Combination of Natural Products as Adjunct Cancer Therapy

Natural supplements can be very helpful adjuvants to drug therapies, for example through chemosensitization of tumor cells. Unfortunately, it seems that very often there's little or no follow-through when readily available natural products show great potential in cancer treatment. Instead of simply providing a list, I’ve created a visual guide with arrows and symbols to highlight the synergistic interactions, key pathways and processes between various compounds. These represent some of the safest and most effective natural substances for inhibiting cancer growth and proliferation through multiple mechanisms.

1. Artemisinin 🛈 CT FER AA HIF →↓DHA docosahexaenoic acid 🛈 ↓ ST3 FER ↓
• → L-alanine 🛈 T RA → Citric acid 🛈 Gi RL RA → Melatonin ↓ 🛈 E⏷* → Shikonin 🛈 
• → Honokiol  🛈 LDHAi RMDR  → (orlistat) FAS FER  🟪🔶 → EGCg ↓ 🛈 FAS * AA
• → (metformin) AA   → Shikonin 🛈 Gi
• → Baicalein 🛈 HIF AA ST3 hsp90 → Silibinin 🛈 Jak2 β-CAT ↓
• → Oroxylin-A Gi          ↑ Chrysin 🛈 ↓
• → Modified Citrus Pectin 🛈 G3 → Ursolic acid 🛈 FAS E⏷→ Luteolin ↓ ST3 
• → Magnolol ↓ 🛈 β-CAT  + Ai 🛈 ↗    Piperine ↑10x → (celecoxib) ↗   I3C🛈 *  AM▼
• → Berberine 🛈 ↓LDHAi  → Coptidis Rhizoma EMT
•    → Andrographis 🛈
• → Curcumin 🛈 RMDR →  Luteolin 🛈 TGF-β 
• +   HDACi 🛈   → Melatonin ☼ 🛈 →  Curcumin ↓ →  Cannabidiol 🛈 → Magnolol
• + PDL1i 🛈 Ellagic acid 🛈 ↑ → Quercetin * 🛈 → Luteolin 🛈 FER 
• →  AHCC 🛈 ↓ MiR → Fucoidan 🛈 ST3 HIF FER RA (+200mg vit. C) 
• → Silibinin 🛈
• → Allicin 🛈 FER RMDR → Ginger/6-Shogaol 🛈 ICD  NO▼ → Anthocyanin 🛈 AM▼ 
• → Ornithine RA
• → Rosmarinic acid 🛈
• → Resveratrol 🛈 E! → 1000:1 Copper 🛈
• → ↓ Apigenin 🛈 CCAA  ↓ → Salvia miltiorrhiza 🛈 FER  → ↓ Astragalus 🛈 T ˃
2. Curcumin 🛈 ST3 G3 MT → Emodin → (celecoxib) 🟪🔶 COX-2 → Luteolin 🛈 → Apigenin 🛈 
• → 2:3 Docosahexaenoic acid 🛈 → Butyrate 🛈  → Citric acid🛈 Gi RL RA → Graviola 🛈
• → Melatonin ☼ → Andrographis 🛈  → Berberine 🛈MT CT HIF → D-limonene 🛈
• Danshen ↑AM▼ 🛈 → Naringin 🛈 RA ↘ → 3:2 Quercetin  
• → Shikonin ICD GI E⏷NK→ Apigenin  ↑        Fisetin 🛈 ↑   
• → Piperlongumine 🛈 FER ST3 → Sanguinarine → Berberine 🛈  ↘  → Caffeine
• → Gallic acid FER → Chlorogenic acid 🛈                                         Evodiamine COX-2
• → Taurine RA ↓                                                                                        
• ⇒ EGCg 🛈 🍋 FAS *↗ → Quercetin  → Grapeseed extract 🛈 AA E⏷ → P. linteus
• → Baicalin 🛈
• → Luteolin ↓ 🛈 nrf2▼ TGFβi → (celecoxib) 🟪🔶 nrf2▲ → Berbamine 🛈 ST3
• →  ↑   Curcumin   → Chrysin HIF → Silibinin 🛈
• → IP6 & Inositol 🛈  (+ 200mg Vit. C) 
• → Ginger / 6-Shogaol 🛈 AM▼ → Licorice  → Boswellia CCAA
• →  Chlorogenic acid 🛈 RAS → Theobromine 🛈 AA E⏷
•  → Cinnamon RA
• →↓ Milk Thistle 🛈 → Baicalein 🛈 HIF AA ST3 → Salvia miltiorrhiza 🛈 AM▼
• → Nigella Sativa ↓ ↓ Thymoquinone  🛈 AA HIF NFi → Emodin
• → Carvacrol
• → Melatonin ☼  🛈 ℹ  HIF SERM NK  → Aloe vera 🛈
• → Fisetin 🛈 EGFR
• → Ascorbyl Palmitate 🛈 
• → Vitamin D ☼ 🛈
• → Vitamin C 🛈 HIF  LDHAi → Vitamin K2 🛈 E⏷* ↑
• → Magnesium RL 
• → Juglone CCAA → Selenium (selenite)
• → Ashwagandha 🛈
• ⇒ Bicarbonate 🛈  → Galla Chinensis LDHAi
• → Quercetin 🛈 nrf2▼
• → ↓ Vitamin D ☼ 🛈  → Lactoferrin RA → Linolenic acid 🛈
• →  (aspirin) 🟪🔶 PDK → Ferulic acid 🛈
• →  Lycopene 🛈 AI FAK → Capsaicin
• → Sulforaphane 🛈 HIF ST5 nrf2▲!  ↑ → Dihydrocaffeic Acid 
  
