Repurposed Drugs in Overcoming Chemoresistance: Exploring how non-cancer drugs can reverse resistance to standard chemotherapy agents.

By Editorial Team
Repurposed non-cancer drugs have emerged as a powerful strategy to overcome chemo-resistance in cancer therapy by targeting multiple mechanisms that cancer cells use to evade standard chemotherapy. This approach offers faster, cost-effective alternatives to developing new drugs and leverages existing safety and pharmacokinetic knowledge.

How Repurposed Drugs Reverse Chemoresistance

  • Multi-targeting cancer hallmarks and signaling pathways: Many repurposed drugs act on key cancer hallmarks such as sustaining proliferative signaling, evading growth suppressors, resisting cell death, and activating invasion/metastasis. They modulate pathways involved in drug resistance, including PI3K-AKT, WNT, NOTCH, and TGF-β, thereby restoring sensitivity to chemotherapy3.

  • Modulating tumor microenvironment (TME): Repurposed drugs can alter the TME to reduce protective niches for cancer cells, enhance immune responses, and disrupt stromal support that contributes to drug resistance32.

  • Targeting metabolic adaptations: Some repurposed agents inhibit altered cancer metabolism (e.g., glycolysis), which is often linked to resistance, thus sensitizing tumors to chemotherapeutics13.

  • Inducing alternative cell death pathways: By activating apoptosis, autophagy, ferroptosis, or necrosis, repurposed drugs can kill cancer cells that have become resistant to conventional apoptosis-inducing chemotherapies4.

  • Reactivating tumor suppressor functions: Drugs that restore or mimic the activity of tumor suppressors like p53 can overcome resistance mechanisms that rely on their inactivation3.

  • Combination therapy to overcome resistance: Repurposed drugs are often used in combination with standard chemotherapy to attack cancer cells on multiple fronts, preventing or reversing resistance development246.

Examples and Advantages

  • Drugs originally developed for non-oncology indications—such as antidiabetics (metformin), antiparasitics (fenbendazole, mebendazole, ivermectin), and others—have demonstrated efficacy in preclinical and clinical studies in reversing chemoresistance16.

  • Repurposing reduces the drug development timeline from approximately 8 years to 3-4 years and significantly cuts costs, making it a practical strategy to address the urgent need for effective treatments against resistant cancers5.

  • The existing safety profiles of these drugs facilitate rapid clinical translation and combination with existing therapies6.

Summary

Repurposed drugs represent a promising and pragmatic approach to overcoming chemoresistance by exploiting their multi-target effects, established safety, and ability to be integrated into combination regimens, ultimately improving cancer treatment outcomes2346.

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