July 17, 2024 | 10 minute read

Researchers are constantly striving to find new ways to make cancer treatments more effective. One area of research that has gained attention is the role of dietary modification. For example, diets higher in fiber have been shown to enhance immunotherapy in patients treated for malignant melanoma.

Scientists are now investigating whether another dietary modification, reducing methionine consumption, could enhance the effectiveness of more traditional cancer therapies such as chemotherapy and radiation therapy. Methionine is an essential amino acid that plays a vital role in cell metabolism, DNA repair and antioxidant protection.

In this article, we will delve into the research surrounding methionine reduction and its potential impact on cancer treatment.

The Role of Methionine in the Body

Methionine is an amino acid (a building block of protein) that is crucial for cell metabolism. It contributes to several pathways that are critical for proper DNA organization and repair. Methionine is also a metabolite precursor for glutathione, a powerful antioxidant. Glutathione helps protect cells from oxidative damage.

While methionine is essential for normal cellular function, cancer cells have a higher demand for methionine due to their rapid growth and division. This increased need for methionine makes cancer cells more vulnerable to effects of methionine restriction.  Although methionine can be ‘recycled’ in cells from other metabolites, most methionine comes from dietary sources.

Methionine Reduction and Cancer Cells

Unlike normal cells, cancer cells constantly replicate and divide, requiring more methionine to support their growth.

Laboratory research, in isolated cells and animal models, suggests that restricting methionine availability can make cancer cells more vulnerable to DNA-damaging therapies such as chemotherapy and radiation therapy and enhance response to these treatments.

Close-up on Research in Progress: Methionine and Lung Cancer

A study supported by funding from AICR is investigating how dietary methionine influences lung cancer progression and response to chemotherapy. The research led by Christine Brainson, PhD, of the Markey Cancer Center (Associate Professor, University of Kentucky) is exploring how methionine levels affect the sensitivity of lung cancer cells to chemotherapy. Using isolated cell cultures and mice, this research also examines the development of normal lung cells into cancer cells when exposed to different levels of methionine.

Preliminary findings suggest that methionine restriction could increase the sensitivity of lung cancer cells to carboplatin (a type of chemotherapy commonly used to treat lung cancer).

“We found that methionine restriction actually starts to turn off the pathway in which the antioxidant glutathione is formed,” says Brainson. “Our hypothesis is that a cell that doesn’t have enough methionine keeps most of it for the most essential reactions and protein-building. And without adequate antioxidants, the cells don’t seem to have as much of an ability to survive.”

Many Unknowns About Methionine Reduction in Cancer Treatment

Research investigating methionine’s potential influence on cancer has been under way for decades, but many questions must be answered before methionine reduction can be considered for clinical practice.

And any recommendations that may develop are likely to have nuances about who might be most likely to benefit and how to implement the strategy.

Which kinds of cancer treatment would benefit?: Evidence of increased effectiveness with lower methionine levels comes mostly from treatments like radiation therapy and many chemotherapy agents that work by causing DNA damage. But chemotherapies that work through a different mechanism might be unaffected by methionine availability, Brainson explains. And, she adds, there would be a lot more caution about using it with immunotherapy. The immune system (especially T cells, which are the ones that immunotherapy response depends on) need methionine to function.

What is the optimal timing in relation to cancer treatment?: Research so far supports initiating methionine reduction before chemotherapy or radiation therapy treatment begins so it can reduce levels in the body and sensitize cells to the effects of the lower levels. It’s unclear if methionine reduction can be effective if initiated after starting treatment or whether intermittent use of restricted methionine diets during treatment could have the same benefits.

What level of methionine is best?: Laboratory studies have tested varying degrees of methionine reduction in the context of cancer research. However, translating these findings to human subjects is a complex task. If methionine reduction is shown to enhance cancer treatment in humans, researchers will then need to identify the ideal methionine level that can do this while supporting overall health.

Human Studies and Misinterpretations

So far, most of the research on methionine and cancer involves laboratory studies in isolated tissue culture or animals, with limited evidence in humans at this time. That has created space for lots of misunderstandings in the media and online sources of information.

• Lower Methionine, Not No Methionine: In cell studies, it’s possible to create conditions with no methionine present at all. Methionine reduction studies in animals typically reduce dietary methionine to cut circulating levels to about half of usual levels, ensuring that physiological needs are still met.
• Reducing Methionine, Not Protein or Calories: In mice studies, diets are formulated to have lower methionine content but supply normal levels of total protein, fat and calories. That’s something easily controlled when feeding lab animals. But implementing this kind of diet for someone who has cancer would require careful attention to ensure they were still meeting nutritional needs and that the diet was acceptable to them.
• Clarifying a Methionine-Restricted Diet: Substantially reducing methionine consumption requires a diet that is either vegan or with very limited amounts of dairy products and eggs. A plants-only diet can be nutritionally adequate when properly planned, although there’s an added challenge to meet increased protein needs during cancer treatment.