• → Ashwagandha 🛈
• → (aspirin) → Methylsulfonylmethane 🛈
• → Biochanin A 🛈
• → Myricetin → Baicalein 🛈
• → Galangal → Tulsi → Piper nigrum
• → ↓ Berberine 🛈 MT CT HIF RMDR → Zinc
• → Oligomeric proanthocyanidins 
• → Garcinol 🛈    
• → Carnosic acid↓ → Fisetin 🛈 → Quercetin → Caffeic acid → Coumaric acid 🛈
3. Mistletoe AA → Chaga 🛈 → Rosmarinic acid 🛈 RMDR EGFR  → Cinnamon RA

→ anticancer synergy with Artemisinin

→ possible additive or synergistic antineoplastic effect ⇒ sequential 24h

→ ferroptosis 

→ combination may offer hepatoprotective effects

˃   anticancer synergy, continue with the first compound on the next line.

→ likely to be a good antineoplastic combination 

(....) OTC medications: I've included a few non-oncology drugs with the potential for enhanced anti-cancer action if used in combination with specific supplements. Repurposing non-oncology drugs is an attractive approach to improving cancer therapy.

Enhancing Absorption and Bioavailability

Consuming fat-soluble supplements alongside dietary fats like ghee butter or coconut oil can improve their absorption and utilization in the body. The ideal dosage for the compounds discussed in this blog is uncertain and would vary based on the type of cancer, the specific target, and the individual patient's response to the treatment.

Timing: Optimizing Supplement Intake for Enhanced Efficacy

It might be beneficial to take anticancer supplements late at night and to include a time during the night in your supplementation schedule e.g. 3AM "study suggests that nighttime is the right time for cancer to grow and spread in the body and that administering certain treatments in time with the body's day-night cycle could boost their efficiency" {ref|ref}. 

Synergistic Combinations

A natural substance may show potential against cancer, but often its effectiveness is limited by the need for excessively high concentrations to achieve significant benefits (in vitro concentrations not achievable in vivo). However, if synergies are present, those same substances may become significantly more effective at lower concentrations. Such combinations of nutraceuticals can also be used to overcome drug resistance or to sensitize cancer cells to therapeutic agents. 

Key Pathways and Processes

• ICD Immunogenic cell death
• Gi inhibitor of glycolysis
• CT cytotoxic
• RMDR reversing/sensitizing multidrug resistance
• MT multiple targets
• CCAA cell cycle arrest and apoptosis
• FAS fatty acid synthase inhibition
• AA anti-angiogenic
• EGFR epidermal growth factor receptor Inhibition
  
• LR lactate reduction
  
• FER ferroptosis induction, avoid co-administration of FER inhibitors EGCG, Sulforaphane, Indole-3-carbinol (I3C), Vitamin K, and other substances. 
  
