Cancer researchers are constantly searching for new and more effective treatments for mesothelioma, in the hope of one day finding a cure. Sometimes, this means developing new targeted drugs and treatments, but sometimes it means applying existing drugs—both mesothelioma drugs and drugs that were initially developed to treat other conditions—in new and innovative ways, often with promising results.
Metformin is one example of a pre-existing drug that may be helpful in mesothelioma treatment. Researchers have found that metformin, which was originally developed to control diabetes, can also help control the growth and spread (or metastasis) of mesothelioma cells. This is a very exciting and potentially ground-breaking development in understanding how mesothelioma cells work and how they can be most effectively combatted.
So, what is metformin, how does it work, and what does that have to do with mesothelioma? Read on for the full run-down.
What is Metformin?
Metformin is a type of medication referred to as a biguanide antihyperglycemic agent. It was initially developed to control blood sugar in people with type 2 diabetes. It also increases a hormonal secretion referred to as GDF15, which reduces appetite.
Metformin is a very well-established drug. It was discovered in the 1920s, was first used in human treatment in the 1950s, and was first FDA-approved for use in the US in 1995. It is sometimes sold under the brand names Glucophage and Glucophage XR but is widely available as an affordable generic.
Currently, metformin is the most widely prescribed oral medication for diabetes and is included in the WHO’s List of Essential Medicines. In 2020, it was the 3rd most prescribed medication in the U.S., with over 92 million prescriptions written at that time. As of 2022, it has been prescribed to over 120 million people around the world for the treatment of type 2 (insulin-resistant) diabetes.
One of the reasons metformin is so commonly used is because it is quite effective while having relatively limited side effects. There are some people who should not take metformin, like those with significant liver disease and some people with severe kidney problems, but it is generally safe to take for most people who may benefit from it.
While it is considered a first-line treatment for type 2 diabetes, metformin has also been studied for various ways that it may help treat other conditions. These include:
- Polycystic Ovarian Syndrome (PCOS): Metformin is being trialed for use in PCOS treatment. Since PCOS and type 2 diabetes are often comorbid, researchers are looking into the use of Metformin to treat many PCOS-related symptoms, especially those that relate to insulin resistance, weight gain, and issues with fertility/live birth.
- Gestational Diabetes: Metformin has shown promising short-term results as an effective and safe way to manage gestational diabetes, but long-term health outcomes are still being studied.
- Weight Change and Antipsychotic Drugs: Because metformin is associated with weight loss (as it curbs appetite and prevents caloric absorption), it has been studied for use in patients who gain weight as a result of a medication—particularly antipsychotic medications like olanzapine and clozapine.
- Heart Disease: Metformin is currently being studied for potential heart health benefits, and has been found to potentially reduce cardiovascular mortality and cardiovascular events in coronary artery disease (CAD) patients.
- Cancer Prevention: Studies on people with type 2 diabetes have found that Metformin may be a protective factor against developing cancer.
- Alzheimer’s Disease: Metformin may help delay the onset or progression of Alzheimer’s disease. Some studies suggest that it may also be helpful as a protective factor, possibly reducing the risk of developing Alzheimer’s in the first place.
- Aging Applications: Associated with research on metformin and Alzheimer’s, recent studies have examined indications that metformin may be helpful in extending lifespan and slowing the effects of aging. It is theorized that these effects may be achieved through similar mechanisms as the ones that make metformin an effective type 2 diabetes treatment (the regulation of insulin and caloric/glucose absorption).
How does Metformin Work?
Scientists do not yet completely understand how Metformin works on a molecular level. There are several potential molecular mechanisms that it may work with, which can be explored here.
When used to treat type 2 diabetes, metformin addresses resistance to a hormone called insulin, which impairs the body’s ability to process blood sugar in people with the condition.
Insulin is produced by the pancreas and sends signals that enable the body to use glucose (sugars found in many carbohydrates) for energy. After you eat, carbohydrates are broken down in the digestive tract, and the glucose created by that breakdown is absorbed into the bloodstream through the lining of the small intestine, causing blood sugar levels to rise. The pancreas then sends out insulin to signal to the body that it should absorb the glucose and use it for energy. If there’s too much glucose in the blood, insulin signals to the body to store the extra glucose in the liver, only to be released when glucose levels in the blood go down.
In people with type 1 diabetes, the body does not make enough insulin to do that job effectively. In people with type 2 diabetes, the body becomes resistant to insulin, which means that enough insulin is being produced, but the body does not respond properly to that insulin. In both cases, people with diabetes have difficulty converting the sugar (or glucose) from the food they eat into energy that the body can use, and also have difficulty controlling their blood sugar levels.
