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 ST3 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 → IP6 🛈
• → Metformin 🟪  → Shikonin 🛈 → Luteolin FER   ↑ ↗ → Ivermectin 🟪 β-CAT
• → Berberine   → ↓ Andrographis 🛈 → Melatonin
• → Apigenin 🛈 → Curcumin 🛈  ↘ 
• → Baicalein 🛈 HIF AA ST3 hsp90 → Silibinin 🛈 Jak2 β-CAT 
• → Oroxylin-A Gi →    ↑ Chrysin 🛈 ↓
• → γ-Tocotrienol HIF ST3
• → Modified Citrus Pectin 🛈 G3 → Ursolic acid 🛈 FAS E⏷→ Luteolin ↓ ST3 
• → Magnolol ↓ 🛈 β-CAT  + Ai 🛈 ↗    Piperine ↑10x → Curcumin↑→  I3C 🛈 * E⏷
• → Berberine 🛈 ↓LDHAi  → Coptidis Rhizoma EMT
• → ↓Curcumin 🛈 RMDR →  Luteolin 🛈 TGF-β  → Silibinin 🛈
• → Piperlongumine 🛈 CT FER ST3 → Sanguinarine → Berberine 🛈   → Caffeine
• → Allicin 🛈 FER RMDR → Ginger/6-Shogaol 🛈 ICD  NO▼ → Anthocyanin 🛈 AM▼ 
• → L-ornithine RA
• → Bicarbonate 🛈  → Galla Chinensis LDHAi
• +  HDACi 🛈 → Melatonin  🛈 →  Curcumin ↓ →  Cannabidiol 🛈 → Magnolol
• +  PD(L)1i 🛈 Ellagic acid 🛈 ↑ → Quercetin * 🛈 → Luteolin 🛈 FER 
• → Silibinin 🛈
• → 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 🛈 ↑   
• → Gallic acid FER → Chlorogenic acid 🛈                                         
• → 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 🛈 
• → 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⏷* ↑
• ⇒ Bicarbonate 🛈  → Galla Chinensis LDHAi
• → Magnesium RL 
• → Juglone CCAA → Selenium (selenite)
• → Vitamin K3
• → Quercetin 🛈 → Piperlongumine
• → Ashwagandha 🛈
• → ↓ Vitamin D  🛈  → Lactoferrin RA → Linolenic acid 🛈
• →  Aspirin 🟪 PDK → Ferulic acid 🛈
• →  Lycopene 🛈 AI FAK → Capsaicin
• → γ-Tocotrienol
• → 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

→ additive or synergistic antineoplastic effect  ⇒ sequential 

→ ferroptosis 

→ combination may offer hepatoprotective effects

→ likely to be a good antineoplastic combination 

(OTC) medications: I've included a few non-oncology drugs that, if used in combination with specific supplements, could enhance their anti-cancer action. 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. Still, its effectiveness is often 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 30 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

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 vital to make sure anything you add to the standard treatment will further improve its effectiveness; hence, discussing any addition of supplements or dietary interventions during active cancer treatment with the oncologist is essential.

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

Ferroptosis and FASN

Ferroptosis, a form of programmed cell death characterized by iron-dependent lipid peroxidation, is a promising avenue in cancer therapy. New research shows that disrupting cancer cells' lipid metabolism can enhance their susceptibility to ferroptosis. Orlistat, an FDA-approved anti-obesity drug known for inhibiting fatty acid synthase (FASN), plays a pivotal role in this context.

A study by Lian and colleagues demonstrated that restricting cancer cells' access to fats increases their sensitivity to ferroptosis. By inhibiting FASN, Orlistat effectively reduces lipid synthesis within cancer cells, thereby promoting ferroptosis. This mechanism was observed in lung cancer cells, where orlistat inhibited cell proliferation and induced ferroptosis-like cell death. 

Combining orlistat with ferroptosis inducers could be an effective strategy for cancer treatment. By simultaneously disrupting lipid metabolism and inducing ferroptosis, this approach could potentially overcome resistance mechanisms that cancer cells employ against conventional therapies.

References

Sokol, K. H., et al (2024) Lipid availability influences ferroptosis sensitivity in cancer cells by regulating polyunsaturated fatty acid trafficking. Cell Chemical Biology. doi.org/10.1016/j.chembiol.2024.09.008.

Zhou, W., Zhang, J., Yan, M. et al. Orlistat induces ferroptosis-like cell death of lung cancer cells. Front. Med. 15, 922–932 (2021). https://doi.org/10.1007/s11684-020-0804-7

Enhanced Cancer Immunotherapy by Targeting Monoamine Oxidase A (MAO-A)

Monoamine oxidase A (MAO-A), an enzyme historically studied for its role in neurotransmitter metabolism, has emerged as a promising target in cancer immunotherapy. By inhibiting MAO-A, researchers have found a potential to improve immune responses within the tumor microenvironment, particularly by enhancing the function of immune cells such as CD8+ T cells and tumor-associated macrophages (TAMs). Findings from recent studies demonstrate that MAO-A inhibition can significantly reduce tumor growth, presenting a dual-purpose pathway that leverages known MAO-A inhibitors for both neurological and oncological applications.