• * Take separately and at least two hours apart from ferroptosis inducers unless it's a synergistic combination.
• AMPK ampk activator
• COX-2 cox-2 inhibitor
• AI anti-inflammatory
• FAK focal adhesion kinase downregulation
• SERM selective estrogen receptor modulator
• HIF hypoxia-inducible factor inhibition  drug resistance▼ 
• AM ▼▲autophagy modulation
• NO▼ Nitric Oxide
• ROSI reduces oxidative stress and inflammation
• NFi NF-κβ inhibition 
• ST3 STAT3 inhibition
• ST5 STAT5 inhibition
• PDK inhibition
• RA reduce ammonia 
• HDACi HDAC inhibition
• MiR modulate immune response
• E⏷ reduces estrogen
• RAS reducing Ras activity
• TGFβi inhibition of TGF-β
• LDHAi inhibition of LDHA
• NK stimulates the production of NK cells (additionally, check #7 here)
• G3 galectin 3 inhibition: MCP, curcumin, spiraeoside (red onions), QiShenYiQi, formic acid (apples, strawberries, raspberries, honey, nettles)
• T activation of T cells
• β-CAT: inhibition of β-catenin protein.
• hsp90 Inhibition of HSP90
• Jak2 JAK2 inhibition
• nrf2 Nuclear factor-erythroid 2 related factor. The transcription factor NRF2 exhibits a dual role in cancer. Its impact can vary depending on conditions such as cancer stage, cancer type, mutations, and cancer therapy. 
• E! Caution in hormonal cancers
• EMT Epithelial-Mesenchymal Transition inhibition
• TGF-β inhibition
• Please refer to the spreadsheet for more details on the effects of 100 supplements against 25 anticancer variables. 

Drug interactions

🔶 Be aware of drug interactions e.g. concurrent use of natural products with anticoagulants may result in prolonged bleeding times and should be avoided. 

🟪  Drug Repurposing

Additional Resources and Information

10 Dietary Strategies to put the brakes on cancer growth

5-Day Protocol

Sunshine, Vitamin D, and cancer

Medicinal herbs

What causes cancer?

Combinations of nutrients, supplements, and medicine

Cancer and Insulin

How To Design Your Supplement Program

Drug repurposing in cancer therapy

Healing Sounds & Music

Special supplement formulations

Pain management

FAQ

        

Safe and responsible use of natural supplements and repurposed medications

Supplements should only be taken under the supervision of a healthcare provider. Supplements or herbal preparations shouldn't be combined with chemotherapy, radiotherapy, immunotherapy, or any other cancer treatment unless the safety and efficacy of such combinations are established. It's especially important to make sure anything you add to the standard treatment will further improve its efficacy, hence the importance of discussing any addition of supplements or dietary interventions during active cancer treatment with the oncologist.

Solely intended for informational use, none of my writing constitutes medical advice.

Mechanisms of Tumor Metastasis and Treatment Approaches

The review article "Multi-stage Mechanisms of Tumor Metastasis and Therapeutic Strategies" provides a detailed review of cancer metastasis, a leading cause of cancer-related mortality. Metastasis refers to the process by which tumor cells spread from their primary site to distant organs, significantly contributing to the disease's lethality. The metastasis cascade involves several stages: invasion, intravasation, circulation, extravasation, and colonization. Circulating tumor cells (CTCs) leave the primary tumor, survive in the bloodstream, and eventually establish secondary tumors in distant organs.

A crucial factor in organ-specific metastasis is the formation of pre-metastatic niches (PMNs). These PMNs prepare distant organs for colonizing CTCs, making them more receptive to tumor growth. Primary tumors release extracellular vesicles that carry factors promoting PMN development, including the modulation of immune responses and enhancing cancer cell survival. The PMN is a dynamic environment composed of immune cells, stromal cells, and the extracellular matrix (ECM), with intricate interactions that facilitate tumor progression.

One of the key challenges in treating metastasis is tumor dormancy. Even after successful cancer treatments, residual cancer cells can remain dormant for years, escaping immune surveillance and avoiding detection. These dormant CTCs often undergo genetic and functional alterations, allowing them to resist treatments and eventually reawaken to form new metastatic tumors. This dormancy poses a significant hurdle in cancer therapy, as metastatic disease can recur long after the primary tumor has been controlled.

