How Caffeine Makes Chemo- Radio- & Immunotherapy More Effective

Caffeine is so well know by all of us, and this is why I will not discuss anything about it’s background. Instead, I will jump directly to discuss the aspects I find the most relevant for the potential of caffeine in cancer treatments. However, before that, I would like to make the point that Caffeine interfere with important mechanisms in cancer. So important, that pharmaceutical industry is investing several hundred of million dollars in developing drugs that can effectively act on some of the mechanisms discussed below. This is why, I also shortly mentioned the pharma and biotech companies working in this area, and the related drugs under development.

Caffeine reactivates the immune system near the tumors

Deprivation of oxygen (hypoxia) limits availability of energy sources and induces accumulation of extracellular Adenosine in tumors (Ref.). Accumulation of Adenosine also happens when chemo or radio therapy attacks tumors (Ref.).

Adenosine, binds to adenosine receptors on the surface of various immune cells (inactivating T cells, NK cells, macrophages/dendritic cells, neutrophils and activating regulatory T (Treg) cells) leading to an immunosuppressive environment (Ref.1, Ref.2). Indeed, the significance of adenosine in tumor survival strategy has been already shown in preclinical studies that demonstrate tumor regression after inactivation of adenosine receptors (Ref.1, Ref.2, Ref.3).

In line with the above points, adenosine has an anti inflamatory action. Which in general is good. However, it’s high occurrence around the tumors is detrimental when fighting cancer. Therefore, when searching for ways to increase immune reactions during anti cancer treatments, the inhibition of adenosine receptors is an important aspect to consider.

Adenosine receptors are of several types, and caffeine (most commonly found in tea, coffee and cacao plants) can inhibit those receptors leading to reactivation of the immune system cells (Ref.1, Ref.2, Ref.3). Adenosine receptors inhibition, is the same mechanism through which caffeine “affects brain functions such as sleep, cognition, learning, and memory, and modifies brain dysfunctions and diseases: Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Epilepsy, Pain/Migraine, Depression, Schizophrenia” (Ref.).

Arcus Bioscience, a biotech company, works on a drug to do exactly that, i.e. antagonize the adenosine receptors. The drug is called AB928 and here is how the company describes it: “AB928 is a potent and selective dual antagonist of the adenosine receptors known as A2aR and A2bR. Adenosine is a powerful immunosuppressive substance produced inside tumors as a result of rapid cancer cell turnover and, in some cases, in connection with certain anti-tumor interventions, such as chemotherapy and radiation. The A2aR and A2bR receptors are expressed on the surface of immune cells (such as T cells, NK cells, dendritic cells and macrophages) and mediate the immunosuppressive effects of adenosine. AB928, a small-molecule drug that will be administered to patients orally, is the only drug currently in development that is able to block both of these adenosine receptors.” (Ref.1, Ref.2).

Caffeine reduces new vessel formation that feed tumors (angiogenesis inhibition)

Adenosine promotes angiogenesis (Ref.1, Ref.2). Indeed, it is known that adenosine stimulates the release of interleukin-8 (IL-8), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF). It converts macrophages from a pro-inflammatory phenotype that generates large amounts of tumor necrosis factor-α and IL-6 to a pro-angiogenic phenotype that predominantly secretes VEGF to promote tissue repair (Ref.1, Ref.2). All thes mechanisms promote new vessel formation at the tumor.

Therefore, adenosine receptors inhibition (and thus, caffeine) will interfere with these angiogenesis mechanisms reducing the new vessel formation.

Note: Theobromine, the substance in cocoa and chocolate that gives it’s bitter taste is also an adenosine receptor antagonist. It has been suggested that might be a potent inhibitor of angiogenesis induced by ovarian cancer cells and its mechanism of action is related to inhibition of VEGF production (Ref.).

Caffeine induces vasodilation & better blood flow to the tumor, supporting the transport of drugs to the tumor locations

In order to grow fast, tumors grow new blood vessels relatively fast to continue receiving the required supplies. As a result the blood vessels grown by the tumors are often malfunctioning, leaking fluids out of the vessels (Ref.1, Ref.2). This hinders effective transit of drugs to the tumor (Ref.).

Caffeine is a well known vasodilation. The mechanisms behind this phenomena are multiple, many of which are an outcome of its adenosine receptor inhibition action (including increase in circulating catecholamines, peripheral vascular resistance, and renin secretion), and are discussed in detail in the references (Ref.1, Ref.2).

This vasodilation characteristic of caffeine is very helpful, as it enables the drug to better reach the tumor location. Indeed, restoring leaky blood vessels could increase chemo effectiveness (Ref.). In addition, more oxygen will reach the tumor which is expected to specifically help both chemotherapy and radiotherapy.

