Ellagic acid and cancer

What is Ellagic acid

Ellagic acid is a natural plant compound found in many fruits and nuts. It is especially known for being present in pomegranates, but it is also found in, for example, strawberries, raspberries, blackberries, and walnuts. This compound has strong antioxidant properties, meaning it can help protect the body’s cells from damage.

When consumed, ellagic acid is partially converted in the intestine by gut bacteria into ellagitannins (large plant molecules), which can then be further broken down by gut bacteria into urolithins (smaller substances formed during this microbial processing of plant molecules). These urolithins are believed to have biological activity and are the subject of research into their potential health effects [4].

History

The use of plants containing ellagic acid dates back centuries in traditional medicine. Pomegranates, which are rich in ellagic acid, were valued as early as antiquity. The substance ellagic acid itself was identified in the 1800s, but research into its effects only gained momentum in the 20th and 21st centuries. This is not least due to its potential health-promoting properties, also in relation to cancer.

Mechanisms of action

Ellagic acid and the substances it is converted into in the body have several ways of acting that can be beneficial when it comes to cancer. These mechanisms of action have been studied extensively in vitro (in test tubes/petri dishes) and in living organisms.

Antioxidant effect

One of the most important ways ellagic acid works is by being a strong antioxidant. Cancer is often associated with an imbalance in the body where there are too many harmful substances called free radicals. These substances can damage cells and contribute to the development of cancer. Ellagic acid helps neutralize these free radicals and protect cells from damage, which can help slow the development of cancer.

Inhibition of cell growth etc.

Laboratory studies in vitro have shown that ellagic acid can make it harder for different types of cancer cells to grow and divide (proliferate). Additionally, ellagic acid can cause cancer cells to die in a controlled manner called apoptosis (programmed cell death). It appears that ellagic acid can affect the signals inside cancer cells that control cell growth and death, thereby causing them to destroy themselves without harming normal cells in the same way [3, 5].

Anti-angiogenesis effect

Cancer tumors need new blood vessels to grow large and spread to other parts of the body (metastasis). This formation of new blood vessels is called angiogenesis. Research in vitro and in vivo (in living organisms) has shown that ellagic acid can help stop this formation of new blood vessels by affecting substances that either promote or inhibit the growth of blood vessels. By limiting the blood supply, ellagic acid can potentially slow the growth and spread of tumors.

Anti-metastatic effect

The spread of cancer (metastasis) is one of the biggest challenges in treatment. Laboratory studies have shown that ellagic acid can make it harder for cancer cells to invade surrounding tissue (invasion) and to move to other parts of the body (migration). This is believed to be related to the fact that ellagic acid can affect the molecules that help cells stick together and the enzymes that break down the tissue around the cells.

Modulation of signaling pathways

Ellagic acid has been shown to be able to change the activity in several important signaling pathways inside cells involved in the development and growth of cancer. This applies, for example, to the signaling pathways NF-κB (which is important for inflammation and cell growth), PI3K/Akt/mTOR (which controls cell growth and survival), and MAPK/ERK (involved in cell division). By affecting these signaling pathways, ellagic acid can potentially interfere with the processes that drive cancer development.

Anti-hormonal effect

In certain cancers that are sensitive to hormones, such as breast cancer and prostate cancer, research has suggested that ellagic acid may have an anti-hormonal effect. Laboratory studies have shown that ellagic acid can inhibit the activity of enzymes involved in producing hormones like estrogen and dihydrotestosterone, potentially reducing the growth of these hormone-sensitive cancer cells.

Potential as a supplementary treatment in cancer

Based on numerous laboratory studies in vitro and in vivo, ellagic acid appears to have significant potential as a supplementary treatment for cancer. Although more studies in humans are needed to confirm these results, current research suggests that ellagic acid can be a support in several aspects of cancer treatment.

