PRAZOSIN
Prazosin is an old drug, first approved by the FDA in 1976 (brand name Minipress) to treat hypertension, through antagonism of α1 and α2B adrenergic receptors (adrenoceptors). It is off-patent and cheap, costing as little as $10 (US) for 30 1mg capsules.
In the spring of 2016, a French group published research showing that prazosin could inhibit the growth of recently-resected human GBM xenografts injected into the brains of immunodeficient NOD scid gamma (NSG) mice [63].
In vitro, five different α-adrenergic receptor antagonists were tested for effects on glioma-initiating cell viability. Of these, only prazosin showed significant inhibitory effects on cell viability, also inhibiting sphere-forming ability of the cells. Prazosin also negatively impacted survival of differentiated GBM cells, while having little effect on healthy neural stem cells.
Freshly-resected human GBM cells were sorted for the markers CD133 and EGFR, and injected into the brains of immunodeficient NSG mice. Upon the detection of tumor mass, the mice were then treated by intraperitoneal injection with prazosin twice weekly for 45 days. Prazosin treatment significantly reduced tumor size and increased mouse survival in these models, compared to untreated tumor-bearing mice. Prazosin treated mice also showed a reduction in the proportion of CD133+ cells in the tumors (CD133 is a marker of GBM stem-like cells, with high tumor initiating potential). A 10-fold lower dose of prazosin, comparable to a typical anti-hypertension dose, also significantly reduced tumor size and increased mouse survival. Additionally, prazosin treatment similarly reduced tumor volume and increased mouse survival in a syngeneic GL-261 mouse glioma model using immunocompetent mice.
The specific mechanism responsible for these observations was next investigated. The researchers found that prazosin causes glioma cell death by apoptosis, both in vitro and in vivo, but did not induce apoptosis in non-tumor cells in the mice. The lack of effect of other adrenergic receptor blockers (besides prazosin) on GBM cells suggested its effects were independent of α-adrenergic receptor blocking activity. Instead, they found that the effects of prazosin on GBM cell death were dependent on PKC𝛿 (protein kinase C, delta isoform), as silencing of PKC𝛿 protected the GBM cells from the effects of prazosin. Prazosin also significantly inhibited the activation of AKT (also known as protein kinase B), which is a central hub in GBM pathology, at the center of the PI3K/AKT/mTOR proliferative signaling pathway. However, the silencing of PKC𝛿 in the cells reversed these effects on AKT. In mice, PKC𝛿-silenced tumors were unresponsive to prazosin.
In summary, these observations indicate that prazosin, a cheap off-patent hypertension drug, may have clinical use in GBM, especially those with alterations in the PI3K/Akt pathway.
