Hallmarks of Cancer & Their Matching Drugs (Oncology and Repurposed Drugs) and Supplements (2025)

Hallmarks of Cancer 101

The hallmarks of cancer describe the key biological capabilities acquired during the multistep development of human cancer. These were first proposed by Douglas Hanahan and Robert Weinberg in 2000 and later updated in 2011 and again in 2022 to reflect emerging knowledge (Cell 2000, Cell 2011, AACR 2022).

Note: Cancer cells have a number of characteristics that distinguish them from normal cells. These characteristics are known as the "cancer hallmarks".

Diverse cancer hallmarks targeted by repurposed non-oncology drugs. This figure was created with Biorender.com. Source: Nature 2024

Hallmarks of Cancer & Their Matching Drugs (Oncology and Repurposed Drugs) and Supplements

Here’s a breakdown of the core hallmarks along with examples of drugs (oncology and repurposed) and supplements that target each hallmark:

---

1. Sustaining Proliferative Signaling

• Cancer cells continuously signal themselves to grow.

• Targeted by:

• EGFR inhibitors (e.g., Erlotinib, Gefitinib)

• HER2 inhibitors (e.g., Trastuzumab)

• Metformin: Inhibits the mTOR pathway and insulin/IGF-1 signaling.

• Statins: Interrupt HMG-CoA reductase, affecting membrane signaling and growth.

• Curcumin: Suppresses growth factors like EGF and VEGF.

---

2. Evading Growth Suppressors

• Cancer cells inactivate tumor suppressor genes (e.g., TP53, RB1).

• Targeted indirectly by:

  • CDK4/6 inhibitors (e.g., Palbociclib) – affect the RB pathway

  • MDM2 inhibitors – stabilize p53 (still experimental)

  • Gendicine (p53 gene therapy) - (experimental)

  • Aspirin: Modulates p53 and COX pathways, affecting inflammation-linked growth.

  • Curcumin: Reactivates tumor suppressor genes via epigenetic modulation.

  • Disulfiram (with copper): Inhibits NF-κB and ALDH, promoting tumor suppressor pathways.

---

3. Resisting Cell Death

• Cancer cells avoid apoptosis (programmed cell death).

• Targeted by:

  • BCL-2 inhibitors (e.g., Venetoclax)

  • Cisplatin and carboplatin (induces DNA damage and apoptosis)

  • 5-Fluorouracil (inhibits DNA/RNA synthesis, induces apoptosis)

  • Mebendazole: Induces apoptosis by destabilizing microtubules.

  • Fenbendazole: Triggers mitochondrial apoptosis and interferes with glucose metabolism.

  • Doxycycline: Targets mitochondria to disrupt cancer cell survival.

  • Ivermectin: Enhances apoptosis by modulating chloride channels and mitochondrial dysfunction.

  • Melatonin: Promotes apoptosis via ROS generation and p53 activation.

---

4. Enabling Replicative Immortality

• Tumors maintain telomeres for unlimited division.

• Targeted by:

  • Telomerase inhibitors (e.g., Imetelstat) – experimental

  • Curcumin & Melatonin: Downregulate telomerase activity in cancer cells.

  • Doxycycline: Can inhibit cancer stem cell populations that are telomerase-positive.

---

5. Inducing Angiogenesis

• Tumors stimulate the formation of new blood vessels.

• Targeted by:

  • VEGF inhibitors (e.g., Bevacizumab)

  • Propranolol: Anti-angiogenic; reduces VEGF production.

  • AHCC*: Modulates cytokines that can affect angiogenesis.

  • Fish Oil: May inhibit angiogenesis via PPAR modulation and eicosanoid signaling.

---

6. Activating Invasion and Metastasis

• Cancer spreads to other tissues.

• Targeted by:

  • MMP inhibitors, 

  • HGF/MET inhibitors, 

  • Integrin inhibitors – many are still in trials

  • Propranolol: Blocks stress-induced invasion via β-adrenergic pathways.