Synergistic effect with conventional treatment

Some laboratory-based trials have investigated whether ellagic acid can enhance the effect of traditional cancer treatments such as chemotherapy and radiation therapy. For example, in vitro research has shown that ellagic acid can make cancer cells more sensitive to certain chemotherapeutic agents and perhaps also reduce the risk of cancer cells becoming resistant to them.

Additionally, in some studies, ellagic acid has been shown to be able to protect normal, healthy cells from some of the harmful side effects of chemotherapy and radiation therapy, potentially making these treatments easier to tolerate.

Supporting the immune system

A strong immune system is crucial in the fight against cancer. Research has suggested that ellagic acid, when consumed, is partially converted in the intestine into ellagitannins and then into urolithins [4].

These converted substances are believed to be able to help regulate and strengthen the immune system’s response. Urolithins can be absorbed into the body and contribute to the potential health effects.

This could mean, for example, an increased activity of natural killer cells (NK cells), T cells, and macrophages. By supporting the immune system, ellagic acid can potentially help the body fight cancer more effectively.

Managing inflammation

Long-term inflammation plays a role in the development and spread of many cancers. Ellagic acid has been shown to have anti-inflammatory properties by inhibiting the production of substances (cytokines and enzymes) that promote inflammation. By helping to reduce inflammation in the body, ellagic acid can potentially create a worse environment for cancer cell growth and spread and perhaps also alleviate some of the symptoms that can be associated with inflammation in cancer [6].

Protection of DNA

Damage to our genetic material (DNA) can cause cancer development. Research suggests that ellagic acid can have a protective effect on DNA against attacks from harmful substances and oxidative stress.

Additionally, research has suggested that ellagic acid can help repair damaged DNA in normal cells, which could potentially help prevent further cancer development.

Advantages of Ellagic acid

In addition to the potential ways ellagic acid works and its potential as a supplementary treatment in cancer, there are several advantages of the substance that make it interesting for research:

Natural origin

Ellagic acid is a natural substance found in common foods like pomegranates and berries. This can make it more appealing and accessible to many as a supplement to the diet.

Apparently good tolerance

Preclinical studies (in vitro) have generally indicated that ellagic acid has relatively low acute toxicity. Small clinical studies in humans have also suggested good tolerability at the doses used.

However, more extensive safety studies in humans are needed, especially with long-term use and in combination with conventional cancer treatments, to identify any potential side effects or interactions. It must be emphasized that the safety profile for ellagic acid as a supplementary treatment for cancer is still being investigated.

Broad-spectrum activity

As described above, ellagic acid has been shown to have many different ways of acting that could potentially be relevant for aspects of cancer development and treatment. This broad activity can be an advantage in a complex disease like cancer.

Potential for prevention

In addition to its potential role as a supplementary treatment, research has also investigated whether ellagic acid can help prevent cancer. The same mechanisms believed to be involved in its treatment effect (antioxidant, anti-inflammatory, DNA-protective) can apparently also play a role in reducing the risk of developing cancer.

Possibility of oral intake

Ellagic acid can be taken by mouth via diet or supplements, making it easy to use.

Disadvantages and limitations

Although research into ellagic acid is promising, there are also certain disadvantages and limitations that one should be aware of:

Limited absorption in the body

One of the biggest challenges with ellagic acid is that the body may not absorb and utilize it very well. Some studies have suggested that only a small part of the ellagic acid you eat actually ends up in the blood in an active form. Research is being conducted to improve how the body can better absorb ellagic acid.

Conversion in the body

As mentioned, ellagic acid is converted into other substances in the body, including urolithins, which are also believed to have an effect. We do not yet know exactly how these substances work and how well the body absorbs them. More research is needed in this area.

Most research in the laboratory

The majority of the research conducted on ellagic acid is in vitro and in vivo. Although these studies provide important knowledge about how ellagic acid potentially works, more studies in humans are needed to confirm whether it is safe and effective as a supplementary treatment for cancer.

Potential interactions with cancer medicine

While research into the potential of ellagic acid as a complementary treatment for cancer continues, it is important to be aware of possible interactions with conventional cancer medicine. Ellagic acid is an antioxidant and can affect various biological processes in the body, which could theoretically interact with certain forms of medicine often used by cancer patients.

