Abstract

   Glioblastoma multiform (GBM) is categorized as the most malignant
   subtype of gliomas, which comprise nearly 75% of malignant brain tumors
   in adults. Increasing evidence suggests that network pharmacology will
   be a novel method for identifying the systemic mechanism of therapeutic
   compounds in diseases like cancer. The present study aimed to use a
   network pharmacology approach to establish the predictive targets of
   sciadopitysin against GBM and elucidate its biological mechanisms.
   Firstly, targets of sciadopitysin were obtained from the
   SwissTargetPrediction database, and genes associated with the
   pathogenesis of GBM were identified from the DiGeNET database.
   Sixty-four correlative hits were identified as anti-glioblastoma
   targets of sciadopitysin. Functional enrichment and pathway analysis
   revealed significant biological mechanisms of the targets. Interaction
   of protein network and cluster analysis using STRING resulted in two
   crucial interacting hub genes, namely, HSP90 and AKT1. Additionally,
   the in vitro cytotoxic potential of sciadopitysin was assessed on GBM
   U87 cells. The findings indicate that the pharmacological action of
   sciadopitysin against GBM might be associated with the regulation of
   two core targets: HSP90 and AKT1. Thus, the network pharmacology
   undertaken in the current study established the core active targets of
   sciadopitysin, which may be extensively applied with further
   validations for treatment in GBM.

   Keywords: sciadopitysin, glioblastoma, network pharmacology, HSP90,
   AKT1

Introduction

   Adult glioblastoma (GBM) is the most common malignant primary brain
   tumor, representing approximately 57% of all gliomas and 48% of all
   primary malignant central nervous system (CNS) tumors [37]^1. It is
   also one of the most deadly and recalcitrant of all malignant solid
   tumors. Despite recent advances that have been made in multimodality
   therapy for glioblastoma incorporating surgery, radiotherapy, systemic
   therapy (chemotherapy, targeted therapy), and supportive care, the
   overall prognosis is still poor, and long-term survival is rare. The
   latest research shows that in the United States alone, the annual
   incidence of glioblastoma is about 34 cases per 1 million people, with
   a median survival of about 8 months, and more than 7,000 people die
   from glioblastoma each year [38]^2. For most patients with GBM, there
   is no known cause of the disease. It may occur at any age and originate
   by genetic alterations affecting neuroglial stem or progenitor cells
   [39]^3. Incidence increases steadily with age. The therapeutic efficacy
   of glioblastoma could be improved by figuring out molecular pathways
   and alterations in the signaling mechanisms of the tumor cells.

   Sciadopitysin (SP), a biflavonoid compound that is common in
   gymnosperms such as Cyperus roxburghii, Cryptomeria fortunei,
   Podocarpus, Taxus chinensis, and Ginkgo biloba, exhibits various
   biological properties [40]^4. In recent years, the biological activity
   of SP has been gradually investigated. Studies have shown that SP has
   various pharmacological effects, such as anti-tumor, antioxidation,
   reducing blood glucose and blood lipid, etc. Bioflavonoids show
   potential proteins or enzymes related to metabolism, growth, and
   survival, which are related to tumor growth, tumor metastasis, and
   angiogenesis [41]^5. Glioblastoma is a kind of heterogeneous disease,
   meaning a distinct understanding of its mechanism is required for
   significant treatment preferences. However, due to limitations in