Repurposing Common Drugs to Overcome Chemotherapy Resistance

Introduction to Drug Repurposing in Overcoming Chemotherapy Resistance

Understanding Drug Repurposing in Cancer

Drug repurposing is the strategy of using existing, clinically approved medications for new therapeutic purposes, particularly in oncology. This approach can significantly shorten the time and reduce the cost compared to developing new cancer drugs from scratch. Many drugs initially approved for other diseases, including diabetes and hypertension, have shown promising anticancer effects through various mechanisms.

The Challenge of Chemotherapy Resistance

One of the biggest hurdles in cancer treatment is chemotherapy resistance. Tumors often develop mechanisms to evade the effects of cytotoxic drugs, leading to treatment failure and cancer recurrence. This resistance can be driven by genetic mutations, drug efflux pumps, cancer stem cells, and the complex tumor microenvironment, making successful therapy increasingly difficult.

How Repurposed Drugs Can Help

Repurposed drugs offer a valuable option to overcome this challenge. With their known safety profiles and established clinical use, they can target cancer hallmarks such as cell proliferation, apoptosis evasion, and tumor metabolism. Additionally, some repurposed agents modulate the immune environment or target cancer stem cells, potentially restoring the sensitivity of tumors to chemotherapy and improving patient outcomes.

Understanding Chemotherapy Resistance: The Hidden Barrier

What causes cancer drug resistance and what can be done?

Cancer drug resistance is a major challenge especially in metastatic cancers, where treatments lose effectiveness over time. This resistance can arise from genetic mutations in cancer cells that alter drug targets or activate survival pathways. Proteins such as P-glycoprotein (P-gp) act as efflux pumps to expel chemotherapy drugs from cancer cells, leading to multidrug resistance.

Molecular and cellular mechanisms of chemoresistance

At the molecular level, chemoresistance involves DNA repair mechanisms that counteract drug-induced damage, mutations in oncogenes and tumor suppressor genes, and activation of signaling pathways like PI3K/Akt, MAPK/ERK, NF-κB, and EMT. Cancer stem cells (CSCs) contribute strongly to resistance due to their enhanced DNA repair, quiescence, and expression of efflux transporters such as ABCB1 and ABCG2.

Resistance also involves epigenetic modifications like DNA methylation and histone acetylation that alter gene expression to survive therapy. Tumor cells evade death by suppressing apoptosis and can employ alternative forms of cell death such as autophagy and necroptosis to maintain survival under chemotherapeutic stress.

Role of tumor heterogeneity and microenvironment

Tumor heterogeneity—genetic and phenotypic variation within cancer cells—and the tumor microenvironment (TME) greatly influence chemoresistance. The TME contains diverse cell types including tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and immune cells that secrete growth factors and cytokines, creating a niche that supports tumor survival and drug resistance.

Hypoxia and acidity within the microenvironment activate survival pathways that blunt drug effectiveness. Intercellular communication through exosomes transfers molecules such as microRNAs that modulate resistance by promoting EMT, immune evasion, and metabolic reprogramming.

Significance of drug efflux pumps and genetic mutations in resistance

Efflux pumps like P-glycoprotein (ABCB1), MRP1 (ABCC1), and BCRP (ABCG2) actively transport drugs out of cancer cells, reducing intracellular drug concentration and efficacy. Genetic mutations in pathways such as EGFR, KEAP1-NFE2L2, and others confer additional resistance by modifying drug target structures or enhancing DNA repair.

Strategies to overcome chemoresistance

Combating chemoresistance requires a multifaceted approach: precision medicine to target specific mutations, combination therapies attacking multiple survival pathways, and immunotherapies like checkpoint inhibitors that activate the immune system. Nanotechnology enables improved drug delivery directly to tumor cells, overcoming efflux and microenvironmental barriers.

Targeting CSCs and tumor microenvironment components, along with utilization of small molecule inhibitors and epigenetic therapies, form promising avenues. Early detection of resistance markers using genomic tools can guide personalized treatment to improve patient outcomes.

Aspect	Role in Chemoresistance	Therapeutic Strategies
Genetic Mutations	Alter drug targets and activate survival pathways	Precision medicine, targeted inhibitors
Drug Efflux Pumps	Expel chemotherapeutic agents	Efflux pump inhibitors, improved drug delivery
Tumor Microenvironment	Supports survival via cytokines, hypoxia, acidity	Immune therapies, microenvironment targeting
Cancer Stem Cells (CSCs)	Quiescence, efflux pump expression, DNA repair	CSC-targeted agents, differentiation therapies
Epigenetic Modifications	Alter gene expression related to drug response	Epigenetic drugs, combination therapies
Signaling Pathways	PI3K/Akt, NF-κB, EMT promote resistance and survival	Pathway inhibitors, combination treatments

Cancer Stem Cells: Key Players in Drug Resistance and Tumor Recurrence

Characteristics and role of CSCs in chemoresistance

Cancer stem cells (CSCs) are a specialized subpopulation within tumors that drive tumor progression, metastasis, and notably, resistance to chemotherapy. Their intrinsic properties such as quiescence (a dormant state), overexpression of drug efflux transporters like ABC transporters, robust DNA repair capabilities, and the ability to evade apoptosis make them particularly resilient against conventional cancer treatments. These properties allow CSCs to survive chemotherapy and later repopulate tumors, leading to relapse and metastasis. Cancer stem cells (CSCs)

Signaling pathways regulating CSCs

Several crucial signaling pathways help maintain CSC characteristics and promote drug resistance. These include the Wnt/β-catenin, Notch, Hedgehog (Hh), and TGF-β pathways. Activation of these pathways sustains CSC stemness, proliferation, and survival despite therapeutic pressure. For example, Wnt/β-catenin signaling supports self-renewal, while Hedgehog signaling modulates the tumor microenvironment to favor CSC maintenance. Together, these pathways form an intricate network that protects CSCs from chemotherapy-induced cell death. Signaling pathways in CSC regulation

Targeting CSCs to improve therapeutic outcomes

Targeting CSCs represents a promising strategy to overcome chemoresistance and improve treatment efficacy. Non-cancer drugs with known safety profiles, such as metformin, aspirin, and all-trans retinoic acid, have shown potential in disrupting CSC-related pathways and sensitizing CSCs to therapy. Additionally, micronutrients like vitamins C, D, and ATRA may also affect CSC populations. Combining conventional chemotherapy with repurposed drugs that interfere with CSC signaling or induce differentiation can reduce tumor recurrence. Ongoing clinical trials are investigating these approaches, aiming to enhance eradication of CSCs and achieve more durable cancer remissions. Drug repurposing strategy

Principles and Advantages of Drug Repurposing in Oncology

What is drug repurposing and why is it significant in cancer treatment?

Drug repurposing is the process of identifying new therapeutic indications for drugs that have already been approved for other diseases. In oncology, this approach harnesses the existing safety data and known pharmacological profiles of these medications to expedite cancer therapy development. It is significant because it offers a strategic solution to the lengthy, costly, and complex nature of traditional cancer drug development (Drug repurposing in oncology).

Definition and scope of drug repurposing

Drug repurposing goes beyond simply finding new uses; it includes the exploration of clinically approved drugs to target various cancer types and mechanisms. These drugs can interact with cancer cell hallmarks such as proliferative signaling, apoptosis resistance, angiogenesis, and metastatic capabilities. By leveraging computational methods like molecular docking and experimental models including organoids, researchers can identify drugs that affect cancer growth and survival pathways (Drug repurposing for cancer).

Economic and time-efficiency benefits

Repurposing reduces the typical drug development timeline from over a decade to as little as three to twelve years. This accelerated development is largely due to known safety and toxicity profiles, which diminishes the need for early-stage testing. Additionally, repurposed drugs are often off-patent and available as generics, making treatments more affordable and accessible globally, especially in resource-limited settings. This cost-effectiveness addresses the rising global cancer burden by offering economically viable therapies (ReDO Project overview).

Common examples of repurposed drugs in cancer treatment

Several non-cancer drugs have already found a role in oncology. For instance, arsenic trioxide and all-trans retinoic acid are established treatments for acute promyelocytic leukemia. Thalidomide, initially used for leprosy, has been repurposed to treat multiple myeloma (thalidomide for multiple myeloma. Metformin, a widely used anti-diabetic medication, demonstrates promising effects in lowering the incidence and progression of cancers such as breast, colorectal, prostate, and pancreatic (Repurposing anti-diabetic drugs in cancer therapy). Beta blockers like propranolol have shown potential in reducing tumor angiogenesis and modulating immune responses (Repurposing anti-diabetic drugs for cancer therapy.

