Swiss researchers report that combining tricyclic antidepressants and blood thinners for the treatment of early stage brain cancer in mice led to the cancer cells eating themselves. This process, called autophagy, resulted in doubling of the cancer-afflicted mice’s lifespan.
Brain cancer is the abnormal growth and proliferation of cells in the brain. The cancer could originate in the brain itself (primary) or could result from metastasis of cancers from other parts of the body. A type of primary brain cancer, called glioma, could progress into glioblastoma or GBM, which is a most severe form of cancer.
Some research studies have reported that antidepressants of the tricyclic class (TCA), which are the oldest among anti-depressants, showed an inverse relationship with cancers of the brain and colon. Research has also shown that injectable blood thinners might improve the survival of glioma patients. The current research used this background to explore the effect of combining a TCA class of anti-depressants with blood thinners in a mouse model of glioma.
The researchers used imipramine, a TCA and anticoagulant ticlopidine, on mice, either alone or together. Mice suffering from early stage human glioblastoma were given the two treatments, separately or in combination, five days a week. Whereas TCA was administered orally, the anticoagulant was injected. The interval between the two treatments was 10-15 minutes. The results of the treatments show that:
- TCA treatment alone rendered modest therapeutic benefits on glioma.
- Combining TCA therapy with anticoagulant doubled the mouse lifespan.
The scientists followed up the animal experiments with cell culture ones to elucidate the mechanism of delay in disease progression. The results of the cell culture experiments were:
- The combined TCA and anticoagulant therapy resulted in increased autophagy.
- The anticoagulant potentiated TCA and increased the levels of cyclic Adenosine Monophosphate (cAMP), which is a modulator of autophagy, ultimately leading to the death of cells in culture.
Dr. Hanahan, the senior author of the study, says in the Press Release, “It is exciting to envision that combining two relatively inexpensive and non-toxic classes of generic drugs holds promise to make a difference in the treatment of patients with lethal brain cancer.” However, Dr. Hanahan cautions that the combination of these drugs does not “cure” glioblastoma in mice, only “delays” the progression of the disease.
However, this delay could potentially provide the much-needed window of opportunity for doctors to wage a multi-pronged attack to eliminate brain cancer in its early stages. In the words of Dr. Hanahan, “It seems likely that these drugs will need to be combined with other classes of anticancer drugs to have benefit in treating glioblastoma patients. One can also envision 'co-clinical trials' wherein experimental therapeutic trials in the mouse models of glioblastoma are linked to analogous small proof-of-concept trials in GBM patients. Such trials may not be far off.”
Written by Mangala Sarkar, Ph.D.
Shchors, K., Massaras, A., & Hanahan, H. (2015). Dual Targeting of the Autophagic Regulatory Circuitry in Gliomas with Repurposed Drugs Elicits Cell-Lethal Autophagy and Therapeutic Benefit. Cancer Cell. doi:10.1016/j.ccell.2015.08.012
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