ABSTRACT
Neurokinin receptors are a family of G protein-coupled receptors that were first identified in the central and peripheral nervous systems. However these receptors were later found in other types of cells, therefore, new perspectives concerning their novel roles were described. Mammalian has three neurokinin receptors, among which neurokinin-1 receptors [NK1R] have been indicated to be involved in most, if not all, intracellular functions, primarily the regulation of cell proliferation. By interacting with its potent agonist, substance P [SP], NK1R can engage a variety of signaling pathways and serve as a platform for cells to proliferate by regulating the expression of the cell cycle-related genes. Furthermore, the activity of SP/NK1R is stimulated by various oncogenes, indicating the involvement of this pathway in human cancers. As a result, numerous NK1R antagonists have been investigated in oncology trials, and the promising anti-- cancer effect of these receptors has opened up new possibilities for incorporating these antagonists into cancer treatment. Considering these factors, gaining a deeper understanding of the SP/NK1R pathway could offer significant advantages for cancer patients. The more knowledge we acquire about this pathway, the greater the potential for exploiting it in the development of effective treatment strategies. Here, we present a comprehensive review of the current knowledge pertaining to the biological function of the SP/NK1R, with a specific emphasis on its recently discovered role in the regulation of cell proliferation. Moreover, we provide insights into the impact of this pathway in human cancers, along with an overview of the most significant NK1R antagonists currently utilized in cancer research studies.
ABSTRACT
Although there is no doubt regarding the involvement of oxidative stress in the development of glioblastoma, many questions remained unanswered about signaling cascades that regulate the redox status. Given the importance of the substance P (SP)/neurokinin 1 receptor (NK1R) system in different cancers, it was of particular interest to evaluate whether the stimulation of this cascade in glioblastoma-derived U87 cells is associated with the induction of oxidative stress. Our results showed that SP-mediated activation of NK1R not only increased the intracellular levels of malondialdehyde (MDA) and reactive oxygen species (ROS) but also reduced the concentration of thiol in U87 cells. We also found that upon SP addition, there was a significant reduction in the cells' total antioxidant capacity (TAC), revealing that the SP/NK1R axis may be involved in the regulation of oxidative stress in glioblastoma cells. The significant role of SP/NK1R in triggering oxidative stress in glioblastoma has become more evident when we found that the abrogation of the axis using aprepitant reduced cell survival, probably through exerting antioxidant effects. The results showed that both MDA and ROS concentrations were significantly reduced in the presence of aprepitant, and the number of antioxidant components of the redox system increased. Overall, these findings suggest that aprepitant might exert its anticancer effect on U87 cells through shifting the balance of oxidant and antioxidant components of the redox system.