Therefore, caffeine taken before and during the chemotherapy, radiotherapy and/or immunotherapy cycles may lead to improvement of the therapy outcome.

Note: Nitroglycerin is a drug with vasodilation capabilities that was shown to enhanced the delivery of the anticancer drugs to tumors (Ref.1, Ref.2).  Other supplements with vasodilation properties are Niacin (Vitamin B3) and Quercetin.

Caffeine doesn’t allow tumors to go into the repair mode, when damaged by cancer theraphies

During their lifetime, cells go through various phases (G1, S, G2, and M phases) before division. Progression from one phase to the next phase in the cell cycle is monitored by checkpoints. Those checkpoints monitor the stability of replication and division of the cells (Ref.1, Ref.2).

When DNA damage is produced by e.g. chemotherapy or radiotherapy, cancer cells stop the cell cycle (called cell cycle arrest) and start repairing the damage before entering the division (M) phase (Ref.1, Ref.2.). This is triggered by signals that are send within the cell once there is a damaged, activating two different pathways (ATR or ATM kinases ) and the related checkpoints (such as Chk1 or Chk2). (Ref.). For example, damage by radiation triggers ATM/Chk2 pathway, while damage by chemo triggers ATR/chk1 pathway (Ref.1, Ref.2).

Cells that are defective and are continuing to divide before being repaired, will move on a path that leads to cell-death after cell division (Ref.). Therefore, inhibiting the signaling pathways (ATR or ATM, or the related checkpoints Chk1 or Chk2) will inhibit the repair of DNA damage and will lead to the cancer cell death (Ref.).

Caffeine is known as an efficient inhibitor of cellular DNA repair (Ref.). It has been reported to inhibit ATM and ATR and was found to indeed lead to the disruption of multiple DNA damage-responsive cell cycle checkpoints (Ref.1, Ref.2, Ref.3). It has been shown that caffeine treatment sensitizes mammalian cells to irradiation and other DNA damaging agents (Ref.1, Ref.2). Administration of caffeine enhances the removal of DNA-damaged cells by inhibiting the ATR, pushing damaged cells towards a lethal division (Ref.).

It has been suggested that although caffeine is an inhibitor of ATM-ATR kinase activity in vitro, it can block checkpoints without inhibiting ATM-ATR activation in vivo (Ref.).

In conclusion, regardless if caffeine blocks the checkpoints via ATM-ATR, or in other ways, the result is clear: caffeine is known as an efficient inhibitor of cellular DNA repair.

This characteristic of caffeine is extremely important in cancer treatment. Inhibitors of cellular DNA repair are currently in development at several biotech & pharma companies and are showing promising results. The companies that are currently developing checkpoint inhibitors are the following:

Administration/Dose:

The fact that caffeine increases plasmatic levels of stress hormones is a drawback and therefore we may not want to use it constantly but only when needed, such as priors and during specific cancer therapies. Also, chronic consumption of caffeine creates a tolerance to its adenosine receptor-dependent effects, so it is better to use it in cycles.

According to this website, here are some reference points on Caffeine oral daily dose:

Common: 50 – 150 mg
Strong: 150 – 400 mg
Heavy: 400 + mg
Lethal: 3-20 grams oral (estimated)
LD50 (Lethal Dose): 192 mg/kg in rats. (LD50 = dose which will kill 50% of the tested animals.)

Here is a study on humans using various daily doses of caffeine with the highest dose used going >600mg/day and minimum <200mg/day (Ref.).

Acknowledgements:

Some of the points above have been kindly brought to my attention by Frank Liu, via comments on this post https://www.cancertreatmentsresearch.com/reduce-cholesterol-in-cancer-cells-to-fight-cancer/ and wold like here to thank for his contribution.

Other References:

The hypoxic tumour microenvironment https://www.nature.com/articles/s41389-017-0011-9

Hypoxia-Driven Adenosine Accumulation: A Crucial Microenvironmental Factor Promoting Tumor Progression https://link.springer.com/chapter/10.1007%2F978-1-4939-3023-4_22

Radiation and the Immune System: Current Knowledge and Future Perspectives (Ref.)

