Exploring the Potentials of S4, A Selective Androgen Receptor Modulator, in Glioblastoma Multiforme Therapy

Abstract Background Glioblastoma multiforme (GBM) ranks among the prevalent neoplastic diseases globally, presenting substantial challenges in therapeutic management. Traditional modalities, encompassing surgical excision, chemotherapy, and radiation therapy, have yielded suboptimal response rates in GBM due to its intrinsic pathological resistance. This underscores the imperative for identifying novel molecular targets to enhance therapeutic efficacy. Literature indicates a notable correlation between androgen receptor (AR) signaling pathways and GBM pathogenesis. Consequently, to mitigate the adverse effects associated with androgenic modulation of AR, the scientific community has pivoted towards the synthesis of non-steroidal anabolic agents known as selective androgen receptor modulators (SARMs). Among these, S4, a relatively unexplored SARM with favorable oral bioavailability has emerged as a candidate of interest. Methods and Results This investigation substantiates the anti-oncogenic potential of S4 in both temozolomide-responsive and -resistant GBM cellular models through comprehensive cellular and molecular evaluations. We observed a marked restriction in GBM cell viability, growth, and motility, coupled with an induction of apoptotic pathways, reactive oxygen species (ROS) generation, and cellular senescence. Additionally, S4 exposure precipitated the upregulation of genes associated with apoptosis, cell-cycle arrest, DNA damage response, and senescence, while concurrently downregulating those involved in cellular proliferation. Conclusion Future research endeavors are warranted to delineate the precise mechanisms underpinning S4's actions, assess its antineoplastic effects in vivo, and evaluate its ability to penetrate the blood-brain barrier.