These examples underscore the broad scope and potential impact of drug repurposing in cancer care, harnessing existing therapies to improve treatment outcomes faster and more affordably (Antitumor properties of repurposed drugs.

Repurposed Drugs Targeting Key Hallmarks of Cancer

How do repurposed drugs inhibit key cancer hallmarks?

Repurposed drugs combat cancer by targeting fundamental biological processes essential for tumor growth and survival. These drugs influence hallmarks such as sustaining proliferative signaling, evading growth suppressors, resisting cell death, inducing angiogenesis, and enabling metastasis. Many act by modulating critical signaling pathways known to be dysregulated in cancer, including PI3K/AKT, mTOR, and NF-κB. Others interfere with cellular metabolism, immune evasion, or tumor microenvironment factors to restore cancer cell sensitivity to therapies or inhibit tumor progression.

What are examples of repurposed drugs targeting proliferation?

• Salidroside: Inhibits tumor cell proliferation by suppressing the PI3K/AKT pathway, demonstrated in cancers like nasopharyngeal carcinoma and prostate cancer.
• Leflunomide: Blocks tumor growth through inhibition of pyrimidine synthesis, affecting breast and prostate cancer models.
• Metformin: Activates AMPK, leading to mTOR inhibition and cell cycle arrest, reducing cancer stem cell renewal.
• Disulfiram: Traditionally an alcoholism drug, it inhibits glycolysis and enhances oxidative stress in cancer cells, disrupting their energy metabolism.
• EGCG (Epigallocatechin 3-gallate): Inhibits telomerase activity and promotes apoptosis in pancreatic and breast cancer cells.

Which repurposed drugs induce apoptosis and cell death?

• Triptolide: Triggers non-apoptotic cell death such as pyroptosis, necrosis, and autophagy, offering a multi-modal approach to killing cancer cells.
• Curcumin: Modulates the tumor mechanical microenvironment and inhibits invasion, aiding apoptotic pathways.
• Ascorbic acid (Vitamin C): Reduces hypoxia-inducible factor 1-alpha (HIF-1α), impairing tumor growth and enhancing oxidative damage.
• Celecoxib: Suppresses tumor-promoting inflammation and supports apoptosis to improve chemotherapy response.

How do repurposed drugs affect angiogenesis and metastasis?

• Artemisinin derivatives: Exhibit anti-angiogenic effects by inhibiting tumor blood vessel formation.
• Dihydroartemisinin (DHA): Suppresses proliferation of endothelial cells and reduces NF-κB activity, a driver of inflammation and angiogenesis.
• Mebendazole: Interferes with microtubule polymerization, reducing tumor invasiveness and metastasis.
• Statins (e.g., Simvastatin): Activate mutant p53 and reduce cancer cell migration, potentially inhibiting metastasis.
• Oleanolic acid and Tanshinone IIA: Modulate immune responses and influence cell death pathways, indirectly affecting tumor progression and metastatic potential.

This array of repurposed drugs demonstrates diverse mechanisms targeting cancer's complex biology, providing promising adjunct or alternative therapies that leverage established safety profiles for faster clinical adoption.

Metformin: From Diabetes to Cancer Therapeutics

How does metformin contribute to overcoming chemotherapy resistance?

Metformin, originally an antidiabetic medication, has gained attention for its potential to combat chemotherapy resistance in cancer treatment. It mainly exerts its effects by activating the AMP-activated protein kinase (AMPK) pathway. Activation of AMPK leads to inhibition of the mammalian target of rapamycin (mTOR) and PI3K/Akt signaling pathways, both of which play crucial roles in cancer cell growth and survival. Metformin can thereby induce cell cycle arrest and promote apoptosis in cancer cells. Furthermore, it reduces cancer stem cell populations, which are often responsible for tumor progression, metastasis, and resistance to conventional chemotherapy (Metformin repurposing for cancer; Cancer stem cells (CSCs); Chemoresistance in cancer).

What are Metformin’s mechanisms targeting cancer cells?

Metformin’s anticancer effects revolve around metabolic regulation and interference with cancer-specific signaling:

• AMPK Activation: Serves as a cellular energy sensor; when activated, it halts proliferation and metabolic pathways favoring cancer cell growth.
• mTOR Inhibition: Decreases protein synthesis and cell growth, disrupting tumor progression.
• PI3K/Akt Pathway Suppression: Reduces survival signals in tumor cells.
• Cell Cycle Arrest and Apoptosis Induction: Limits tumor cell replication and triggers programmed cell death.
• Cancer Stem Cell Reduction: Targets and diminishes cells responsible for drug resistance and tumor relapse.

Collectively, these mechanisms help sensitize cancer cells to chemotherapy and may overcome intrinsic and acquired resistance (Metformin and cancer therapy; Cellular components of TME; Cancer stem cells (CSCs)).

What clinical evidence supports metformin’s anticancer potential?

Epidemiological studies and clinical trials have provided encouraging data:

• Cancer Incidence and Mortality: Diabetic patients on metformin have shown a 20–30% reduction in overall cancer incidence and mortality.
• Supported Cancers: Associations include decreased risks for colorectal, breast, pancreatic, prostate, lung, cervical, and ovarian cancers.
• Adjunct Therapy: Preclinical and some clinical trials suggest metformin can improve outcomes when combined with chemotherapy, radiotherapy, and immunotherapy.
• Ongoing Investigation: Multiple clinical trials are ongoing to evaluate its efficacy as adjunctive cancer therapy, particularly in patients with diabetes and certain genetic backgrounds.

These findings underscore metformin as a promising repurposed agent in cancer therapy (Metformin clinical evidence in cancer; Metformin repurposing for cancer; Drug repurposing for cancer therapy.

What challenges arise in translating preclinical findings to clinical practice?

Although preclinical studies show promise, translating these benefits clinically faces hurdles:

• Dosage Discrepancies: Effective doses in laboratory cancer models are often much higher than clinically safe antidiabetic doses.
• Pharmacokinetics: Differences in drug metabolism and tissue distribution between humans and models affect efficacy.
• Patient Heterogeneity: Variable genetic backgrounds, co-morbidities, and cancer subtypes influence responses.
• Trial Outcomes: Many clinical trials have yielded modest or inconclusive benefits, with some terminated early.
• Confounding Factors: Observational benefits may be influenced by factors related to diabetes control rather than direct anticancer action.

Further well-designed, adequately powered clinical trials are needed to establish clear guidelines for metformin use in oncology (Challenges in drug repurposing; Repurposing anti-diabetic drugs in cancer therapy.

---

Aspect	Description	Implication
Mechanism	AMPK activation, mTOR & PI3K/Akt inhibition	Tumor growth suppression
Clinical Evidence	Reduced cancer risk & mortality in diabetics	Potential adjunct therapy
Challenges	Dose translation, heterogeneity, inconclusive trials	Need for precise clinical protocols

Metformin exemplifies the potential of repurposed drugs that leverage known safety profiles for innovative cancer therapies, especially in overcoming chemotherapy resistance.

Anti-Hypertensive Drugs with Promising Anti-Cancer Effects

Types of anti-hypertensive drugs repurposed in cancer therapy

Anti-hypertensive medications represent a valuable category of repurposed drugs for cancer therapy. Common classes of these drugs include:

• Beta-blockers (e.g., propranolol, atenolol)
• Angiotensin-Converting Enzyme (ACE) inhibitors (e.g., captopril, enalapril)
• Angiotensin II Receptor Blockers (ARBs) (e.g., losartan, irbesartan, candesartan)
• Calcium channel blockers
  These drugs, originally used to manage high blood pressure, are under evaluation across a range of cancers such as pancreatic, breast, colorectal, prostate, lung, ovarian, and brain cancers.

Mechanisms of action including angiogenesis inhibition and apoptosis induction

Anti-hypertensive drugs exhibit several mechanisms targeting cancer progression:

• Inhibition of Tumor Angiogenesis: Many of these drugs reduce new blood vessel formation essential for tumor growth. For example, ACE inhibitors and ARBs suppress vascular endothelial growth factor (VEGF) signaling, reducing angiogenesis.
• Induction of Cancer Cell Apoptosis: Some drugs, like captopril, have been shown to upregulate tumor suppressor proteins such as p53, triggering programmed cell death in tumors.
• Modulation of Tumor Microenvironment: Beta-blockers like propranolol downregulate pathways such as p-AKT, p-ERK, and p-MEK, disrupting proliferative signaling and enhancing immune response.
• Enhancing Chemosensitivity: By modifying tumor stroma and blood flow, these drugs can improve delivery and effectiveness of chemotherapy agents.
  All these mechanisms are detailed in studies of Mechanisms of anti-hypertensive drugs in cancer inhibition.