This can lead to diabetics having high levels of blood glucose (i.e., high blood sugar) for longer than is healthy. High levels of blood sugar, when uncontrolled, can lead to health complications like kidney disease, eye damage, increased risk of heart disease, and nerve damage in the hands and feet (neuropathy), among other issues.
Metformin works for type 2 diabetics by doing several things in the body, including:
- Increasing the body’s sensitivity to insulin cells (lessening insulin resistance), which helps the body understand and appropriately respond to the signals sent out by insulin.
- Controlling the amount of sugar that is produced and held by the liver and released into the blood.
- Decreasing the absorption of sugar from food by the gastrointestinal tract, thereby reducing the amount of sugar that gets absorbed into the bloodstream generally
- Increasing peripheral glucose uptake and increasing fatty acid oxidization so as to enable the body to better utilize blood glucose for energy
- Reducing appetite and caloric intake.
What does this have to do with mesothelioma? Can Metformin treat mesothelioma?
Metformin has been studied for its potential ability to combat malignant mesothelioma. Previous studies and animal trials have established that metformin may help control the spread and growth of malignant mesothelioma cells and potentially extend the projected lifespan of mesothelioma patients.
A more recent study led by researchers at the University of Ferrara in Italy provided further insight into how metformin may be useful in mesothelioma treatment. The researchers hypothesized that the aggressive way that mesothelioma cells spread may be linked to a communication breakdown in an essential signaling protein in the body referred to as the Notch pathway, which leads to the uncontrolled proliferation, growth, and spread of malignant cells.
This communication breakdown is present in type 2 diabetes and is one of the main issues that prevents type 2 diabetics from appropriately responding to insulin. In type 2 diabetics, the signaling issues caused by Notch pathway malfunction are treated effectively by metformin. The study theorized that since metformin is effective in treating Notch-related cellular communication issues in type 2 diabetes, it may also be effective in treating the same sort of communication breakdown in malignant mesothelioma.
The researchers proceeded to test mesothelioma cells to see if they demonstrated key characteristics of Notch pathway communication problems. Encouragingly, testing revealed that malignant pleural mesothelioma cells did indeed have the characteristics of Notch pathway communication issues when compared with normal pleural cells. They then further tested their hypothesis to see whether metformin may be similarly effective in mesothelioma treatment as it is in type 2 diabetes treatment.
Their findings were very promising: metformin appeared to hamper the growth and proliferation of malignant pleural mesothelioma cells and reduce the amount of Notch activation (i.e., the communication issue related to the Notch pathway). It also appeared to enhance the apoptotic process (i.e., the process by which aging or harmful cells self-destruct to be replaced with healthy cells). In malignant mesothelioma cells, apoptosis is drastically reduced or stops altogether, which—combined with unchecked cell growth—is how tumors are formed.
Hampering the growth/proliferation of mesothelioma cells, reducing Notch-related communication problems, and promoting the apoptotic process in mesothelioma cells are all crucial areas of mesothelioma treatment, and metformin shows significant promise in being effective in these areas for a wide range of mesothelioma patients.
Is this a cure for mesothelioma?
The study’s authors were careful to state that they do not believe that metformin is a cure for mesothelioma—that is, it is not considered a treatment that would eliminate the presence of cancer cells in the body.
However, it is a very promising potential treatment for mesothelioma, which may significantly slow the progress and potentially prevent the further spread (metastasis) of malignant mesothelioma cells. This may significantly increase the lifespan and improve the prognoses of malignant pleural mesothelioma patients (and potentially all mesothelioma patients), providing a significant source of hope in the mesothelioma treatment landscape.
Metformin is especially promising as a treatment for mesothelioma due to its characteristics as a drug. It is very widely available, as it is so commonly prescribed for type 2 diabetes. It is available as a generic medication, meaning it is far less expensive than most cancer treatments and medications. It can be taken orally from the comfort of a patient’s home, and requires no travel, time commitments, hospitalization, or recovery time. It also has few to no side effects and may be helpful for patients with later stage mesothelioma, for whom other treatment options are limited.
While more studies are needed in order to test the efficacy of metformin in a wider range of mesothelioma patients, research up to this point has showed the exciting potential of metformin to potentially revolutionize mesothelioma treatment and improve the lives of mesothelioma patients and their loved ones.