Friday, June 20, 2025

Citric acid-mediated ferroptosis strategy

click to view larger image (created with biorender.com)


For further details, please read the forum post.

For informational and research purposes only; none of my writing should be considered medical advice.

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Combinations of Natural Products and Repurposed Drugs 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. However, rational combination therapies can significantly improve outcomes.  I’ve created a visual guide with arrows and symbols highlighting synergistic interactions, key pathways, and processes between various compounds. These represent some of the safest and most effective natural substances and repurposed drugs that impair cancer growth and metastatic potential through multiple mechanisms. Top 10 natural substances are yellow-colored (refer to this spreadsheet containing a table with over 100 substances, providing a quick overview of those with broad-spectrum anticancer activity and helping to identify potential areas of concern).
  1. Artemisinin ðŸ›ˆ ⓟ🟥CT FER ST3 HIF  →  ↓ DHA docosahexaenoic acid ðŸ›ˆ ST3 FER  
  2. Curcumin ðŸ›ˆ ST3 G3 MT → Emodin → Celecoxib ðŸŸª COX-2 → Luteolin ðŸ›ˆ → Apigenin ðŸ›ˆ 
    • → 2:3 Docosahexaenoic acid ðŸ›ˆ → Butyrate ðŸ›ˆ  → Citric acid🛈 Gi RL RA → Graviola ðŸ›ˆ
      • → Melatonin  → Andrographis ðŸ›ˆ  → Berberine ðŸ›ˆ MT CT HIF → D-limonene ðŸ›ˆ
          • Danshen ↑ AM▼ ðŸ›ˆ → Naringin ðŸ›ˆ RA ↘ → 3:2 Quercetin  
        • → Shikonin ICD GI E⏷NK→ Apigenin  ↑        Fisetin ðŸ›ˆ →  Aspirin ðŸŸª PDK  
    • → Gallic acid FER → Chlorogenic acid ðŸ›ˆ                                         
    • → Taurine RA ↓                                                                                        
    • ⇒  EGCg ↓ +24h ♻ ðŸ›ˆ FAS Bcl2 → Quercetin  → Grapeseed extract ðŸ›ˆ AA E⏷ → P. linteus
    • → Nigella Sativa ↓ ↓ Thymoquinone  ðŸ›ˆ AA HIF NFi → Emodin
    • → Vitamin C ðŸ›ˆ HIF  LDHAi → Vitamin K2 ðŸ›ˆ E⏷* ↑
      • ⇒ Bicarbonate ðŸ›ˆ  → Galla Chinensis (gallic acid) LDHAi
      • → Magnesium RL 
      • → Juglone CCAA → Selenium (selenite)
      • → Vitamin K3
      • → Quercetin ðŸ›ˆ → Piperlongumine 
            • → Thymoquinone Bcl2/BAX
      • → Ashwagandha ðŸ›ˆ → CAPE ðŸ›ˆ
    • → ↓ Vitamin D  ðŸ›ˆ  → Lactoferrin RA → Linolenic acid ðŸ›ˆ
              • ⇒+72h Artemisinin ⓟ  → -1h Ivermectin 🟪 P-gp
          • →  Aspirin ðŸŸª PDK → Ferulic acid ðŸ›ˆ
          • →  Lycopene ðŸ›ˆ AI FAK → Capsaicin
          • → Î³-Tocotrienol
    • → Sulforaphane ðŸ›ˆ HIF ST5 nrf2▲!  ↑ → Dihydrocaffeic Acid 
    • → Galangal → Tulsi → Piper nigrum
      • → ↓ Berberine ðŸ›ˆ MT CT HIF RMDR → Zinc
    • → Oligomeric proanthocyanidins 
    • → Garcinol ðŸ›ˆ 
    • → Lactoferrin   
    • → Carnosic acid↓ → Fisetin ðŸ›ˆ → Quercetin → Caffeic acid → Coumaric acid ðŸ›ˆ
    • Mistletoe AA → Chaga ðŸ›ˆ → Rosmarinic acid ðŸ›ˆ RMDR EGFR  → Cinnamon RA → Berberine

    Top 10 natural substances (refer to spreadsheet) yellow colored
    → anticancer synergy with Artemisinin
    → ↑ ↘ ↗ additive or synergistic antineoplastic effect  ⇒ sequential 
    → ferroptosis 
    → combination may offer hepatoprotective effects
    → likely to be a good antineoplastic combination 
    🟥 ROS Classification of Natural Compounds in Cancer Therapy
    🟪 I've included a few non-oncology drugs that could enhance their anti-cancer action if combined with specific supplements. Repurposing non-oncology drugs is an attractive approach to improving cancer therapy.
    Ⓟ Link to blog or forum post
    🛈 Information about the substance

    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 exist, 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: Vitamin K, and other substances. 
    • * don't use in a ferroptosis strategy
    • 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
    • TMA: target metabolic adaptability of cancer cells
    • 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. 


    Safe and responsible use of natural supplements and repurposed medications


    Supplements should only be taken under the supervision of your healthcare provider or oncologist. 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. 


    For informational and research purposes only, none of my writing should be considered medical advice.
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    Sunday, November 3, 2024

    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

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