Examples reaching advanced clinical trial phases

Several anti-hypertensive drugs have progressed into advanced clinical trials indicating promising therapeutic potential:

• Propranolol: A non-selective beta-blocker that has reached Phase IV clinical trials against benign tumors like infantile capillary hemangioma and spinal hemangioma, and is being studied for its immunomodulatory and anti-proliferative effects.
• Captopril: An ACE inhibitor under evaluation for its ability to induce apoptosis and inhibit angiogenesis, with studies demonstrating increased p53 expression particularly in prostate cancer.
• Losartan and other ARBs: In early-phase clinical trials for pancreatic and lung cancers, showing potential to modify the tumor microenvironment and improve treatment outcomes.

These developments reflect over 52 clinical trials investigating these drugs, pointing toward their repositioning as cost-effective, safe adjunct or standalone cancer therapies. Their established safety profiles and tolerability make them attractive options in oncology, offering new hope particularly in cancers resistant to conventional treatments (Ongoing clinical trials of anti-diabetic and anti-hypertensive drugs for cancer.

Statins and Beta Blockers: Repurposed Cardiovascular Agents Against Cancer

How Do Statins Contribute to Cancer Therapy?

Statins, commonly used to lower cholesterol, have shown promising effects in cancer treatment. Particularly, statins like simvastatin can activate mutant p53, a tumor suppressor gene often mutated in cancer cells. Activation of mutant p53 helps restore its normal function, leading to inhibition of cancer cell growth and reduction of cancer cell migration, which is crucial in limiting tumor spread (Statins activating mutant P53.

What Role Do Beta Blockers Play in Cancer Treatment?

Beta blockers, traditionally prescribed for cardiovascular conditions, influence the tumor microenvironment and immune response. Drugs like propranolol are observed to downregulate pathways such as p-AKT, p-ERK, and p-MEK, which are involved in tumor proliferation and survival. Additionally, beta blockers activate immune responses, creating conditions less favorable for tumor growth and progression (Beta blockers in multiple myeloma, Propranolol in clinical trials for tumor treatment.

What Is the Evidence Base and Status of Clinical Trials?

Several clinical trials in the United States and globally are evaluating the anticancer potential of statins and beta blockers. Some beta blockers, including propranolol, have advanced to Phase IV clinical trials, indicating substantial evidence for safety and potential efficacy in cancer therapy. Statins have shown improved survival rates in head and neck cancers, with ongoing investigations into their combined use with immunotherapies to enhance treatment responses. These efforts reflect a growing interest in repurposing cardiovascular drugs to augment current oncological treatments and improve patient outcomes (Safety and tolerability of repurposed chronic-use drugs, Statins improving cancer survival.

Disulfiram and Leflunomide: Targeting Cancer Cell Metabolism

How does disulfiram inducing oxidative stress in cancer cells inhibit glycolysis and induce oxidative stress in cancer cells?

Disulfiram, traditionally used for alcoholism treatment, has been repurposed to target cancer cells by disrupting their metabolism. It inhibits glycolysis, the primary process that many cancer cells rely on for rapid energy production, effectively starving the tumor cells of energy. Alongside glycolysis inhibition, disulfiram induces oxidative stress by promoting the accumulation of reactive oxygen species (ROS) within cancer cells. This dual action damages the cellular components, leading to impaired cancer cell growth and cell death, enhancing its potential as an anticancer agent.

In what way does Leflunomide and pyrimidine synthesis inhibition suppress tumor growth through pyrimidine synthesis inhibition?

Leflunomide operates by inhibiting mitochondrial enzymes critical to pyrimidine synthesis, which is essential for DNA and RNA production. Cancer cells require increased nucleotide synthesis for their rapid proliferation. By suppressing pyrimidine synthesis, leflunomide effectively slows down DNA and RNA replication, resulting in impeded tumor cell proliferation. This mechanism has shown promising effects in models of breast and prostate cancers where tumor growth is notably suppressed.

What impact do these metabolic actions have on tumor growth and chemoresistance?

The ability of disulfiram and leflunomide to interfere with cancer metabolism directly affects tumor growth by limiting the energy supply and the building blocks required for cell division. Not only do these actions reduce tumor proliferation, but they also help overcome chemoresistance, a major hurdle in cancer treatment. By targeting metabolic pathways unique to cancer cells, these drugs can sensitize tumors to conventional chemotherapy, potentially reducing resistance and improving therapeutic outcomes.

Together, disulfiram and leflunomide represent potent examples of Drug repurposing for cancer strategies that target distinct metabolic vulnerabilities of cancer cells. Their combined effects on glycolysis inhibition, oxidative stress induction, and nucleotide synthesis suppression highlight an innovative approach to combat tumor growth and enhance responsiveness to existing treatments.

Natural Compounds Repurposed for Oncology: EGCG, Curcumin, and Oleanolic Acid

How do EGCG, curcumin, and oleanolic acid act in cancer therapy?

Epigallocatechin 3-gallate (EGCG), curcumin, and oleanolic acid are natural compounds increasingly studied for their potential in repurposed cancer therapies. EGCG, a polyphenol extracted from green tea, targets cancer cells by inhibiting telomerase activity, which is crucial for cellular immortality in tumors. This inhibition promotes apoptosis, or programmed cell death, effectively reducing cancer cell proliferation. Curcumin, derived from turmeric, influences the mechanical microenvironment of tumors and inhibits invasive processes, thereby suppressing metastasis. Oleanolic acid modulates immune responses and can downregulate immune checkpoints such as PD-L1, which helps tumors evade detection by the immune system.

What effects do these compounds have on the tumor microenvironment and invasiveness?

Beyond direct cancer cell targeting, these compounds impact the tumor microenvironment (TME) substantially. Curcumin's inhibition of tumor invasion relates to altering the extracellular matrix and reducing mechanisms that facilitate cancer spread. Oleanolic acid enhances the immune microenvironment by promoting antitumor immunity, thereby improving the body's natural cancer-fighting capabilities. EGCG's capacity to induce apoptosis further supports the clearing of malignant cells within the TME, limiting tumor progression.

How can these natural agents work with conventional cancer therapies?

These compounds show promise as adjuncts to established cancer treatments. EGCG has been shown to enhance chemotherapy effects in pancreatic and breast cancers by sensitizing cancer cells through telomerase inhibition and apoptosis induction. Curcumin's modulation of the tumor microenvironment and prevention of invasion can complement surgery, chemotherapy, and radiation. Oleanolic acid's immune-modulating properties might improve responses to immunotherapies by reversing immune evasion strategies of tumors.

Together, EGCG, curcumin, and oleanolic acid embody a class of repurposed natural compounds offering multifaceted anti-cancer effects—ranging from telomerase inhibition and apoptosis to immune modulation and microenvironmental remodeling—that can synergize with traditional therapies to improve cancer treatment outcomes.

Artemisinin Derivatives and Mebendazole: Anti-Angiogenic and Anti-Microtubule Activities

What is the role of artemisinin derivatives anti-angiogenic effects in inhibiting tumor angiogenesis?

Artemisinin and its derivatives are known for their anti-angiogenic effects in cancer therapy. Angiogenesis — the formation of new blood vessels — is essential for tumor growth and metastasis, supplying cancer cells with oxygen and nutrients. Artemisinin compounds suppress tumor angiogenesis by inhibiting proliferation of endothelial cells that form blood vessels. They also suppress key signaling pathways such as NF-κB, which promotes inflammation and vascular growth within tumors. By disrupting these processes, artemisinin derivatives effectively starve tumors of their blood supply, limiting their ability to grow and spread.

How does Mebendazole inhibiting tumor microtubules disrupt microtubule polymerization and prevent metastasis?

Mebendazole, traditionally an anti-parasitic medication, has been repurposed for cancer treatment due to its ability to inhibit microtubule polymerization. Microtubules are structural components important for cell division and migration. By disrupting their polymerization, mebendazole impairs cancer cell proliferation and invasiveness. This action reduces the metastatic potential of tumors by preventing cancer cells from detaching, moving, and invading other tissues.

What is the clinical relevance of artemisinin and mebendazole in glioblastoma and oral cancers?