Epithelial-mesenchymal transition (EMT) is a critical process in metastasis, enabling tumor cells to acquire the migratory and invasive capabilities necessary for spreading. However, only a tiny fraction of CTCs undergoing EMT survive through the bloodstream and successfully colonize distant organs. These surviving cells enhance their metastatic potential through interactions with immune and stromal cells, which help them evade destruction by the immune system.

Immune evasion plays a fundamental role in tumor progression, particularly within the PMN. Tumor cells can manipulate their microenvironment to create an immunosuppressive niche, reprogramming immune cells like macrophages and T cells into pro-tumorigenic states. The microenvironment's hypoxic and metabolically altered conditions further contribute to immune cell exhaustion, allowing tumor cells to thrive unchecked.

The authors emphasize the importance of early intervention to combat metastasis. Rather than passively waiting for macrometastasis, it advocates for treatments that disrupt the metastatic process at its earlier stages. Therapeutic strategies targeting the PMN, enhancing immune responses, and preventing the reawakening of dormant cells show significant promise. The article also looks at potential therapies to prevent circulating tumor cells (CTCs) from adapting to new environments and disrupting epithelial-mesenchymal transition (EMT) processes.

A significant challenge in treating metastatic cancer is the development of drug resistance. Cancer cells often acquire resistance through genetic mutations or epigenetic changes, complicating the efficacy of current treatments. The article outlines various mechanisms of drug resistance observed during different stages of metastasis. It highlights the need for novel therapeutic strategies to overcome resistance, including targeting metabolic pathways and leveraging immune-based therapies to restore effective anti-tumor responses.

Liu, Z., Chen, J., Ren, Y. et al. Multi-stage mechanisms of tumor metastasis and therapeutic strategies. Sig Transduct Target Ther 9, 270 (2024). https://doi.org/10.1038/s41392-024-01955-5

Synergistic Anticancer Effects of Diclofenac and Metformin

Repurposing non-oncology drugs for cancer treatment has become an area of increasing interest. In particular, combinations of well-known pharmaceuticals are being explored to enhance anticancer effects, minimize toxicity, and reduce dosages necessary for clinical efficacy. The following study evaluated the potential synergistic anticancer effects of diclofenac (an anti-inflammatory drug) and metformin (a diabetes medication) in a hamster fibrosarcoma model. Fibrosarcoma, a malignant tumor derived from fibrous connective tissues, provides a relevant animal model to investigate tumor growth and response to treatment in vivo.

Study: Diclofenac and metformin synergistic dose dependent inhibition of hamster fibrosarcoma, rescued with mebendazole. Biomed Pharmacother. 2023 Nov;167:115528. doi: 10.1016/j.biopha.2023.115528. Epub 2023 Sep 20. PMID: 37738800.

Background and Rationale

Both diclofenac and metformin have been shown to possess anticancer properties. Diclofenac is recognized for its inhibition of cyclooxygenase-2 (COX-2) and suppression of the nuclear factor-kappa B (NF-κB) signaling pathway, which plays a crucial role in the development and progression of cancer. Metformin has been widely studied for its ability to regulate glucose metabolism, inhibit NF-κB, and impact various oncogenic pathways. Given their individual effects, the combination of these drugs could act synergistically to inhibit cancer cell proliferation more effectively than either drug alone.

Methods

The study employed an established hamster fibrosarcoma model using BHK-21/C13 cells inoculated into Syrian golden hamsters. The experimental design included several treatment groups: control (saline), diclofenac alone, metformin alone, a combination of diclofenac and metformin, and a triple combination of diclofenac, metformin, and mebendazole (an antiparasitic drug used as a rescue experiment to stimulate NF-κB).

The study evaluated the following aspects of tumor growth:

Tumor volume

Tumor weight

Tumor surface area

Tumor burden (relative to body weight)

The tumors' histological and immunohistochemical characteristics included markers of proliferation (Ki-67, PCNA), glucose metabolism (GLUT-1), nitric oxide production (iNOS), angiogenesis (CD34, CD31), and apoptosis (COX4, cytochrome C).

The primary objective was to assess the efficacy of the diclofenac-metformin combination compared to the control and single-agent treatments.

Results

Tumor Reduction with Diclofenac and Metformin

The study's most significant finding was the marked tumor reduction in the combination treatment group. Hamsters treated with the combination of diclofenac and metformin showed the following improvements over single-agent treatments and the control group:

Tumor Volume: The combination therapy significantly decreased tumor volume, with mean tumor sizes smaller than those observed in the diclofenac or metformin monotherapy groups. For example, tumors in the combination group exhibited approximately a 90% reduction in volume compared to the control.

