Double repositioning refers to repurposing an existing pharmaceutical agent across different species (e.g., from veterinary care to human medicine) and different disease indications (e.g., from antiparasitic treatment to human oncology) simultaneously.
1. Rationale and Advantages
Overcoming High Attrition & Development Costs: Traditional de novo anticancer drug discovery is costly (estimated at $1 to $2.5 billion per approved drug), time-consuming (taking 10 to 15 years), and carries a high failure rate—only ~5% of candidate molecules entering Phase I clinical trials reach market approval.
Expedited Clinical Translation: Repositioning existing compounds reduces safety risks and shortens development timelines because their general toxicity, safety profile, and pharmacokinetics are already well characterized.
2. Primary Chemical Classes in Double Repositioning
Your sources highlight two main chemical classes of veterinary antiparasitics being evaluated for human cancer therapy:
Benzimidazole (BZ) Carbamates: Includes veterinary and human antiparasitic agents such as fenbendazole (FZ), flubendazole (FLU), mebendazole (MZ), albendazole (ABZ), and ricobendazole (RBZ).
Halogenated Salicylanilides (HS): Include antiparasitic compounds such as niclosamide (Nic), rafoxanide (RFX), and closantel.
3. Divergent Mechanisms of Action
When repurposed as anticancer therapeutics, these two chemical classes exert anti-tumor effects through distinct biological pathways:
Microtubule & Metabolic Disruption (BZ Carbamates): Selectively bind tubulin, inhibiting tubulin polymerization and disrupting the microtubular network essential for cell division and intracellular transport. This disruption blocks cellular glucose uptake by downregulating GLUT transporters and key glycolytic enzymes like hexokinase, starving cancer cells of energy. They also trigger G2/M phase cell cycle arrest and caspase-mediated apoptosis.
Mitochondrial Uncoupling & Pathway Blockade (HS Compounds): Act as uncouplers of mitochondrial oxidative phosphorylation by suppressing key enzymes like succinate dehydrogenase and fumarate reductase, halting ATP generation. At the same time, compounds like niclosamide downregulate major oncogenic signaling cascades, including Wnt/β-catenin, STAT3, Hedgehog, mTOR, and NF-κB pathways.
4. Major Translational & Clinical Challenges
Poor Systemic Bioavailability: Many BZ carbamates and HS compounds suffer from low water solubility, poor intestinal absorption, and rapid hepatic first-pass metabolism, making it difficult for conventional oral doses to reach therapeutic concentrations in human systemic circulation.
Unmonitored Self-Medication: Fueled by social media reports, some late-stage cancer patients self-administer veterinary antiparasitic protocols alongside standard treatments without informing their physicians. This unmonitored use can alter treatment outcomes and confound clinical trial evaluation.
Anti-cancer effects of fenbendazole on 5-fluorouracil-resistant colorectal cancer cells
Park D, Lee J, Yoon S. Anti-cancer effects of fenbendazole on 5-fluorouracil-resistant colorectal cancer cells. Korean J Physiol Pharmacol 2022;26:377-387.
https://www.kjpp.net/journal/view.html?uid=2811&vmd=Full
Double Repositioning: Veterinary Antiparasitic to Human Anticancer
Sultana, T.; Jan, U.; Lee, J.I. Double Repositioning: Veterinary Antiparasitic to Human Anticancer. Int. J. Mol. Sci. 2022, 23, 4315. https://doi.org/10.3390/ijms23084315