Both artemisinin derivatives and mebendazole have demonstrated promising effects in preclinical cancer models including glioblastoma and oral cancers. In glioblastoma, mebendazole's ability to block microtubule dynamics hinders aggressive tumor growth and spread. For oral cancers, it also reduces invasiveness and metastatic behavior. Artemisinin, with its anti-angiogenic properties, complements these effects by cutting off the tumor blood supply necessary for progression. These drugs' dual mechanisms make them attractive candidates for combined therapeutic strategies against difficult-to-treat tumors, with ongoing research aiming to translate these findings into effective clinical applications.

Celecoxib and Quercetin: Modulators of Tumor Inflammation and Immune Microenvironment

Celecoxib’s Anti-inflammatory and Chemosensitizing Effects

Celecoxib and apigenin in tumor inflammation, a well-known nonsteroidal anti-inflammatory drug (NSAID), exhibits significant anti-inflammatory properties by selectively inhibiting cyclooxygenase-2 (COX-2). This inhibition reduces tumor-promoting inflammation, a hallmark of the tumor microenvironment that contributes to cancer progression and chemoresistance.

Beyond its anti-inflammatory role, celecoxib can improve responses to chemotherapy and immunotherapy. It modulates the immune microenvironment by reducing inflammatory cytokines and can sensitize tumor cells to chemotherapeutic agents, leading to enhanced cell death. Clinical studies highlight celecoxib’s potential to improve outcomes when combined with standard cancer therapies.

Quercetin’s Induction of Senescence and Immunomodulation

Quercetin inducing cancer cell senescence, a plant-derived flavonoid, demonstrates multiple anti-cancer effects including the induction of senescence in cancer cells. Cellular senescence here refers to a state of permanent cell cycle arrest, which stops tumor cell proliferation.

Additionally, quercetin has immunomodulatory properties. It influences immune system components by regulating inflammatory pathways and enhancing anti-tumor immunity. Ongoing clinical trials explore quercetin’s capacity to modulate the tumor microenvironment and improve cancer treatment outcomes.

Potential for Incorporation into Combination Treatments

Both celecoxib and quercetin hold promise as adjuncts in combination therapies to overcome drug resistance. Their ability to alter tumor-promoting inflammation and reprogram the immune microenvironment complements conventional treatments, potentially reducing cancer cell survival and improving therapeutic efficacy.

Incorporating these agents into combination regimens might also help lower required dosages of more toxic drugs, minimizing side effects while maintaining or enhancing cancer control.

Continued investigation through clinical trials is vital to optimize dosing strategies and verify synergistic effects with existing chemotherapies and immunotherapies, particularly in resistant cancer types.

Vitamin C and Inulin: Micronutrient Approaches to Enhance Cancer Treatment

How Does Ascorbic Acid Affect Tumor Growth?

Ascorbic acid, commonly known as vitamin C, plays a significant role in cancer therapy by targeting the tumor's hypoxic environment. It reduces the levels of hypoxia-inducible factor 1-alpha (HIF-1α), a transcription factor that promotes tumor growth under low oxygen conditions. By impairing HIF-1α, vitamin C disrupts cancer cell adaptation to hypoxia, ultimately inhibiting tumor progression (ascorbic acid reducing HIF-1α in tumors.

How Does Inulin Modulate the Immune Response Against Cancer?

Inulin, a natural dietary fiber, exerts its anti-cancer effects primarily through modulation of the gut microbiota. By improving the composition and diversity of beneficial gut bacteria, inulin enhances systemic immune responses, supporting the body's ability to recognize and fight cancer cells. This immunomodulatory effect helps strengthen the tumor immune microenvironment (inulin modulating gut microbiota in cancer.

What Is the Potential of Vitamin C and Inulin as Adjuncts to Conventional Cancer Therapies?

Both vitamin C and inulin show promise as adjunctive agents in cancer treatment. Their ability to reduce tumor growth and bolster immune responses complements existing therapies such as chemotherapy and immunotherapy. By targeting different aspects of tumor biology—including hypoxia and immune regulation—they may increase treatment efficacy and potentially reduce resistance (drug repurposing for cancer therapy.

These micronutrients offer cost-effective, low-toxicity options and are being actively studied in clinical trials, reflecting growing interest in their integration with standard cancer care (drug repurposing for cancer.

Nanotechnology Approaches Improving Delivery of Repurposed Drugs

How are liposomes, micelles, and nanoparticles used in drug repurposing for cancer

Nanotechnology techniques such as liposomes, micelles, and nanoparticles have become pivotal in enhancing the delivery of repurposed drugs for cancer therapy. Liposomes are spherical vesicles that encase drugs, protecting them from degradation and allowing controlled release. Micelles, formed by the self-assembly of amphiphilic molecules, improve the solubility of hydrophobic repurposed drugs, increasing their bioavailability. Nanoparticles, including polymeric and metallic forms, provide targeted delivery by exploiting the enhanced permeability and retention effect in tumors, allowing higher drug concentrations at the cancer site while sparing normal tissues.

In what ways do these nanotechnology systems improve targeting and reduce toxicity?

By facilitating precise delivery of repurposed drugs directly to tumor cells, these nanocarriers offer improved specificity compared to conventional dosing. This targeted approach reduces systemic exposure to the drugs, lowering the harmful side effects often associated with cancer treatments. For example, nano-formulations can shield drugs from premature metabolism, prolong circulation time, and enable controlled drug release in the tumor microenvironment. Such delivery methods enhance the therapeutic window of repurposed drugs, allowing their anticancer properties to be maximized safely. Nanotechnology in drug repurposing for cancer and Nanoparticles used in cancer drug delivery are key advances in this area.

How does nanotechnology help overcome drug efflux and resistance mechanisms?

Drug resistance in cancer often arises due to overexpression of efflux pumps like P-glycoprotein (P-gp) that expel drugs from tumor cells, lowering intracellular drug levels. Nanoparticles can bypass these pumps by facilitating endocytosis-mediated cellular uptake rather than passive diffusion, thereby avoiding recognition by efflux transporters. Additionally, nanocarriers can be engineered to co-deliver efflux pump inhibitors alongside the repurposed drugs, further enhancing drug retention. Nanotechnology also aids in overcoming resistance by modifying drug pharmacokinetics and improving penetration into the tumor microenvironment, which is often a barrier to effective therapy (Therapeutic resistance in cancer). These advanced delivery platforms are being actively developed and evaluated within clinical research in the United States to exploit the full potential of repurposed drugs in combating chemotherapy resistance (source. By integrating nanotechnology with drug repurposing, the challenges of dosage optimization, safety, and efficacy in cancer therapy can be more effectively addressed, offering promising avenues for future cancer treatment strategies.

Combination Strategies: Integrating Repurposed Drugs with Standard Chemotherapy and Immunotherapy

Why combine repurposed drugs with conventional cancer treatments?

Combining repurposed drugs for cancer therapy with standard chemotherapy and immunotherapy offers a promising approach to overcome cancer drug resistance. Conventional treatments often face challenges such as acquired resistance mechanisms, including enhanced DNA repair, drug efflux by transporters, cancer stem cell (CSCs) niches, and tumor microenvironment-mediated protection. Repurposed drugs frequently target distinct pathways related to these resistance mechanisms. Leveraging their known safety and cost-effectiveness, these agents can synergize to improve treatment efficacy and potentially reduce toxicity.

How do repurposed drugs and conventional agents work together?

Several repurposed drugs for cancer have demonstrated synergy with traditional cancer therapies by targeting complementary pathways:

• Metformin: Commonly used as an antidiabetic, metformin activates the AMPK pathway and inhibits mTOR signaling. It reduces cancer stem cell renewal and enhances sensitivity to chemotherapy, radiotherapy, and immunotherapy across various cancers like breast, pancreatic, and lung. (Metformin repurposing for cancer; Repurposing anti-diabetic drugs in cancer therapy

• Statins: Beyond cholesterol-lowering effects, statins activate mutant p53 and inhibit cancer cell migration. Ongoing clinical trials test their combination with chemotherapy to improve outcomes in breast and head and neck cancers. (Statins activating mutant P53 in breast cancer; Repurposed drugs for various cancers

• Disulfiram: Originally an alcoholism drug, disulfiram inhibits glycolysis and induces oxidative stress in tumor cells, enhancing the cytotoxic effects of platinum-based chemotherapy. (Disulfiram in cancer metabolism modulation

• Celecoxib: A COX-2 inhibitor with anti-inflammatory properties, celecoxib improves responses to chemotherapy and immunotherapy by modulating tumor-promoting inflammation. (Celecoxib improving chemotherapy and immunotherapy

• Low-dose doxorubicin: Repurposed at lower-than-standard doses, it disrupts pathways like Wnt/β-catenin and stimulates anti-tumor immunity while reducing toxicity, suggesting combinational benefits. (low-dose chemotherapy efficacy)

What clinical evidence supports these combinations?

