Towards Effective Treatment of Glioblastoma: The Role of Combination Therapies and the Potential of Phytotherapy and Micotherapy

Abstract

Glioblastoma multiforme (GBM) is one of the most aggressive and difficult-to-treat brain tumors, with a poor prognosis due to its high resistance to conventional therapies. Current treatment options, including surgical resection, radiotherapy, and chemotherapy, have limited effectiveness in improving long-term survival. Despite the emergence of new therapies, monotherapy approaches have not shown significant improvements, highlighting the need for innovative therapeutic strategies. Combination therapies appear to be the most promising solution, as they target multiple molecular pathways involved in GBM progression. One area of growing interest is the incorporation of phytotherapy and micotherapy as complementary treatments, which offer potential benefits due to their anti-tumor, anti-inflammatory, and immunomodulatory properties. This review examines the current challenges in GBM treatment, discusses the potential of combination therapies, and highlights the promising role of phytotherapy and micotherapy as integrative therapeutic options for GBM management.

Keywords: combined therapy; conventional therapy; glioblastoma; innovative therapy; natural adjuvant; resistance.

Figure 1

Schematic representation of therapeutic strategies for glioblastoma. The diagram illustrates key molecular targets and pathways involved in GBM progression, highlighting therapies discussed in this review. Specifically, alginate microspheres containing dying GBM cells, peptide-based immunotherapy, and cancer vaccines act as positive regulators of T lymphocyte activity. In parallel, immune checkpoint inhibitors and various agents such as imiquimod, ipilimumab, and AB154 exert inhibitory effects on specific receptors of these leukocytes. On the other hand, cell-based therapies using CAR-T and CAR-NK cells mediate an inhibitory effect on glioblastoma cells through recognition and interaction with specific tumor antigens. Transcription/replication inhibitors, alkylating agents, DDR pathway and HDAC inhibitors directly target tumor cells at the nuclear level, regulating transcription, replication, and gene expression. Defactinib inhibits mechanisms of focal adhesion and cellular migration. Specific molecules, e.g., autophagy/proteasome, IDH, LDH, and GLS inhibitors, metformin, and starvation therapies, block the metabolic processes of neoplastic cells. Tadalafil, azeliragon, phytotherapy, and micotherapy act as modulators of intracellular oxidative stress levels. Cell growth pathways are inhibited by protein kinase C, PI3K/AKT/mTOR pathway, ERK pathway, cell cycle, and RTK inhibitors. In particular, RTK inhibitors block cell growth pathways by interacting with specific tyrosine kinase receptors. Bevacizumab, regorafenib, and nivolumab inhibit both VEGF molecules and its receptors. Additionally, oncolytic viruses mediate an inhibitory effect on GBM cells, as do proton therapy, sonodynamic and photodynamic therapy, hyperthermia, and tumor treating fields. Red arrows indicate inhibitory effects, while green arrows represent activation or promotion of therapeutic pathways. Abbreviations: ACNU (nimustine), BCNU (carmustine), CAR-NK (chimeric antigen receptor natural killer cell), CAR-T (chimeric antigen receptor T-cell), CCNU (lomustine), DDR (DNA damage repair), GBM (glioblastoma), GLS (glutaminase), HDAC (histone deacetylase), IDH (isocitrate dehydrogenase), LDH (lactate dehydrogenase), PI3K/AKT/mTOR (phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin), RTK (receptor tyrosine kinases), TIGIT (T cell immunoreceptor with IG and ITIM domains), TMZ (temozolomide), VEGF (vascular endothelial growth factor), VEGFr (vascular endothelial growth factor receptor).

Figure 2

Schematic representation of phytotherapeutic and micotherapeutic strategies for glioblastoma. The diagram illustrates key molecular targets and pathways involved in GBM progression, highlighting therapies discussed in this review. Specifically, quercetin and resveratrol play a role in stimulating the maturation of dendritic cells. In particular, resveratrol also regulates oxidative stress in tumor cells while simultaneously inhibiting migration, cellular adhesion, and angiogenesis. These processes, i.e., vascular neogenesis, migration, and adhesion, are further negatively regulated by α-mangostin. Compounds such as betulinic acid, berberine, quercetin, withanolides, polyphenols, α-mangostin, resveratrol, muscone, trichoderma asperelloides extract, mycophenolic acid, medicinal mushrooms, soloxolone para-methylanilide, and a derivative of indole-3-carbinol demonstrate inhibitory effects on tumor growth, mitochondrial activity, and cell cycle. These compounds also impact oxidative stress pathways and stimulate apoptotic cell death mechanisms. Their mitochondrial action further affects the oxidative stress pathway, enhancing apoptotic signaling. Additionally, the release of mitochondrial cytochrome c and the influence on the cell cycle by these molecules drive the activation of apoptotic pathways. The regulation of DNA/RNA is inhibited by withanolides, polyphenols, and mycophenolic acid. Notably, mycophenolic acid also suppresses MGMT expression, an effect shared by polydatin and curcumin, both of which concurrently inhibit autophagy. However, autophagic cell death is promoted by berberine. Red arrows indicate inhibitory effects, while green arrows represent activation or promotion of therapeutic pathways. Abbreviations: DCs (dendritic cells), GBM (glioblastoma), MGMT (O6-methylguanine-DNA methyltransferase), ROS (reactive oxygen species).