The Therapeutic Potential of Aprepitant in Glioblastoma Cancer Cells through Redox Modification.

Miguel Muñoz,Hossein Javid,Soodabeh Rezaei,Seyed Isaac Hashemy,Reza Assaran Darban

doi:10.1155/2022/8540403

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.

Highlights

As one of the most challenging malignancies to treat, glioblastoma has an adverse prognosis and poor quality of life [1]
Recent disclosures showed that changes in redox state in tumorigenesis may correlate with tolerance to chemotherapeutic drugs [22]
A new perspective has been aroused in the treatment strategy that proposes adding antioxidant agents may be befitting for therapeutic protocols

Summary

Introduction

As one of the most challenging malignancies to treat, glioblastoma has an adverse prognosis and poor quality of life [1]. Numerous therapeutic interventions have been developed for managing this cancer; these were not successful enough to induce a complete remission [2]. Recurrence of the tumor is inevitable in glioblastoma, which makes the development of more accurate and less toxic treatment strategies more crucial [3]. Numerous molecular investigations have introduced oxidative stress as a hallmark of the progression of many cancers, including glioblastoma [4–6]. Despite the importance of oxidative stress in the pathogenesis of glioblastoma, the precise molecular mechanism responsible for the regulation of this event has not yet been identified. Attention has been attracted to tachykinins, as they have a critical movement in the pathogenesis of glioblastoma [7] and control both oxidative stress and antioxidant systems [8]. NK1R expression was found in other tissues, and the discovery of noncanonical activities of SP/NK1R added a new perspective to this signaling axis as a regulator of tumorigenesis [7, 10]

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