Numerous clinical trials are exploring repurposed drugs in combination with standard cancer therapies. Highlights include:

• Metformin Trials: Multiple trials assess metformin as an adjunct to chemotherapy and immunotherapy. Despite mixed results, some subgroups show improved progression-free survival, especially diabetic patients. (Metformin clinical evidence in cancer; Metformin cancer treatment evidence)

• Beta-blockers: Propranolol is in Phase IV trials examining its efficacy combined with chemotherapy for vascular tumors. (Beta-blockers in cancer treatment

• Statins and Chemotherapy: Trials at institutions like Winship Cancer Institute are investigating statins with chemotherapy and immunotherapy in head and neck and breast cancers. (Repurposed drugs for various cancers

• Nanotechnology-enhanced delivery: Combining repurposed drugs with nano-delivery systems such as liposomes and PLGA nanoparticles is under clinical evaluation to enhance drug targeting and reduce side effects. (Nanotechnology in drug repurposing for cancer

These studies underscore the potential of combination approaches to combat tumor heterogeneity, cancer stem cell (CSC)-driven resistance, and immune evasion.

Looking forward

As understanding of resistance mechanisms and tumor biology deepens, integrating repurposed drugs into multi-modal cancer therapies remains a practical and innovative strategy. Continued rigorous clinical trials will be critical to define the optimal combinations, dosages, and patient subsets for enhanced efficacy and safety.

Targeting the Tumor Microenvironment and Immune Modulation to Combat Resistance

How does the tumor microenvironment (TME) influence chemoresistance?

The tumor microenvironment is a complex and dynamic network surrounding cancer cells, consisting of cellular components such as tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, and mesenchymal stem cells, alongside non-cellular elements including extracellular matrix (ECM), cytokines, and growth factors.

These components significantly contribute to chemoresistance by promoting survival pathways and creating physical and biochemical barriers that reduce drug penetration. Hypoxia, acidity, and altered metabolism within the TME activate signaling cascades like PI3K/Akt/mTOR and NF-κB, enhancing tumor cell survival and evading apoptosis. Furthermore, tumor-derived exosomes and extracellular vesicles mediate intercellular communication that sustains drug resistance by transferring oncogenic molecules, microRNAs (e.g., miR-21), and efflux transporters among cells. Therapeutic resistance in cancer treatment

Which repurposed drugs modulate immune checkpoints and stromal interactions within the TME?

Several repurposed agents show promise in modulating the TME and immune responses to overcome chemoresistance. For example, celecoxib, a COX-2 inhibitor, suppresses tumor-promoting inflammation and enhances chemotherapy and immunotherapy efficacy by reducing pro-inflammatory cytokines.

Natural compounds like oleanolic acid inhibit immune checkpoints such as PD-L1, thereby enhancing antitumor immunity. Sulconazole, originally an antifungal drug, blocks NF-κB and calcium signaling pathways involved in PD-1 expression, interrupting immune evasion mechanisms. Beta blockers (propranolol) downregulate oncogenic pathways (p-AKT/p-ERK/p-MEK) and activate immune modulation.

Nano-delivery systems, including liposomes and nanoparticles, have been leveraged alongside repurposed drugs to improve targeting of stromal and immune components within tumors, minimizing adverse effects and maximizing therapeutic outcomes. Drug repurposing for cancer therapy

What are the implications for pancreatic cancer and other malignancies?

Pancreatic cancer, notorious for its dense stromal microenvironment and resistance to chemotherapy, is a prime candidate for therapies targeting the TME. Drugs like losartan (an angiotensin receptor blocker) have shown promise in modifying stromal barriers to improve drug delivery. Metformin, known for metabolic modulation, also impacts TME signaling pathways like AMPK/mTOR to inhibit cancer stem cell renewal.

Combining repurposed drugs that target both cancer cells and the TME holds potential in multiple malignancies. For instance, targeting immune checkpoints and the hypoxic niche may resensitize tumors to standard therapies, reduce metastatic spread, and improve overall survival. Clinical trials are ongoing to optimize usage protocols of these agents, with a focus on enhancing immune response while reducing resistance. Repurposing anti-diabetic drugs in cancer therapy

---

Aspect	Role/Effect in TME Chemoresistance	Representative Repurposed Drugs
Immune Checkpoints	Promote immune evasion, reduce anti-tumor immunity	Oleanolic acid (PD-L1 inhibition), Sulconazole (PD-1 block)
Inflammation	Supports tumor growth and resistance	Celecoxib (COX-2 inhibitor)
Stromal Barrier and ECM	Limits drug delivery, promotes survival signaling	Losartan (angiotensin receptor blocker)
Signaling Pathways	Activates survival and proliferative signaling	Metformin (AMPK/mTOR), Propranolol (p-AKT/p-ERK pathway)
Nanotechnology-based Delivery	Enhances targeting, reduces toxicity	Liposomes, nanoparticles integrating repurposed drugs

Targeting the tumor microenvironment and immune modulation through repurposed drugs represents an innovative strategy to combat chemoresistance, particularly in challenging cancers like pancreatic carcinoma. Therapeutic resistance in cancer treatment

The Role of Genomic and Molecular Profiling in Revitalizing Drug Repurposing

Identification of actionable mutations and pathways

Genomic and molecular profiling techniques, including next-generation sequencing, have revolutionized the ability to identify critical mutations and dysregulated pathways in cancer cells. Mutations in genes such as EGFR, KRAS, and those involved in DNA repair pathways serve as actionable targets that can be exploited with repurposed drugs. For example, alterations in signaling pathways like PI3K-Akt-mTOR signaling pathway alterations and MAPK often contribute to tumor survival and chemoresistance, providing targets for repurposed agents originally designed for other indications.

Personalizing repurposed drug use based on molecular signatures

By analyzing molecular signatures unique to a patient's tumor, clinicians can tailor drug repurposing strategies to individual profiles. This precision approach helps select repurposed drugs that specifically inhibit aberrant signaling or metabolic pathways active in the tumor. For instance, Metformin repurposing for cancer may be more effective in tumors exhibiting related pathway dysregulation, while inhibitors acting on immune checkpoints can be chosen for tumors showing PD-L1 overexpression. Molecular profiling thus optimizes patient selection and maximizes therapeutic benefits of repurposed drugs.

Enhancing efficacy and reducing off-target effects

Molecular profiling aids in defining the key drivers in cancer cells, which allows repurposed drugs to be applied more effectively with reduced toxicity. Targeting specific molecular abnormalities minimizes off-target interactions, improving safety profiles. Coupled with advanced drug delivery systems such as Nano-delivery systems in cancer therapy these approaches enhance drug accumulation in tumor tissues and avoid damage to healthy cells. Moreover, profiling supports combination therapies that synergize repurposed drugs with conventional treatments, overcoming resistance mechanisms and improving overall outcomes.

Molecular and genomic profiling is an indispensable tool for revitalizing drug repurposing by enabling actionable target identification, personalizing therapies, and improving efficacy while mitigating adverse effects.

Challenges and Limitations in Repurposing Drugs for Cancer Treatment

What are the pharmacokinetic and dosage hurdles in drug repurposing?

One of the major challenges in drug repurposing for cancer therapy lies in achieving effective concentrations and dosing schedules suitable for oncological indications. Many repurposed drugs, such as metformin, show anticancer activity in preclinical models at doses much higher than those approved for their original use, raising concerns about the translatability to patients. Obtaining an optimal dose that maximizes anticancer effects while minimizing toxicity is complex. Differences in drug absorption, metabolism, and distribution in cancer patients compared to the original patient population can further complicate dosing.

What are the patent, regulatory, and reimbursement barriers?

Drug repurposing for cancer therapy often involves off-patent or generic medications, which may have limited commercial incentives for pharmaceutical companies to invest in expensive clinical trials. This creates a barrier to obtaining regulatory approval for new indications, as comprehensive evidence on efficacy and safety must still be generated. Additionally, navigating reimbursement policies poses hurdles, since insurers may be reluctant to cover repurposed drugs without clear FDA-approved cancer indications. Regulatory pathways, although available, require rigorous scientific validation and can be time-consuming and costly, limiting rapid adoption. More details about pharmacological challenges in drug repurposing and patent and regulatory barriers for repurposed drugs further illustrate these difficulties.

How is safety and efficacy ensured in diverse patient populations?