MAO-A metabolizes monoamines like serotonin, dopamine, and norepinephrine in the brain, influencing emotional and behavioral states. However, recent studies reveal that MAO-A regulates immune cell functions, especially within the tumor microenvironment. This dual role makes MAO-A a unique target in cancer, as inhibiting it may enhance the body’s antitumor immune response. For instance, high MAO-A activity has been linked to immune suppression, fostering a pro-tumor environment by regulating immune cell metabolism and suppressing T-cell activity.

The reviewed study highlights how MAO-A inhibition upregulates key antitumor cytokines, such as interferon-gamma (IFN-γ), and cytotoxic molecules like granzyme B. These findings support the theory that reducing MAO-A activity alleviates immune cell exhaustion and promotes the proliferation and effectiveness of tumor-infiltrating T-cells, essential players in targeting cancer cells.

One of the critical mechanisms by which MAO-A inhibition supports antitumor immunity is through serotonin, a neurotransmitter often degraded by MAO-A. CD8+ T cells produce serotonin as an activation signal, which supports their proliferation and cytotoxic function. However, high MAO-A activity in the tumor environment degrades serotonin, leading to suppressed T-cell activity. Inhibiting MAO-A has been shown to maintain serotonin levels, facilitating a robust T cell response and enhancing T cell activation through serotonin signaling pathways.

According to recent findings, MAO-A inhibitors like phenelzine, clorgyline, and moclobemide significantly enhance serotonin-mediated T-cell activation, amplifying downstream pathways critical for immune responses. These inhibitors effectively prevent immune cell exhaustion by maintaining elevated serotonin levels, promoting a sustained immune assault on tumor cells.

MAO-A inhibitors could become valuable alongside existing immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 blockers. MAO-A inhibition reduces the expression of exhaustion markers in T cells, allowing these cells to better respond to checkpoint inhibition therapies. Combining MAO-A inhibitors with anti-PD-1 therapy demonstrated enhanced antitumor efficacy, with significant tumor suppression in preclinical models.

Furthermore, MAO-A inhibition has been shown to impact other immunosuppressive cells in the tumor microenvironment, such as TAMs. MAO-A influences TAM polarization by promoting an immunosuppressive phenotype through increased reactive oxygen species (ROS) production, which fosters oxidative stress and dampens immune responses. Blocking MAO-A reduces ROS levels, reprogramming TAMs toward a pro-inflammatory state, thereby boosting the immune response against the tumor.

Given MAO-A inhibitors’ long history in treating neurological disorders, side effects related to serotonin syndrome and hypertensive crises from dietary tyramine intake are known challenges. The reviewed research suggests combining MAO-A inhibitors with nanoformulations, such as cross-linked multilamellar liposomal vesicles, could mitigate these side effects while preserving antitumor efficacy. This approach has already demonstrated superior results in preclinical melanoma models, offering a promising pathway for safer clinical applications.

Methylene Blue (MB) may be a safe alternative to traditional MAO-A inhibitors for enhancing antitumor immunity. Unlike irreversible MAO-A inhibitors such as phenelzine and clorgyline, which carry risks of serotonin syndrome and hypertensive crises when combined with certain foods or medications, MB acts as a reversible MAO-A inhibitor. This reversible action maintains MAO-A activity at a modulated level, reducing the likelihood of adverse interactions, but also leverages MB’s inherent antioxidant properties, which help regulate reactive oxygen species (ROS) levels in immune cells. By balancing oxidative stress and preserving serotonin within the tumor microenvironment, MB may sustain CD8+ T cell activity and support TAM reprogramming without the side effects associated with traditional MAO-A inhibitors. This dual action could make MB a compelling candidate for cancer immunotherapy, presenting a safe, accessible approach to amplifying immune responses against tumors.

The dual role of MAO-A in both neurological and immunological regulation makes it an exciting target in cancer therapy. Repurposing MAO-A inhibitors offers a feasible approach to enhance antitumor immunity, leveraging their established safety profiles for new therapeutic avenues. 

References

Wang, Xi & Li, Bo & Kim, Yu & Wang, Yu-Chen & Li, Zhe & Yu, Jiaji & Zeng, Samuel & Ma, Xiaoya & Choi, In Young & Di Biase, Stefano & Smith, Drake & Zhou, Yang & Li, Yan-Ruide & Ma, Feiyang & Huang, Jie & Clarke, Nicole & To, Angela & Gong, Laura & Pham, Alexander & Yang, Lili. (2021). Targeting monoamine oxidase A for T cell–based cancer immunotherapy. Science Immunology. 6. eabh2383. 10.1126/sciimmunol.abh2383. 

Ma, Y., Chen, H., Li, H. et al. Targeting monoamine oxidase A: a strategy for inhibiting tumor growth with both immune checkpoint inhibitors and immune modulators. Cancer Immunol Immunother 73, 48 (2024). https://doi.org/10.1007/s00262-023-03622-0

Gillman, Ken & Ng, Bradley & Cameron, Andrew & Liang, Rhea. (2008). Methylene blue is a potent monoamine oxidase inhibitor. Canadian Journal of Anesthesia/Journal canadien d'anesthésie. 55. 311-312. 10.1007/BF03017212.