Tumor Weight and Surface Area: Similarly, tumors' weight and surface area were reduced by more than 80% in the combination group. In contrast, single-agent treatments showed moderate reductions but were not statistically significant compared to the control.

Tumor Burden: The combination therapy also reduced tumor burden (tumor weight as a percentage of total body weight), demonstrating that the diclofenac-metformin regimen effectively inhibited tumor growth.

Single-Agent Treatments: Diclofenac and Metformin

While diclofenac and metformin showed some potential to reduce tumor growth, their effects were modest compared to the combination. Neither diclofenac nor metformin as monotherapies significantly reduced tumor volume, weight, or burden. This highlights the importance of combining these two agents to achieve a potent anticancer effect.

Diclofenac Alone: In the diclofenac treatment group, tumor volume reductions were observed, but they were less pronounced and did not reach statistical significance. The drug's anti-inflammatory properties may have contributed to a slight inhibition of tumor progression, but the drug alone was insufficient to halt tumor growth.

Metformin Alone: Metformin alone had minimal effects on tumor size and volume. While metformin is known to modulate glucose metabolism and inhibit NF-κB, its influence on tumor growth in this model was limited without the addition of diclofenac.

Histological and Immunohistochemical Findings

The combination of diclofenac and metformin not only reduced tumor size but also exerted significant effects on several tumor growth processes:

Proliferation Markers (Ki-67, PCNA): Tumors treated with the combination therapy had significantly lower levels of Ki-67 and PCNA, indicating reduced cell proliferation. These markers are commonly used to assess tumor growth rate, and their reduction suggests that the combination therapy effectively slowed down the replication of cancer cells.

Glucose Metabolism (GLUT-1): GLUT-1 is a marker of glucose uptake and metabolism in cancer cells. The reduced expression of GLUT-1 in the combination therapy group implies that the tumor's metabolic activity was impaired, potentially due to metformin’s effect on glucose regulation.

Nitric Oxide Production (iNOS): The combination therapy also resulted in a significant decrease in iNOS expression, suggesting that the tumor's inflammatory environment was suppressed. This could be attributed to diclofenac’s anti-inflammatory properties.

Angiogenesis (CD34, CD31): the formation of new blood vessels to supply the tumor with nutrients was significantly reduced in the combination therapy group. This is a critical finding, as the inhibition of angiogenesis can starve the tumor of the necessary resources to grow and spread.

Apoptosis (COX4, Cytochrome C): Markers of apoptosis, including COX4 and cytochrome C, were significantly increased in the combination therapy group. This suggests that diclofenac and metformin together induced programmed cell death, a desirable outcome in cancer treatment.

The Role of Mebendazole

Interestingly, the triple therapy that included mebendazole did not provide additional benefits. In fact, adding mebendazole to the diclofenac-metformin combination "rescued" tumor growth; mebendazole blocked the anticancer activity of the diclofenac and metformin combination. 

Mebendazole is known to stimulate NF-κB, a pathway inhibited by diclofenac and metformin, which may explain why its addition negated the anticancer effects. This finding underscores the importance of careful consideration when combining multiple drugs in cancer therapy, as certain combinations may lead to antagonistic effects.

This study provides compelling evidence that combining diclofenac and metformin can significantly reduce tumor growth in a hamster fibrosarcoma model. The synergistic effects of the two drugs were evident across multiple parameters, including tumor volume, weight, and key markers of proliferation, metabolism, and apoptosis. Importantly, this combination was well-tolerated and did not induce significant toxicity in the treated animals, making it a promising candidate for further investigation in cancer therapy.

Single-agent treatments with diclofenac or metformin were relatively ineffective, highlighting the power of combination therapy to target multiple pathways simultaneously. The role of NF-κB inhibition appears to be crucial, as demonstrated by the failure of the triple therapy with mebendazole, which activated NF-κB and reversed the anticancer effects of diclofenac and metformin.

In sum, the combination of diclofenac and metformin represents a promising approach to cancer treatment. By repurposing these affordable, well-established drugs, this strategy offers a potential low-toxicity, cost-effective solution to improving cancer patients' outcomes.