  • Statins: Reduce migration and invasion by affecting cytoskeletal function.

  • Curcumin: Inhibits MMPs (enzymes that degrade tissue barriers).

---

7. Genome Instability and Mutation

• Cancer cells accumulate mutations.

• Targeted by:

  • PARP inhibitors (e.g., Olaparib) – especially effective in BRCA-mutant cancers

  • 5-Fluorouracil (disrupts DNA synthesis)

  • Curcumin & Resveratrol: Antioxidants that protect against DNA damage.

  • Doxycycline: May indirectly affect mutation rates by disrupting mitochondrial integrity in cancer stem cells.

---

8. Tumor-Promoting Inflammation

• Chronic inflammation promotes tumor growth.

• Targeted by:

  • NSAIDs (e.g., Aspirin) – some evidence of cancer prevention

  • IL-1/IL-6 inhibitors – under investigation

  • Aspirin: Inhibits COX enzymes, key drivers of inflammatory pathways.

  • Fish Oil: Reduces pro-inflammatory prostaglandins.

  • Curcumin & Melatonin: Broad anti-inflammatory effects.

---

9. Deregulating Cellular Energetics

• Cancer cells rely on altered metabolism (e.g., Warburg effect).

• Targeted by:

  • Metformin, IDH inhibitors (e.g., Ivosidenib)

  • Fenbendazole & Metformin: Disrupt glucose metabolism.

  • Disulfiram: Disrupts mitochondrial respiration.

  • CoQ10: Supports normal mitochondrial function, indirectly opposing cancer's metabolic reprogramming.

---

10. Avoiding Immune Destruction

• Tumors evade the immune system.

• Targeted by:

  • Immune checkpoint inhibitors

    • PD-1/PD-L1 inhibitors (e.g., Nivolumab, Pembrolizumab)

    • CTLA-4 inhibitors (e.g., Ipilimumab)

  • Cellular Therapy
  • NK Cells

  • Cimetidine: Enhances immune response by blocking histamine receptors.

  • AHCC & Turkey Tail Mushroom: Activate NK cells and macrophages.

  • Melatonin: Modulates immune surveillance and cytokine activity.

---

New Emerging Enabling Characteristics (Hanahan, 2022 update):

• Unlocking phenotypic plasticity

• Non-mutational epigenetic reprogramming

• Polymorphic microbiomes

• Senescent cells

11. Unlocking phenotypic plasticity

• Ability to switch between cell states
• Targeted by:
• EMT inhibitors (under research), 
• epigenetic modulators

12. Non-mutational epigenetic reprogramming

• Gene expression changes without mutations
• Targeted by:
• DNMT inhibitors (Azacitidine), 
• HDAC inhibitors (Vorinostat)

13. Polymorphic Microbiomes

• Microbes modulate cancer environment and immune response
• Targeted by:
• Probiotics, 
• antibiotics, 
• fecal microbiota transplant (exploratory)

14. Senescent Cells

• Accumulated cells that promote inflammation
• Targeted by:
• Senolytics (Navitoclax, FOXO4-DRI – under development)
• Fisetin
• Resveratrol

Hallmarks of Cancer & Their Matching Drugs (Oncology and Repurposed Drugs) and Supplements - Table

A structured table summarizing the Hallmarks of Cancer, their descriptions, and examples of targeted oncology drugs, repurposed drugs, and supplements that address each hallmark, including the emerging characteristics from the 2022 update by Hanahan.

Notes:

• Oncology Drugs: These are FDA-approved or in clinical trials, specifically designed for cancer treatment.
• Repurposed Drugs: Non-cancer drugs with evidence of anti-cancer effects, often used off-label or in research.
• Supplements: Natural compounds with preclinical or limited clinical evidence for cancer-related effects; should be used cautiously and under medical supervision.
• Emerging Hallmarks: Based on Hanahan’s 2022 update, these are newer areas of research with fewer established treatments.
• Always consult a healthcare professional before using any drugs or supplements for cancer treatment.