Although repurposed drugs have known safety profiles from their original approved uses, cancer patients often present with complex comorbidities and undergo combination therapies that may alter drug pharmacodynamics and toxicity. Ensuring safety requires extensive clinical evaluation, including trials that address diverse patient groups with varying genetic backgrounds and disease stages. Moreover, the anticancer mechanisms may interact differently within repurposed drug effects on tumor microenvironment, necessitating careful monitoring for unexpected adverse effects or interactions. Ultimately, confirming efficacy in heterogeneous cancer types and patient populations remains a significant challenge in drug repurposing.

These challenges highlight the importance of continued research, well-designed clinical trials, and collaborative efforts among researchers, clinicians, and regulatory bodies to fully realize the potential of drug repurposing for cancer therapy in oncology.

Clinical Trials and Evidence Supporting Repurposed Drug Use

Status of key clinical trials

Several repurposed drugs are currently under extensive clinical evaluation for their potential use in Repurposing anti-diabetic drugs in cancer therapy. Anti-diabetic and anti-hypertensive medications such as metformin, propranolol, captopril, and losartan have been particularly prominent in this arena. Over 92 clinical trials are investigating anti-diabetic drugs, while more than 52 trials focus on anti-hypertensive agents for their anti-cancer properties. These trials cover various malignancies including colorectal, breast, pancreatic, prostate, lung, and ovarian cancers.

Examples of drugs reaching Phase III and IV

Some repurposed drugs have advanced to late-stage trials showing promising results. Metformin, for instance, has reached Phase III trials evaluating its adjunctive effect in cancers like breast and pancreatic cancer. Propranolol, a beta-blocker, is in Phase IV clinical trials assessing its effect on benign tumors, such as infantile capillary hemangioma, and demonstrating immunological impact and reduction in tumor proliferation. Captopril, an ACE inhibitor, is also undergoing advanced clinical evaluation for its ability to induce apoptosis and inhibit angiogenesis, evidenced by increased p53 expression in prostate cancer patients.

Interpretation of mixed results and future directions

While preclinical studies often highlight significant anti-cancer efficacy of repurposed drugs, clinical trials sometimes yield mixed or modest outcomes. For example, metformin's anti-cancer benefits have been more prominent in diabetic subpopulations, with some trials terminated early or showing limited efficacy in broader cohorts. These disparities may stem from differences in drug dosing, pharmacokinetics, patient heterogeneity, and the complexity of cancer biology.

To maximize clinical success, future research emphasizes combination therapies, targeting cancer stem cells, and integrating repurposed drugs with nanotechnology-based delivery systems. Larger, well-designed randomized trials are necessary to establish effective dosing regimens, timing, and patient selection criteria. Ultimately, these efforts aim to harness the safety profiles and affordability of repurposed drugs to improve cancer treatment outcomes efficiently and broadly.

Case Study: Enhancing Cisplatin Efficacy by Targeting NPEPPS to Overcome Resistance

What is the mechanism of cisplatin resistance via NPEPPS?

Cisplatin, a platinum-based chemotherapy drug, exerts its antitumor effects predominantly by binding to DNA in cancer cells, causing cross-links and triggering cell death pathways including apoptosis and necroptosis. Despite its effectiveness, many tumors develop resistance, limiting cisplatin's clinical success. One emerging mechanism involves the gene NPEPPS, which has been identified as a negative regulator of cisplatin uptake into tumor cells. When NPEPPS activity is high, the import of cisplatin into cancer cells is reduced, leading to lower intracellular drug concentrations and thus diminished efficacy. For more details on Platinum drugs and cell death modes.

What are the preclinical findings on gene inhibition increasing drug uptake?

Research led by Cedars-Sinai Cancer investigators demonstrated that inhibiting NPEPPS significantly increases the sensitivity of bladder cancer cells to cisplatin. Using laboratory cell lines, tumor organoids, and 3D cell cultures, they observed enhanced drug uptake and increased tumor cell killing after NPEPPS inhibition. These findings suggest that by targeting NPEPPS, cisplatin can more effectively penetrate resistant cancer cells, overcoming one barrier to chemotherapy resistance. This insight has broad implications, as cisplatin is widely used in multiple cancer types including ovarian, lung, cervical, testicular, and breast cancers. See more on Combating Chemotherapy Resistance.

What is the potential for new combination therapies?

The identification of NPEPPS as a modulator of cisplatin uptake opens avenues for combination treatments that pair cisplatin with agents that inhibit NPEPPS. Such combination strategies could enhance drug effectiveness and reduce the likelihood of resistance development. Ongoing research aims to discover or design small molecule inhibitors of NPEPPS that could be safely combined with cisplatin in clinical settings. By enabling greater drug delivery inside resistant tumors, this approach could improve patient outcomes across cancers where platinum-based chemotherapy remains a frontline treatment. Related insights on Novel approaches to chemotherapy resistance.

Table: Summary of NPEPPS Role in Cisplatin Resistance

Aspect	Details	Implications
Gene involved	NPEPPS	Regulates cisplatin uptake
Effect of inhibition	Increased drug uptake and sensitivity	Potential to overcome resistance
Cancer models studied	Bladder cancer cells and organoids	Applicable to multiple cisplatin-treated cancers
Therapeutic opportunity	Development of NPEPPS inhibitors	Enhances cisplatin efficacy in combination therapy

Emerging Advances in Low-Dose Chemotherapy Repurposing: The Example of Doxorubicin

How does low-dose doxorubicin affect cancer signaling pathways like Wnt/β-catenin and PI3K/Akt?

Low-dose doxorubicin interferes with the cooperation between the Wnt/beta-catenin and PI3K/Akt pathways interaction, two signaling routes that promote tumor growth and resistance. By inhibiting the interaction of these pathways, it helps reduce cancer cell proliferation and can sensitize cells to therapy. This targeted molecular effect contrasts with high-dose chemotherapy, which often causes non-specific damage and immunosuppression.

How does low-dose doxorubicin impact leukemia stem cells and immune checkpoint expression?

Research in pediatric leukemia models found that low-dose doxorubicin significantly reduces the population of therapy-resistant leukemia stem cells, which are critical drivers of disease relapse and resistance. Moreover, it lowers the expression of immune checkpoints such as PD-L1, TIM3, and CD24 on these stem cells. Since these checkpoints help cancer cells evade immune detection, their downregulation by doxorubicin may restore immune system capability to recognize and attack malignant cells.

What are the implications of using low-dose doxorubicin for developing less toxic and more effective cancer treatments?

Using doxorubicin at low doses offers a promising strategy to overcome drug resistance and immune evasion while minimizing the severe toxicities commonly associated with high-dose treatments, including lasting heart damage. This approach exemplifies the potential of drug repurposing in cancer therapy with classic chemotherapy agents at optimized dosing to maintain efficacy, stimulate the immune response, and reduce adverse effects. It underscores the value of revisiting existing drugs within new therapeutic paradigms to improve patient outcomes and expand treatment options in oncology. Ongoing studies and clinical trials are expected to clarify the broader applicability of this low-dose strategy across other cancers beyond leukemia.

Innovations in Targeted Small Molecule Drugs to Circumvent Resistance

What FDA-approved targeted small molecule drugs are used, and what resistance mechanisms limit their efficacy?

Since 2001, more than 80 targeted small molecule drugs have received FDA approval for cancer treatment in the United States. These agents are designed to penetrate tissues efficiently and selectively inhibit cancer-associated pathways. However, therapeutic resistance remains a significant challenge, arising from diverse mechanisms including genetic mutations, drug efflux pumps, and tumor microenvironment factors.

Key resistance mechanisms include overexpression of efflux transporters such as P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), which actively pump drugs out of cancer cells, reducing intracellular drug concentrations. Mutations in drug targets or alterations in downstream signaling pathways like PI3K/Akt/mTOR can also enable cancer cells to survive despite treatment. Additionally, cancer stem cells (CSCs) with high drug efflux capacity and enhanced DNA repair contribute to persistent resistant populations.

What strategies can improve the efficacy of targeted small molecule drugs and reduce their toxicity?

Combination therapies serve as a promising approach to enhance drug efficacy while minimizing damage to healthy cells. Integrating targeted small molecules with chemotherapy, immunotherapy, or novel agents can overcome resistance pathways synergistically. Advanced drug delivery methods, such as nanoparticle-based systems, improve drug targeting specifically to tumor cells, reducing systemic toxicity and bypassing efflux mechanisms.