Certain types of chemotherapy

Some chemotherapeutic agents, such as cisplatin, doxorubicin, and vincristine, work by producing free radicals that damage cancer cells. Since ellagic acid is an antioxidant, there is a theoretical risk that high doses could neutralize these free radicals and potentially reduce the effectiveness of these specific chemotherapies. This risk has primarily been observed in laboratory studies, and the clinical significance in humans has not yet been fully clarified.

Hormone treatment

In hormone-sensitive cancers such as certain types of breast and prostate cancer, hormone treatment is used, including tamoxifen and aromatase inhibitors. In vitro studies have suggested that ellagic acid may have anti-estrogenic effects. Therefore, there is a potential risk that ellagic acid could affect the action of these specific hormone treatments. Further research in humans is necessary to understand the clinical significance.

Medicine metabolized by liver enzymes (Cytochrome P450 system)

Ellagic acid has been shown in laboratory studies to be able to affect the activity of certain enzymes in the liver, including CYP3A4, CYP2C9, and CYP2D6. These enzymes are involved in the breakdown of many drugs, including certain cancer drugs and pain medications. If ellagic acid inhibits these enzymes, it could potentially lead to increased concentrations of the medicine in the body and thus increase the risk of side effects or change the effect of the medicine. Listing the most frequently used preparations that could be problematic in this context is difficult, as very many drugs are metabolized in the liver via the enzymes in question (CYP450 system).

Here are some general examples of types of cancer drugs where there is a known interaction with substances that affect the CYP450 system:
Certain forms of chemotherapy: Some chemotherapeutic agents that can be affected by substances interacting with liver enzymes include, among others:
- Taxanes (e.g., paclitaxel, docetaxel)
- Vinca alkaloids (e.g., vincristine, vinblastine)
- Anthracyclines (e.g., doxorubicin)
- Epipodophyllotoxins (e.g., etoposide)
- Certain tyrosine kinase inhibitors (a type of targeted therapy)
Certain forms of targeted therapy: Many targeted therapies are also broken down in the liver, and their concentration in the blood can potentially be affected. Examples may include certain tyrosine kinase inhibitors (e.g., imatinib, gefitinib, erlotinib) and mTOR inhibitors (e.g., everolimus, sirolimus).
Certain forms of hormone treatment: As mentioned earlier, some hormone treatments like tamoxifen and aromatase inhibitors can also be metabolized in the liver and potentially be affected.
It should be emphasized
These are only general examples, and it does not mean that there is a known interaction between ellagic acid and all these specific drugs. Research into specific interactions with ellagic acid is still extremely limited.
Each patient’s treatment is unique. The specific chemotherapy or targeted therapy a patient receives depends on their cancer type and stage.

Blood-thinning medicine (Anticoagulants)

Although there is limited research specifically on the interaction between isolated ellagic acid and blood-thinning medicine like warfarin, it is known that certain polyphenols can affect blood coagulation. Patients taking blood-thinning medicine should exercise particular caution.

Blood sugar-regulating medicine

Some studies suggest that ellagic acid may have a blood sugar-lowering effect. If cancer patients with diabetes take medicine to regulate blood sugar, such as insulin or metformin, concurrent intake of ellagic acid could potentially enhance this effect and lead to hypoglycemia (too low blood sugar). Careful monitoring of blood sugar is recommended in such cases.

Important

If you, as a cancer patient, are considering using ellagic acid as a supplement, you should discuss this with your practitioner.

Clinical studies

There are only a few clinical studies (investigations in humans) that have looked at the effect of ellagic acid or extracts containing high amounts of ellagic acid in connection with cancer.

Some smaller studies have suggested that it may have a positive effect in certain cancers, such as prostate cancer and breast cancer, but the results are still preliminary. Larger and better studies with more participants and over longer periods are needed to be able to say something certain.

