Neurokinin-1 Receptor (NK-1R) Antagonists: Potential Targets in the Treatment of Glioblastoma Multiforme

Abstract

: The current standard of care in glioblastoma multiforme (GBM), as the most morbid brain tumor, is not adequate, despite substantial progress in cancer therapy. Among patients receiving current standard treatments, including surgery, irradiation, and chemotherapy, the overall survival (OS) period with GBM is less than one year. The high mortality frequency of GBM is due to its aggressive nature, including accelerated growth, deregulated apoptosis, and invasion into surrounding tissues. The understanding of the molecular pathogenesis of GBM is, therefore, crucial for identifying, designing, and repurposing potential agents in future therapeutic approaches. In recent decades, it has been apparent that several neurotransmitters, specifically substance P (SP), an undecapeptide in the family of neuropeptides tachykinins, are found in astrocytes. After binding to the neurokinin-1 receptor (NK-1R), the SP controls cancer cell growth, exerts antiapoptotic impacts, stimulates cell invasion/metastasis, and activates vascularization. Since SP/NK-1R signaling pathway is a growth driver in many cancers, this potential mechanism is proposed as an additional target for treating GBM. Following an evaluation of the function of both SP and its NK-1R inhibitors in neoplastic cells, we recommend a unique and promising approach for the treatment of patients with GBM.

The Neurokinin-1 Receptor Is Essential for the Viability of Human Glioma Cells: A Possible Target for Treating Glioblastoma

“…This means that NK-1R is crucial for tumor cell survival, and a common antitumor strategy could be applied to treat any tumor. In these previous studies and after applying the knockdown gene silencing method, the technique to demonstrate necrotic mechanisms was not performed, and in all cases, the death of tumor cells was reported to be due to apoptotic mechanisms [ 3 , 15 , 18 , 26 , 58 ]. In cancer cells, NK-1R silencing promoted G2/M phase arrest/apoptosis and suppressed the proliferation of these cells; similar results were found when the NK-1R antagonist aprepitant was administered, but SP rescued the effects of the NK-1R silencing regarding apoptosis and cell proliferation [ 44 ].…”

“…In melanoma, acute lymphoblastic leukemia, lung cancer, and breast cancer, NK-1R is involved in the viability of human tumor cells [ 15 – 17 ]. NK-1R antagonists have been shown to promote apoptotic mechanisms in tumor cells after binding its receptor [ 3 , 8 , 9 , 18 ].…”

“…SP promotes the proliferation of human glioma cell lines through NK-1R activation [ 24 , 25 ]. NK-1R antagonists (e.g., L-733,060, aprepitant) inhibit the proliferation in a dose-dependent manner and promote the apoptosis of glioma cells [ 9 , 18 , 26 , 27 ]. In GB, the inhibition of NK-1R by L-733,060 decreased the basal kinase activity of Akt, increased the expression of cell cycle regulatory proteins (e.g., p21 and p27), and induced G1/S cell cycle arrest and programmed cell death [ 28 ].…”

Discovery of a New CaMKII-Targeted Synthetic Lethal Therapy against Glioblastoma Stem-like Cells

“…NK1R plays a crucial role in cancer development by regulating cell survival, proliferation, migration, invasion, and angiogenesis [ 39 ]. NK1R is overexpressed in many human cancers, including GBM, and its increased expression is strongly associated with higher tumor malignancy and a poor prognosis [ 40 ]. NK1R stimulation induces GBM cell proliferation through activation of the ERK and AKT pathways [ 38 ].…”

Involvement of the Substance P/Neurokinin-1 Receptor System in Cancer

“…What if it was simply a question of dosage [ 17 ]? The knowledge on the involvement of SP/NK-1R in cancer has increased in recent years thanks to a few researchers and laboratories around the world [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 17 , 18 , 19 , 20 , 21 , 22 ]; the findings reported by these researchers greatly support the initiation of clinical studies to confirm the antitumor action of aprepitant. We hope that this Special Issue will serve to increase the scientific interest for the SP/NK-1R system, not only among basic researchers but also in the pharmaceutical industry, to join forces to fight cancer.…”