Identifying and inhibiting signaling networks that promote survival, like the NF-κB pathway and epithelial-mesenchymal transition (EMT), can sensitize resistant cells. Furthermore, targeting CSCs and key regulatory non-coding RNAs may dismantle the cellular networks underlying resistance. Tailored treatment regimens informed by molecular profiling enhance the precision and success of therapies.

How does the tumor microenvironment and exosomes influence resistance to targeted therapies?

The tumor microenvironment (TME) is a complex ecosystem of cellular (e.g., tumor-associated macrophages, cancer-associated fibroblasts) and non-cellular components (e.g., extracellular matrix, cytokines, exosomes) that profoundly impact drug resistance. Exosomes, small extracellular vesicles secreted by tumor and stromal cells, facilitate intercellular communication by transferring bioactive molecules such as proteins, microRNAs, and long non-coding RNAs.

These exosomal cargos can modulate the TME to favor tumor progression, immune evasion, and drug resistance by promoting EMT, autophagy, and metabolic reprogramming. They also contribute to the horizontal transfer of resistance traits among cancer cells. Targeting exosome production, release, or uptake represents an emerging frontier to disrupt these resistance-promoting interactions.

Addressing the intricate interplay between targeted small molecules and the TME, including exosome-mediated signaling, is crucial for developing innovative therapies that can effectively overcome resistance and improve patient outcomes in cancer treatment.

The ReDO Project: Pioneering Drug Repurposing for Global Oncology Needs

What is the goal of the ReDO project and why is it important?

The [ReDO Project overview] aims to identify and promote the use of existing non-cancer drugs for the treatment of cancer. This approach shortens the traditionally long drug development timelines and lowers costs compared to new drug approvals. By repurposing well-known drugs, ReDO leverages their established safety profiles, enabling faster translation to clinical use. The project's overarching goal is to overcome drug development productivity challenges, offering effective treatments for refractory and metastatic cancers, where new drugs show slow and costly approval rates.

What economic and development challenges does the ReDO project address?

Since the 1950s, productivity in cancer drug development has declined, with a steady reduction in approval rates despite rising cancer incidence worldwide. The typical development time for new cancer drugs ranges from 10 to 17 years, with approval success rates of only around 6.7%. These extended timelines and low success rates pose economic burdens on healthcare systems and limit access to novel therapies.

The ReDO project seeks to address these challenges by

• Decreasing the development timeline to 3-12 years for repurposed drugs.
• Reducing research and clinical trial costs due to existing safety data.
• Minimizing the risk of failure because of extensive knowledge of drug properties.
• Encouraging use of low-cost generic medications, making treatments more affordable.

How does the ReDO project impact low- and middle-income countries?

Globally, cancer incidence is rising, with projections indicating that by 2030, over half of new cancer cases will arise in low- and medium-Human Development Index (HDI) countries. These regions often face limited healthcare resources and financial constraints that hinder access to advanced cancer treatments.

The ReDO project offers a promising solution in these settings by providing:

• Affordable treatment options using generics and widely available medications.
• Simplified drug development that circumvents expensive and lengthy R&D.
• Opportunities for combination therapies that enhance efficacy without escalating costs.
• A practical approach for addressing the unmet needs of patients with refractory and metastatic tumors.

By facilitating collaboration among researchers, clinicians, and non-profit organizations, the project also works to overcome economic and political barriers, promoting equitable cancer care worldwide.

Integrating Compassionate Care and Scientific Innovation: Hirschfeld Oncology's Approach

Who leads the medical team at Hirschfeld Oncology specializing in pancreatic cancer care?

Dr. Azriel Hirschfeld stands at the forefront of Hirschfeld Oncology as the leading physician specializing in pancreatic cancer care. Under his leadership, a dedicated team harmonizes cutting-edge scientific knowledge with deep compassion and rich clinical experience. This team is committed to delivering highly personalized care plans tailored to the unique needs of each patient, ensuring that every individual receives the best possible treatment outcomes in a supportive setting.

How does Hirschfeld Oncology integrate compassion and experience in their pancreatic cancer care?

At Hirschfeld Oncology, compassion is not an add-on but an integral part of treatment. The team prioritizes empathetic communication, fostering open and honest dialogues where patients actively participate in decision-making about their care. Emotional support is woven into every step, acknowledging the heavy toll pancreatic cancer can take. This approach promotes a healing environment where patients feel understood, respected, and empowered.

Physician Dr. Hirschfeld has cultivated a multidisciplinary team that combines years of clinical expertise with a sincere commitment to holistic patient care. This team carefully balances the application of standard therapies with innovative treatments and the latest scientific advances to improve patient outcomes.

Combining standard therapies with novel approaches in pancreatic cancer

The care strategy at Hirschfeld Oncology seamlessly integrates established treatment modalities with novel approaches seen in contemporary research. By embracing drug repurposing for pancreatic cancer30610-0/fulltext) initiatives, targeted therapies, and immunotherapy combinations, the team expands options beyond conventional chemotherapy. This integrative model helps address challenges such as drug resistance and cancer stem cell survival, which are critical obstacles in pancreatic cancer management.

In summary, Hirschfeld Oncology represents a model where clinical excellence meets compassionate care, championed by Dr. Azriel Hirschfeld's leadership. Their approach ensures that pancreatic cancer patients benefit not only from scientific innovation but also from an empathetic, patient-centered treatment environment.

Innovative Strategies at Hirschfeld Oncology to Overcome Pancreatic Cancer Resistance

What innovative strategies are being used in pancreatic cancer treatment at Hirschfeld Oncology?

Hirschfeld Oncology applies several cutting-edge approaches to combat resistance in pancreatic cancer, which is known for its aggressive nature and treatment challenges.

KRAS Inhibitors and Precision Medicine: Pancreatic cancers frequently harbor mutations in the KRAS gene, a key driver of tumor growth. Hirschfeld Oncology focuses on using KRAS inhibitors to directly target these mutations. This precision medicine strategy also extends to other genetic alterations such as BRCA1/2 and BRAF mutations, enabling tailored therapies that improve treatment responses (Drug repurposing in oncology).

Immunotherapy with Personalized Vaccines: The center pioneers personalized immunotherapy by developing mRNA vaccines based on a patient's unique tumor profile. These vaccines can include neoantigens from mutant KRAS, helping stimulate the immune system to recognize and attack cancer cells effectively (Personalized mRNA vaccines for cancer immunotherapy, Personalized mRNA vaccines for cancer immunotherapy).

Combination Therapies and Novel Clinical Trial Designs: Recognizing that pancreatic cancer often resists monotherapies, Hirschfeld Oncology explores combination treatments integrating targeted agents, immunotherapies, and chemotherapy. These regimens aim to overcome resistance mechanisms, enhance tumor kill, and improve survival. Additionally, innovative clinical trial designs facilitate rapid evaluation of these novel approaches, accelerating the path from discovery to patient benefit (Drug repurposing in oncology.

These strategies at Hirschfeld Oncology exemplify a multi-faceted approach to tackling pancreatic cancer's resistance by integrating genetic insights, immunology, and treatment combinations, offering hope for improved outcomes.

The Critical Role of Combining Standard Therapies with Drug Repurposing and Innovation in Pancreatic Cancer

What is the importance of combining standard therapies with innovative strategies in pancreatic cancer treatment?

Pancreatic cancer is notorious for its aggressive nature and resistance to conventional treatments like surgery and chemotherapy. Combining these standard therapies with innovative approaches such as drug repurposing for pancreatic cancer and advanced drug delivery systems is vital. This multilayered strategy helps to overcome the tumor microenvironment's protective barriers — including hypoxia, acidity, and dense stroma — which traditionally limit drug penetration and efficacy.

For example, nanotechnology-based delivery systems like liposomes and nanoparticles enhance targeted drug delivery, thereby improving drug concentration at tumor sites while reducing systemic toxicity. Additionally, repurposed drugs such as metformin and losartan in cancer metabolism can modulate the tumor microenvironment and disrupt cancer stem cell pathways, making tumors more susceptible to treatment. Immunotherapy combined with repurposed agents can boost antitumor immunity and overcome immune evasion mechanisms.

Overcoming the tumor microenvironment and chemoresistance

The pancreatic tumor microenvironment is complex, featuring cellular components like cancer-associated fibroblasts (CAFs) and immune cells that contribute to drug resistance. Pancreatic tumors often show heightened activity of drug efflux pumps and DNA repair mechanisms, which help cells evade chemotherapy. By integrating repurposed drugs that inhibit key survival pathways (such as PI3K/Akt or mTOR), alongside nanocarrier-based delivery, these resistance factors can be targeted more effectively (Chemoresistance in cancer, Therapeutic resistance in cancer treatment.

