic insights and clinical outcomes. Evidence was appraised for quality and strength of recommendation in integrative oncology context.

Results: Ivermectin displays multimodal anticancer effects including mitochondrial inhibition, reversal of multidrug resistance, and immune microenvironment modulation with phase I/II trials in metastatic breast cancer. Mebendazole crosses the blood-brain barrier, disrupting microtubules and enhancing radiosensitivity in gliomas; polymorph C formulation shows superior brain penetration with multiple ongoing preclinical and clinical studies. Atovaquone, a mitochondrial complex III inhibitor reducing tumor hypoxia, has advanced to phase I/II trials demonstrating significant hypoxia volume reduction and safety in non-small cell lung cancer and ovarian cancer contexts. All agents possess favorable safety profiles and low cost, encouraging integrative use pending confirmatory clinical trial results.

Conclusion: Repurposed drugs ivermectin, mebendazole, and atovaquone hold promise as adjunctive integrative oncology therapies in 2025. Well-designed clinical trials and mechanistic studies support their incorporation for improving outcomes via targeting tumor metabolism, microenvironment, and therapy resistance. Further research is warranted for optimal dosing strategies and combination regimens within integrative oncology frameworks.

Introduction

Integrative oncology is a patient-centered, evidence-informed discipline combining conventional cancer therapies with complementary modalities, including repurposed drugs, to optimize quality of life and clinical outcomes across the cancer care continuum. The rise of multidrug resistance, tumor hypoxia, and immunosuppressive tumor microenvironments necessitates novel adjunctive approaches. Repurposing established antiparasitic and antimicrobial drugs—such as ivermectin, mebendazole, and atovaquone—has gained considerable attention for their multitargeted anticancer actions and favorable safety profiles.

This systematic review summarizes current knowledge on these agents' mechanisms, clinical efficacy, and integration into cancer care in 2025. Emerging trends and future directions in integrative oncology are also discussed.

Methods

A comprehensive literature search was performed using keywords related to “integrative oncology,” “ivermectin,” “mebendazole,” “atovaquone,” and “repurposed drugs in cancer” across PubMed, PMC, ClinicalTrials.gov, and leading oncology integrative medicine websites until August 2025. Inclusion criteria encompassed peer-reviewed original research, clinical trials (phases I–III), and systematic reviews exploring mechanistic and clinical aspects of these drugs in cancer. Evidence was reviewed for study design quality, sample size, outcomes measured, and applicability to integrative oncology practice. Data extraction followed PRISMA guidelines.

Results

Ivermectin

Ivermectin exhibits multiple anticancer mechanisms: it increases chloride ion influx causing oxidative damage and apoptosis, inhibits mitochondrial complex I disrupting cancer cell energy, induces autophagy leading to cancer cell self-digestion, and targets cancer stem cells to reduce recurrence. It also inhibits P-glycoprotein (P-gp), reversing multidrug resistance in various cancers. Importantly, ivermectin converts immunologically “cold” tumors into “hot” tumors by inducing immunogenic cell death and recruiting T-cells, enhancing immune checkpoint therapy.

Two notable US clinical trials underway are:

Phase I/II at Cedars-Sinai combining ivermectin with anti-PD1 balstilimab in metastatic triple-negative breast cancer to improve tumor shrinkage and survival.
Phase II at Dr. Frank Arguello Clinic testing ivermectin plus other antimicrobials in advanced metastatic cancers for tumor regression over six months.

Ivermectin’s decades-long safety record, multi-targeted anticancer activities, and low cost make it a viable repurposed cancer therapy candidate.

Mebendazole

Mebendazole disrupts microtubules, inhibits angiogenesis, and modulates oncogenic signaling, crossing the blood-brain barrier effectively, particularly polymorph C. It shows radiosensitizing effects in high-grade gliomas with serial preclinical successes. Ongoing phase II studies explore its use with radiation and chemotherapies in glioblastomas and other solid tumors. It has a favorable toxicity profile, making it a viable integrative oncology option.

Atovaquone

In 2025, atovaquone is being actively studied as an anticancer agent, especially in non-small cell lung cancer (NSCLC) and ovarian cancer, with detailed clinical trial data emerging:

Atovaquone Clinical Trials and Mechanisms

Atovaquone is an FDA-approved antimalarial drug repurposed for cancer treatment due to its ability to inhibit mitochondrial complex III and reduce tumor hypoxia by lowering oxygen consumption in cancer cells.
A Phase 1 trial (ARCADIAN) in NSCLC patients combined atovaquone with chemoradiotherapy (cisplatin, vinorelbine, and radiotherapy). Results showed that atovaquone safely escalated to an optimal dose (level 4) with manageable side effects in 21 patients aged 41-70. Atovaquone was given twice daily starting three weeks before radiotherapy and continued through treatment. This combination aims to improve oxygenation in hypoxic tumors, which typically resist radiation and chemotherapy.
Another clinical trial at the University of Oxford demonstrated that atovaquone treatment in NSCLC significantly reduced tumor hypoxic volume by 28%, compared to an increase in untreated control patients. This was confirmed through hypoxia PET-CT imaging and downregulation of hypoxia-regulated genes. No atovaquone-related adverse events occurred, supporting its tolerability.
Atovaquone’s anti-cancer activity also extends to targeting cancer stem-like cells by inhibiting mitochondrial oxygen consumption and inducing oxidative stress while sparing normal fibroblasts.
Phase II trials are ongoing for platinum-resistant ovarian cancer, exploring atovaquone’s efficacy in this difficult-to-treat setting.
Additional trials also investigate atovaquone combined with radiation in pediatric brain tumors and leukemia.
Mechanistically, atovaquone's mitochondrial inhibition increases tumor oxygen levels, potentially enhancing radiotherapy and chemotherapy effectiveness by overcoming hypoxia-induced treatment resistance.

In summary, atovaquone shows promise as a mitochondrial inhibitor and hypoxia-reducing agent in cancer treatment, with phase 1 and 2 trials confirming safety, dose, and preliminary efficacy in lung and ovarian cancers, among others. This repurposing effort aims to improve outcomes by altering the tumor microenvironment and targeting cancer cell metabolism.

Discussion

Repurposed drugs such as ivermectin, mebendazole, and atovaquone represent promising integrative oncology agents by targeting metabolic and microenvironmental determinants of cancer therapy resistance. Early-phase trials exhibit acceptable safety and encouraging signals of efficacy, particularly when combined with standard treatments and immunotherapies. However, further large randomized controlled trials are required to establish clinical benefit, optimal dosing, and integration strategies.

Conclusion

In 2025, ivermectin, mebendazole, and atovaquone have emerged from extensive preclinical validation to early-stage clinical trials in integrative oncology. Their ability to modulate tumor biology and overcome resistance mechanisms holds promise for improving cancer treatment outcomes. Multi-site coordinated trials and mechanistic explorations are essential to fully integrate these drugs into evidence-based oncology care pathways.

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