Breakthrough discovery made in cancer treatment https://www.sciencedaily.com/releases/2015/03/150304190238.htm

Caffeine Inhibits Adenosine-Induced Accumulation of Hypoxia-Inducible Factor-1α, Vascular Endothelial Growth Factor, and Interleukin-8 Expression in Hypoxic Human Colon Cancer Cells http://molpharm.aspetjournals.org/content/72/2/395

Introduction to Adenosine Receptors as Therapeutic Targets https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3415694/

Why are tumour blood vessels abnormal and why is it important to know? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661770/

Extracellular Adenosine-Mediated Modulation of Regulatory T Cells https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091046/

Checkpoint kinase 1 in DNA damage response and cell cycle regulation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3731415/

Cell Cycle Regulation by Checkpoints https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990352/

Cell Cycle, Checkpoint Control and DNA Damage Resources https://www.cellsignal.com/contents/science-cst-pathways/cell-cycle-checkpoint-control-and-dna-damage-resources/science-pathways-cell-cycle

The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle http://jcs.biologists.org/content/128/4/607

Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. https://www.ncbi.nlm.nih.gov/pubmed/10485486?dopt=Abstract&holding=npg

Caffeine-suppressed ATM pathway leads to decreased p53 phosphorylation and increased programmed cell death in gamma-irradiated leukaemic molt-4 cells http://jab.zsf.jcu.cz//9_1/tichy9_1.htm

Disclaimer:

This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.

Please read an extended version of the Disclaimer here: https://www.cancertreatmentsresearch.com/?page_id=1794

 

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12 thoughts on “How Caffeine Makes Chemo- Radio- & Immunotherapy More Effective

  1. Hi, Daniel!
    Thank You for this interesting article! I love coffee. Black espresso and much :). First thing in the morning after good sleep with melatonin.
    For some time I am trying to understand relationship of adenosine, dipyridamole, caffeine, cancer. But I could not get clear idea for me. What do You think about those?

    Kindly,
    i.

    1. Hi ieva,

      Nice to hear from you. That is a very good question, indeed. I think the relevant facts for triple negative breast cancer (which I member were of your interest) are the following:
      1. triple negative breast cancer growth is stimulated by Adenosine, via A2B adenosine receptor http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167445
      2. caffeine is a nonselective blocker of adenosine receptors (A1, A2a, A2b and A3) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115368/
      3. dipyridamole is a adenosine-uptake-inhibitor, it inhibits the adenosine transport inside the cell (which is a different mechanism compared to the interaction of adenosine with the A2B cell receptor on the cell surface)
      4. it is also known that dipyridamole prevents triple negative breast cancer progression https://www.ncbi.nlm.nih.gov/pubmed/22760522
      5. however, the study above did not connected the effectiveness of dipyridamole with its adenosine-uptake-inhibitor capability, instead that was connected with WNT, MAPK and NF-kB modulation
      6. in line with the above, there are two main routes of action for adenosine: via the receptors on the cell and via it’a uptake through the transporters
      7. there are a few studies suggesting that for cancer such as cervical cancers, inhibiting adenosine uptake may not be good, implying that for those cases the use of dipyridamole would not be good – however, dipyridamole shows anti cancer effects via different other pathways and so far most of the literature suggest enough evidence for positive expectations from dipyridamole. I discussed this one a few times shortly (e.g. in the anti-cholesterol strategy post) but I find it relevant enough so that I would like to write a post on it

      I hope my answer clarifies a bit the connection and difference between caffeine (adenosine receptor inhibitor) and dipyridamole (adenosine transporter inhibitor) related to adenosine and cancer.

      Kind regards,
      Daniel

        1. Hi Ergin,

          Nice to hear from you! I was wondering how are you.

          On my side, very busy. Between my job, answering e-mails and calls related to the contend on this website, and at the same time putting together the things along the oncology line to fit my plans I discussed sometime ago. I will write an update very soon on this. But what is important is that things are coming together nicely. I just need perseverance and patients. Good things take time to happen, but they happen 🙂

          How are you? I hope you are doing well.

          Kind regards,
          Daniel

          1. Hi Daniel,
            Very bad days i have living.Heart problem or panic atacks noone understand what is happening to me.
            Thanks for asking,i dont want to disturb this thread with my problems😀 but i am not ok.
            İ hope i will see you this summer in Romania,if you ll be there.
            By this time i was reading books about how brain+mind causes cancer or other illneses.Nothing is coinsidence in this world.
            İf i feel ok on coming months i will write a post about it.
            Kind Regards
            Ergin

            1. Hi Ergin,
              It will be my pleasure to meet you this summer.
              If you like we can also have a call before that, sometime next week?
              Kind regards,
              Daniel

            2. Brother, please take care of yourself, relax the mind. This is why many times i said NO when thinking of talking to you.
              You had too many problems, you must relax, sleep and relax very much. Good food and excercise, fluids, showers and sleep again.

              I hope Daniel will be reading this too. I would like to meet here in Romania please. For us to be together, in person.
              All of us who can come and meet, if not more than at least us. I’ll be available on skype as usual.

              Please take care,
              Alex

  2. Hi Daniel, nice article

    I was wondering 3 years ago there was a lot of articles suggesting to use caffeine with DCA as it will maximize the effect, but after a while they start to warn people from combining them together, I felt like they are synergistic but maybe also have more side effects

    but clearly now we have better understanding to caffeine and its good effect 🙂

    wish you all the best

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