Moreover, targeting cancer stem cells (CSCs) via repurposed compounds—like metformin as an anti-cancer agent and aspirin in cancer treatment—addresses a primary source of chemoresistance, tumor relapse, and metastasis. This approach disrupts CSC-related pathways (e.g., Wnt/β-catenin, Hedgehog), thereby sensitizing cancer cells to chemotherapy and improving long-term treatment success.

Synergistic benefits of combination treatments

Using combination therapies enhances the effectiveness of each modality. For instance, incorporating anti-hypertensive drugs such as losartan with chemotherapy can reduce stromal density, facilitating better drug perfusion. Concurrent use of immunomodulatory repurposed drugs helps in activating immune cells to recognize and destroy cancer cells, while chemotherapy and radiotherapy induce tumor cell death (Repurposing anti-diabetic and anti-hypertensive drugs in cancer therapy.

Additionally, combining low-dose chemotherapy with repurposed agents can minimize toxicity and target resistant tumor subpopulations, such as therapy-resistant leukemia stem cells or chemoresistant pancreatic cancer cells (low-dose chemotherapy efficacy. This synergy allows for potentially lower doses and schedules that reduce side effects while maintaining efficacy.

Potential for extending survival and improving quality of life

Together, these combined strategies present a promising path to improve survival outcomes and quality of life for pancreatic cancer patients. Repurposed drugs bring advantages of known safety profiles, affordability, and accessibility, which can complement cutting-edge therapies without drastically increasing costs (Drug repurposing in oncology.

Ongoing clinical trials in the United States are evaluating such combination approaches, aiming to translate laboratory findings into improved patient care. By overcoming barriers like chemoresistance and physical drug delivery challenges, these integrative methods support longer remission periods and better management of pancreatic cancer symptoms.

---

Aspect	Role in Combination Therapy	Example or Detail
Tumor Microenvironment	Barrier to drug delivery; source of resistance	Dense stroma reduced by losartan
Repurposed Drugs	Modulate metabolism, immunity, and CSC pathways	Metformin activates AMPK, aspirin targets CSCs
Nanotechnology	Enhances drug targeting and bioavailability	Liposomes, nanoparticles for chemotherapy delivery
Chemoresistance Overcoming	Targets efflux pumps, DNA repair, apoptosis evasion	Inhibition of PI3K/Akt by repurposed agents
Immunotherapy Synergy	Boosts anti-cancer immune responses	Beta blockers modulate inflammation
Clinical Impact	Potential improved survival and reduced toxicity	Ongoing trials testing combinations

Future Perspectives: Personalized, Multi-Modal Approaches to Overcome Resistance

How are biomarkers, liquid biopsies, and genomic profiling shaping personalized cancer treatment?

The use of biomarkers and genomic profiling technologies has revolutionized cancer treatment by enabling physicians to tailor therapies to the unique molecular features of each tumor. Liquid biopsies—non-invasive tests detecting circulating tumor DNA or cells in the bloodstream—provide real-time insight into tumor heterogeneity and emerging resistance mutations. These tools facilitate early detection of drug resistance and help guide therapeutic adjustments. Advanced genomic techniques like next-generation sequencing identify mutations in key pathways such as EGFR, PI3K/Akt/mTOR, and DNA repair genes, offering targets for precision therapies. This molecular customization enhances treatment efficacy and reduces unnecessary toxicity (Genetic mutations and drug resistance, Cancer drug resistance causes, Therapeutic resistance in cancer treatment.

How can repurposed drugs be integrated into personalized cancer regimens?

Repurposed drugs with known safety profiles—such as metformin, statins, propranolol, and aspirin—are increasingly incorporated into personalized therapy plans. Their diverse mechanisms include inhibition of cancer stem cell pathways (e.g., Wnt/β-catenin, Notch), metabolic modulation, anti-inflammatory effects, and angiogenesis blockade. Coupled with genomic profiling, these agents can be matched to specific tumor vulnerabilities, for example, metformin's effect on mTOR in tumors with PI3K pathway activation. Combination strategies using repurposed drugs alongside standard chemotherapy, targeted agents, or immunotherapies show promise in overcoming drug resistance, particularly by targeting cancer stem cells and the tumor microenvironment (Drug repurposing for cancer, Cancer stem cells (CSCs), Repurposing anti-diabetic drugs in cancer therapy, Drug repurposing.

What emerging clinical trials and translational research are advancing this multi-modal approach?

Numerous clinical trials in the United States and worldwide are evaluating repurposed drugs in combination with conventional therapies. For instance, metformin is under investigation in pancreatic, breast, and lung cancers for its ability to enhance chemotherapy and radiotherapy responses. Beta blockers like propranolol are being tested for tumor microenvironment modulation. Research integrating nanotechnology for improved drug delivery—such as nanoparticle systems to bypass drug efflux pumps—further supports these efforts. Translational studies using organoid and patient-derived xenograft models enable better prediction of treatment outcomes. This synergistic approach, combining molecular profiling, repurposed agents, and innovative delivery methods, aims to deliver personalized, effective cancer treatments that can circumvent resistance and improve patient prognoses (Repurposing anti-diabetic drugs for cancer therapy, Nanotechnology in drug repurposing for cancer, Tumor Organoids Research, Drug repurposing in oncology.

Economic and Practical Benefits of Drug Repurposing for Oncology Patients

Affordable access due to off-patent status

Many repurposed drugs are off-patent, which allows for significantly lower costs compared to newly developed cancer therapies. These drugs, such as metformin and propranolol, are widely available as generics, making them more affordable and accessible to patients globally. The reduced price points help bridge gaps in cancer care accessibility, especially in resource-limited settings or countries with high patient volumes. This aligns with the advantages of drug repurposing advantages and Drug repurposing.

Known safety and tolerability profiles aiding chronic use

Unlike novel drugs that require lengthy safety testing, repurposed medications come with established safety records from their original use. This advantage reduces the time and expense of evaluating toxicity and adverse effects, promoting confidence in chronic administration alongside standard cancer treatments. Drugs like anti-diabetics and anti-hypertensives, with decades of clinical use, offer predictable tolerability, which is beneficial for long-term cancer therapy regimens. The Safety and tolerability of repurposed chronic-use drugs and Repurposing of chronically used drugs in cancer therapy provide evidence for these benefits.

Potential to alleviate healthcare system burdens

Drug repurposing has the potential to diminish the financial and logistical pressures on healthcare systems. Lower-cost agents that can be integrated into effective cancer regimens help alleviate high medication expenditures typical of oncology care. Moreover, by potentially shortening development timelines and facilitating earlier patient access to therapies, repurposed drugs can reduce the overall burden on oncology infrastructure and improve treatment availability, particularly in the United States where cancer incidence and healthcare costs are substantial. See insights on Economic impact of drug repurposing in oncology and Advantages of repurposed drugs.

In summary, repurposed drugs provide a cost-effective, safe, and scalable option to enhance cancer treatment delivery while easing economic challenges for patients and healthcare providers alike.

Conclusion: The Promise of Repurposed Drugs in Combating Chemotherapy Resistance

The Potential of Repurposed Drugs in Cancer Therapy

Drug repurposing offers a promising, cost-effective approach to tackle chemotherapy resistance by harnessing existing drugs with known safety profiles. Agents like metformin, statins, beta-blockers, and disulfiram have demonstrated abilities to target pathways involved in cancer proliferation, metabolism, and immune evasion. Additionally, repurposed drugs can disrupt cancer stem cells, alter tumor microenvironment dynamics, and complement standard therapies, thus potentially overcoming major barriers to treatment effectiveness.

Integrating Novel Therapies with Compassionate Care

While repurposed drugs present innovative treatment options, their integration into clinical practice requires thoughtful application alongside patient-centered care. Addressing drug resistance is not just a molecular challenge but also involves personalized approaches that consider tumor heterogeneity, patient comorbidities, and quality of life. Combining repurposed drugs with emerging delivery technologies and immunotherapies fosters a comprehensive strategy for better outcomes.

Looking Ahead to Enhanced Cancer Outcomes

The future of cancer treatment hinges on innovative multi-modal strategies that include repurposed drugs, precision medicine, and nanotechnology. Ongoing clinical trials and translational research continue to clarify the utility of these therapies, especially for resistant and metastatic cancers. The convergence of repurposing efforts with advances in genomics, biomarker-driven therapies, and patient-centric models holds significant promise in improving survival and reducing relapse rates in cancer patients worldwide.