An antihistamine drug has been shown to halt the most aggressive form of brain cancer in mice, by triggering a cell death pathway without harming healthy cells.
Glioblastoma – or glioblastoma multiforme (GBM) – is a highly aggressive form of brain cancer. Glioblastomas start in astrocytes, the star-shaped cells that nourish and support nerve cells in the brain. While the tumors rarely spread to other parts of the body, GBM is often fatal and particularly difficult to treat. Patients diagnosed with GBM have a median life expectancy of around 10-12 months with surgery, chemotherapy and radiation therapy.
Part of the reason why the tumors are difficult to treat is the they take on the shape of the cells in which they form. The arms of the tumor are difficult to remove surgically, and some parts of the tumor are inevitably left behind. Recurrence of clioblastomas after surgery is very common.
The tumors also have a rich blood supply which helps them grow fast and they contain glioma stem cells which regenerate the tumor. The cells that remain after surgery are often multidrug resistant. For the majority of patients diagnosed with GBM, the prognosis is dismal.
However, hope may be on the horizon. A team of researchers in Finland, Sweden, and Switzerland have shown that it is possible to stop the growth of glioblastomas in mouse glioblasoma cell lines using a first-generation antihistamine called clemastine (meclastin); a histamine H1 antagonist that crosses the blood-brain barrier.
The researchers showed that there was an association between the protein mammary-derived growth inhibitor (MDGI) and a poorer prognosis in patients. MDGI binds to fatty acids and transports them into cells. By blocking the MDGI gene, the researchers reduced the level of fatty acid transport into cells which meant less were available to be incorporated into lysosomal membranes. That resulted in lysosomal membrane permeabilization (LMP). LMP causes lysosome contents to leak into cells, which results in cell death. Since MDGI regulates the structure of the lysosomal membrane, the MDGI pathway could serve as a potential drug target for treating GBM.
The researchers had previously conducted studies which showed certain antihistamines can trigger LMP. They tested a range of antihistamines and found that clemastine mimicked MDGI and increased the permeability of the lysosomal membrane, but only caused cell death in glioblastoma cells. While the drug has potential to cause cell death in healthy cells, at the dose required to kill glioblastoma cells, healthy cells were not harmed.
Following positive results in their cell lines, the drug was used on mice carrying tumors. Treatment with clemastine blocked tumor growth and survival time was greatly increased due to the eradication of invasive glioma cells.
The discovery of the fragility of aggressive infiltrating cells to LMP opens up new possibilities for treatment using clemastine and other LMP-inducing agents.
The research is detailed in the paper – Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilization – which was recently published in the journal EMBO Molecular Medicine. DOI: 10.15252/emmm.201809034