Safety

In general, ellagic acid has been shown to be relatively safe in laboratory studies and in the few investigations conducted in humans. The doses used have generally been tolerable. However, more extensive investigations of safety with long-term use and in potential combination with traditional cancer treatments are needed to find out if there are any side effects or interactions.

One should discuss the use of supplements with their practitioner.

Dispensing and application

Ellagic acid can be purchased as a supplement in various forms, for example, capsules and powder. It is also found naturally in certain foods:

Pomegranates: You can eat the whole fruit, drink pomegranate juice (be aware of the sugar content), or use pomegranate extract.
Berries: Eat different kinds of berries like strawberries, raspberries, and blackberries.
Nuts: Walnuts and pecans also contain ellagic acid. You can eat them in moderate amounts.

How much ellagic acid is in supplements varies. There are as yet no fixed guidelines for how much to take as a supplementary treatment for cancer.

One should follow the dose stated on the product and always talk to their practitioner before starting to take supplements, especially in connection with cancer treatment.

Foods high in Ellagic acid

In prioritized order. This overview is general. Precise measurements can vary greatly:

Pomegranates: Considered one of the richest sources of ellagic acid. Both the fruit, the peel, and the juice contain significant amounts.
Berries:
- Raspberries: Especially golden raspberries are believed to have a particularly high content.
- Strawberries: A good source of ellagic acid.
- Blackberries: Also contain a fair amount of ellagic acid.
- Cranberries: Also mentioned as a source.
Nuts:
- Walnuts: Contain measurable amounts of ellagic acid.
- Pecans: Like walnuts, they are a good source.

Important notes

Variability: The content will vary and depend on the season, degree of fruit ripeness, etc. It is thus not constant when speaking about food.
Other sources: Ellagic acid is also found in smaller amounts in other fruits and nuts than those mentioned above.
Supplements: Pomegranate extract, often used in supplements, is standardized to contain a certain percentage of ellagic acid (e.g., 40% or 60%).
Absorbability: It must be emphasized that ellagic acid is difficult to absorb, regardless of how it is consumed.

Absorbability

It appears that the limited absorption (bioavailability) of ellagic acid applies to both natural foods and supplements. Research points to several reasons for this general problem:

Low solubility: Ellagic acid has a relatively low solubility in water, which can limit how well it is absorbed in the intestine.
Conversion in the intestine: When you consume ellagic acid (either from food or supplements), a large part of it is converted by the bacteria in our gut into other substances like ellagitannins and urolithins. While urolithins are believed to have biological activity, this conversion means that the amount of ellagic acid itself absorbed directly into the blood can be low.
Rapid metabolism: The ellagic acid that is actually absorbed seems to be rapidly metabolized and removed from the body.

Differences between supplements and natural sources

Some studies suggest that ellagic acid in the form of ellagitannins (the form primarily found in foods like pomegranates) may have a slightly different absorption profile and metabolism pathway than pure, free ellagic acid often found in supplements. It is possible that other plant substances present in natural foods along with ellagic acid can affect absorption and metabolism.

However, the general picture is that the bioavailability of ellagic acid itself is limited, whether it comes from supplements or natural sources. Therefore, research is actively being conducted into methods to improve the absorption of ellagic acid, both in the form of supplements and by optimizing the intake of natural sources.

Conclusion

Ellagic acid is a natural plant compound with promising results from laboratory and animal studies suggesting that it can be a supplementary treatment for cancer in several ways, including by acting as an antioxidant, inhibiting cell growth and spread, affecting blood vessel growth, and supporting the immune system as well as dampening inflammation [2, 6].

Although there is limited research in humans, preliminary results, combined with the apparently good safety profile, indicate that ellagic acid is an interesting area for further study. This applies partly as a support in combination with traditional cancer treatments, partly as part of Integrative Oncology (holistic cancer treatment with evidence), and finally as part of a complementary approach to cancer treatment.

One should discuss the use of supplements like ellagic acid with their practitioner to ensure that it is safe in one’s specific situation and that it does not interact adversely with other treatment.

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