Methionine Reduction for Cancer Prevention Is a Separate Question

Some speculate that reducing methionine consumption could also reduce the risk of developing cancer. Brainson’s team found that in mice induced to have gene mutations that lead to lung cancer, a low-methionine diet slowed tumor progression and reduced overall tumor burden compared to a high-methionine diet. Other laboratory studies have shown that rodents on methionine-restricted diets live longer than others.

However, the long-term impact and potential unanticipated effects of methionine reduction for cancer prevention are still unknown. Methionine is essential for immune function, muscle mass and neurotransmitter production. Further research is needed to fully understand the long-term implications of methionine reduction for cancer prevention.

Future Research and Clinical Trials

To further explore the potential benefits of methionine reduction in cancer treatment, more human studies are needed. However, conducting clinical trials on methionine-restricted diets has proven challenging, due to the lack of people willing to sign up to participate.

Brainson’s team is hoping to study this in a clinical trial of lung cancer patients. The first step will be to confirm, in mouse models, that methionine restriction is not detrimental to immunotherapy response, since immunotherapy is now a common component of first-line treatments for lung cancer.  They will assign half the tumor-bearing mice given chemo immunotherapy to methionine restriction and the other half will have no methionine restriction. If successful, a similar approach could be tested in humans. After six to eight weeks when patients get a second scan, they plan to look at the objective tumor response to see if tumors shrink significantly more with methionine restriction than without the intervention. Based on those results, the next step would be to look at whether someone would continue that diet through the remaining cycles, at least intermittently.

Researchers are actively working on developing ways to make methionine-restricted diets more accessible and feasible. This includes investigating the use of meal replacement shakes or prepackaged meals to simplify the implementation of a methionine-restricted diet. Additionally, researchers are exploring other avenues to reduce body methionine levels, such as the development of enzyme-based pills that can break down methionine.

Research is also needed to address the concerns about methionine restriction possibly interfering with immunotherapy treatment for cancer.

How to Advise Patients Who Ask About Methionine Restriction

While awaiting further research, health-care professionals play a critical role in guiding patients who inquire about methionine restriction and putting current evidence in the context of their health and clinical care.

What is Dr. Brainson’s take, based on where research stands today? “If someone was interested in a methionine-restricted diet during chemotherapy or radiation therapy, I’d encourage a health professional to consider supporting that choice, as long as the patient understood the need to meet nutritional needs, including total protein and calories, and was ready to learn how to implement this diet of mainly plant foods.”

There are important nuances, however:

• Understand the strength of evidence: People need to understand that for now, most of the evidence is from studies of mice and isolated cell cultures.
• Impact on immunotherapy is unclear: Methionine reduction may be more beneficial for therapies that cause DNA damage. Brainson says she would not currently suggest a low-methionine diet for use with immunotherapy; this is a current research priority.
• The amount of added benefit may vary: “For someone with an early-stage cancer, current therapies are so effective that any added benefit from a methionine-restricted diet might be very small. But for someone with late-stage cancer, I think it could be worth a try since even a modest reduction in tumor burden could make a meaningful difference in lifespan,” says Brainson.

Health professionals can help patients base their decisions on the best available evidence and not pursue unproven approaches out of a sense of desperation.

The Flip Side of Methionine Reduction: Avoiding Excess Methionine

While research on methionine reduction continues, one reasonable step could be avoiding excessive methionine intake. While there is little evidence in humans, cell culture studies have suggested that high levels of methionine can protect cancer cells from chemotherapy-induced destruction.

People could consider meeting their increased protein needs with foods lower in methionine (pulses such as dry beans and lentils, soy foods, nuts and limited dairy or eggs) rather than boosting high-methionine foods (meat, poultry and fish).

“At this point, this option is based on mouse studies and tissue culture studies,” Brainson qualifies. “We just don’t have that evidence in humans [yet].” The choice must be individualized. For someone who wants to feel that they’ve done everything they could, avoiding an excess of high-methionine foods can be a reasonable choice. But for someone struggling to manage meeting their nutritional needs, other steps may be higher priorities for now.

Conclusion

Reducing methionine consumption shows promise as a potential strategy to enhance cancer treatment. Methionine restriction could make cancer cells more sensitive to DNA-damaging therapies, potentially leading to improved treatment outcomes. While human research is still in its early stages, the findings from isolated cells and animal models are encouraging.

Human studies are needed to confirm these findings and determine the best level of methionine reduction. Moreover, changes in food choices change the amounts of a wide range of nutrients and compounds. Plant-focused diets show potential to reduce cancer risk and support cancer survivorship through many mechanisms. It’s possible that changes in methionine intake could be one of those factors. But it won’t be a solution all on its own.

Health-care professionals play a critical role in guiding patients who are interested in methionine restriction, ensuring that nutritional needs are met while considering the specific cancer treatment being pursued. As research progresses, more insights into the benefits and limitations of methionine reduction will be uncovered, bringing us closer to personalized and effective cancer treatment strategies.