CBD reduces the size of glioblastoma, favorable environment in the experimental model

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Inhaled CBD reduces the size of the highly aggressive and deadly brain tumor glioblastoma in an animal model by reducing essential support for its microenvironment, the researchers report.

“We observed a significant reduction in the size of the tumor and its microenvironment was different” Dr Babak Baban, immunologist and associate dean of research at Georgia Dental College at Augusta University said after just seven days of treatment.

Researchers from DCG and Georgia Medical College say the inhaler approach not only helped ensure that the compound found in cannabis reaches the brain, but that the method of delivery could, like asthma inhalers, eventually be easily used by patients.

It was the first study to use CBD in an animal model of glioblastoma, they report in the journal Cannabis and cannabinoid research.

Using modified human glioblastoma cells, they created what is called a model of orthotopic glioblastoma, in order to provide the most realistic model possible for this most common and deadly malignant brain tumor. By day 8, the aggressive tumor had established itself in the brains of the mice, and by day 9, they began administering daily doses of inhaled CBD or a placebo that continued for seven days. They then looked again at an image of the tumor and directly at the tumor tissue.

While the approach is likely easily applicable to humans, at this point they are primarily looking at the tumor’s biological response to CBD, says Dr Martin Rutkowski, MCG neurosurgeon whose expertise includes the operation on those patients who tend to present after a seizure or sudden loss of consciousness, or with a slower onset of neurological deficits such as a weak arm, vision or cognitive problems.

“This is probably one of the most aggressive cancer periods. We are in desperate need of research and more treatments, ”said the neurosurgeon and co-author of the study. “What we have right now is not working very well,” he says.

“Family members will bring in patients and say they just don’t think right, their memory is pervasive, or they’ve been fired from their jobs because they haven’t been doing what they’ve been doing for 30 years. years, “says Rutkowski.

Treatment today includes surgery, followed by chemotherapy and radiation therapy. “Surgery does not offer a cure, but it does offer an important first step in maximizing quality of life and prognosis,” says Rutkowski, noting that there is a clear relationship between the amount of tumor that can be removed surgically and survival time.

They found that CBD appears to be adept at modifying the tumor ecosystem, or the supporting tumor microenvironment, including restoring levels of inflammation that target rather than protect glioblastoma, potentially making it a therapy for. safe, effective and novel adjunct for these patients.

“It’s all about immune balance,” says Baban, corresponding author. Inflammation is increased in response to a first-line attack on a tumor, which is a normal response; our immune system regularly attacks cancerous or precancerous cells. But when a tumor does manage to establish itself, the tumor takes matters into its own hands, moving into a more chronic state of inflammation that ultimately protects it from the immune system, he says.

The tumor microenvironment established by cancer cells includes elements such as immune cells as well as blood vessels and growth factors to allow increased growth of blood vessels, which is essential for tumor growth and survival. allowing it to thrive where it begins and spread.

For a glioblastoma, the tumor microenvironment has been shown to have increased activity of natural immune checkpoints, which, as the name suggests, helps prevent an overzealous immune response that could harm the body, such as causing damage to the body. happens in autoimmune diseases like rheumatoid arthritis. But in this case, cushioning means protecting the tumor. There is also a particularly low presence of cytotoxic T cells, which are particularly adept at putting a tumor or other invader into the reticle.

CBD may have improved the immune mix against the tumor, including reducing the co-optation of tumor glial cells – a type of brain cell that normally protects neurons, including producing inflammation to fight off invaders – to become instead a major component of the tumor, now called associated macrophage glioblastoma, which helps support and protect it.

It also suppresses the P-selectin protein, which usually plays a role in important functions like wound repair, and one of the things it recruits to help is platelets. However, in cancer, P-selectin helps tumors spread and resist treatment. In fact, it is a target for new cancer treatments. Like many other inhabitants of the microenvironment, there is evidence that P-selectin acts on tumors by also serving as an immune checkpoint.

Apelin, a ubiquitous enzyme made by many different cell types, is normally present at low levels in the brain. But in glioblastoma, its expression is much higher, the researchers say, and it supports the critical growth of blood vessels, in addition to promoting cancer stem cells believed to give rise to the tumor and being the key to resistance. the tumor to treatment. There is also some evidence that apelin works as an immune checkpoint in the tumor microenvironment, and others have shown that inhibiting apelin, which CBD does, decreases the rate of tumor growth. brain fatal.

CBD also suppresses IL-8, which macrophages normally release to promote inflammation and help repair injuries, and which recruits other immune cells in the process. But glioblastoma also secretes IL-8 to help promote cell migration and angiogenesis, and its level has been shown to be high in many cancers, including glioblastoma. In fact, these rapidly growing tumors are effective in the growth of blood vessels, which in turn support their growth, and drugs that target this specific skill have been shown to help.

CBD also lowers other key immune checkpoints, like the enzyme indoleamine 2,3 dioxygenase, or IDO, another localized blockade of the immune response that tumors are known to use.

CBD also improved the mix by increasing the expression of certain good things, like CD103, a complex believed to help the immune system recognize cancer, and which is generally associated with a better prognosis for cancer, as well as CD8, a protein. coated in sugar which also promotes an immune response. There is evidence suppressing immune checkpoints, which CBD does, increases levels of both.

“It’s a puzzle and that’s why we need good immune regulators,” says Baban. “CBD is a very smart regulator,” which can make adjustments depending on its environment, such as lowering apelin in glioblastoma and increasing in lungs damaged by COVID, he says. DCG and MCG investigators reported last year that CBD actually increases the levels of apelin, which they say drops dramatically with SARS-CoV-2 infection, and in this scenario, the increased apelin reduced inflammation and the “cytokine storm” that caused destruction in patients’ lungs.

“Right now, we’re excited that the tumor is shrinking,” Baban said of the cannabinoid’s impact on glioblastoma. He and Rutkowski note that the positive results from inhaled CBD have occurred without being combined with other therapies, such as surgery. They predict that if CBD is ultimately used for these patients, it will be a new adjunct to these therapies.

The next steps are to see how long the positive changes last and to deepen the impact on cancer stem cells. They also want to assess the impact of CBD on high rates of glioblastoma recurrence. They have more evidence of hope: In an earlier study, they incubated tumor cells in CBD before implantation, and no tumors resulted, Baban says.

The latest significant breakthrough in the treatment of glioblastoma came over 15 years ago, with the addition of the chemotherapeutic drug temozolamide to radiation therapy, which extended survival by about a month and a half and was celebrated by patients. and caregivers, says Rutkowski.

CBD’s skills in controlling inflammation and their research experience with other conditions where inflammation is critical, including Alzheimer’s disease, led Baban and his colleagues to research the cannabis derivative for glioblastoma. Other researchers are studying CBD in combination with other cannabis derivatives, including THC, but since CBD is such an interactive compound, including with other active compounds in cannabis, such as THC, researchers at DCG and MCG thought it would be more effective on its own.

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