Posted on May 13, 2019, 4 p.m.
Glioblastoma, the most aggressive form of brain cancer, can be stopped by an antihistamine that triggers a form a cell death caused by leaky lysosomes according to studies from Switzerland, Findlana, and Sweden as reported in EMBO Molecular Medicine.
The studies demonstrate an association between fatty acid binding protein mammary derived growth inhibitor and poorer prognosis and patients. MDGI carries fatty acids into cells, blocking the MDGI gene in glioblastoma cell lines disrupted fatty acid transport into cells and incorporation into lysosomal membranes, this compromised lysosomal membrane composition and integrity resulting in lysosomal membrane permeabilization. LMP is an intracellular cell death pathway triggered when the lysosome contents leak into the cell.
Cell line and live mice studies have found treatment with clemastine antihistamine effectively mirrored the effects of MDGI triggering LMP and causing glioblastoma cell death without harming healthy cells; findings may help scientist develop new treatments for glioblastoma.
“Our research demonstrates that MDGI is a key factor regulating and maintaining the structure of the lysosomal membrane. This is the first gene found to regulate the stability of the membrane … Our findings demonstrate that antihistamines and other drugs that increase the permeability of the lysosomal membrane can be considered as an enhancing therapy for patients with glioblastoma alongside established treatments.” explains Pirjo laakkonen, PhD of the University of Helsinki.
MDGI has been established as a glioma biomarker of invasive gliomas, increased expression of the protein is linked with more severe glioma grade. Heart type fatty acid binding protein MDGI is a fatty acid binding protein involved in uptake of fatty acids and polyunsaturated fatty acid uptake into glioma cells.
Analyses of lower grades of gliomas confirmed a link between increased expression of MDGI and poorer patient survival. “… both MDGI expression and high tumor grade independently associated with unfavorable overall survival, increasing the risk of death by the factor of two.” Significantly more MDGI was noted to be expressed in glioblastomas than in lower grade gliomas.
MDGI was shown to be essential to survival of glioma cells, cells engineered to overexpress MDGI grew more aggressively and invasively than non-engineered tumour cells after implantation into mice. Silencing MDGI was observed to reduce viability of patient derived glioma cells and blocked cell proliferation, human cells lacking MDGI transplanted into mice were unable to form tumours. “These results demonstrate a dose-dependent effect of MDGI silencing on glioblastoma cell growth and viability.”
Cell line studies indicate blocking MDGI prevented transport of fatty acids, particularly linoleic acid, to cells for incorporation into lysosomal membranes; without MDGI glioma cells could not access enough linoleic acid. Lysosomal membranes became more permeable without correct fatty acid composition, and enzymes and other components leaked out into cell cytoplasm which triggered cell death. “Our lipid analyses show that MDGI silencing impaired trafficking of polyunsaturated fatty acids (FA) into cells, resulting in significant alterations in the lipid composition of lysosomal membranes.”
Some classes of antihistamine can trigger LMP, a series of tests were carried out to evaluate clemastine antihistamine on cultured human glioblastoma cells and on growth of human glioblastoma xenografts in mice models; Clemastine effectively killed lab grown tumour cells at doses that were not harmful to other tested cells types, as well as blocked tumour growth and increased survival in the animals. Use of CAD antihistamine was linked to reduced all cause mortality among cancer patients in previous studies.
“We observed a dramatic loss of the glioblastoma cell viability that was associated with the loss of lysosomal membrane integrity at doses that did not affect the proliferation or viability of several normal cells in vitro. When we evaluated the preclinical efficacy of clemastine, the survival of animals bearing intracranial glioblastoma xenografts was significantly prolonged compared to controls due to the eradication of invasive glioma cells.”
“Our study demonstrates the crucial role of MDGI in glioma cell survival, linking this fatty acid binding protein to the maintenance of lysosomal membrane integrity. This unexpected fragility of the aggressive infiltrating cells to LMP provides new opportunities for clinical interventions, such as repositioning of an established antihistamine drug, to eradicate the inoperable, invasive, and chemo-resistant glioma cells from sustaining disease progression and recurrence … More widely, LMP-inducing agents should be considered as a possible novel treatment option for gliomas.”
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