Current Pharmaceutical Design - Volume 32, Issue 11, 2026

Glioblastoma (GBM), the most aggressive form of primary brain tumor in adults, remains a significant clinical challenge due to its high recurrence and poor prognosis. Characterized by rapid growth, invasiveness, and resistance to therapy, GBM relies on a sophisticated vascular network to sustain its progression. Angiogenesis, the process of forming new blood vessels, is central to meeting the metabolic demands of the tumor. To address this issue, there is a growing consensus on the need for multi-pronged therapeutic strategies that not only inhibit angiogenesis but also disrupt alternative neovascular mechanisms. Promising approaches include combining anti-angiogenic drugs with agents targeting pathways like neurogenic locus notch homolog protein (NOTCH), Wnt, and C-X-C motif chemokine receptor 4 (CXCR4)/stromal cell-derived factor 1 alpha (SDF-1α) to impede vessel co-option, VM, and GSC trans-differentiation.

The search strategy consisted of using material from the PubMed data, focusing on key terms such as: “angiogenesis”, “glioblastoma”, “glioma”, “oncogenesis”, “anti-VEGF treatment”, “signaling pathways”, “hypoxia”, “vessels”, “resistance”, and “neurosurgery.

Аs a result of the analysis of existing recent studies, GBM exhibits an adaptive capacity to utilize various neovascular mechanisms, including vessel co-option, vasculogenic mimicry (VM), and the trans-differentiation of glioma stem cells (GSCs) into vascular-like structures, to circumvent traditional anti-angiogenic therapies. Initial successes with anti-angiogenic treatments targeting vascular endothelial growth factor (VEGF) showed improvements in progression-free survival. Still, they failed to significantly impact the overall survival due to the tumor's activation of compensatory pathways. Hypoxia, a critical driver of angiogenesis, stabilizes hypoxia-inducible factors (HIF-1α and HIF-2α), which upregulate pro-angiogenic gene expression and facilitate adaptive neovascular responses. These adaptations include vessel co-option, where tumor cells utilize pre-existing vasculature, and VM, where tumor cells form endothelial-like channels independent of typical angiogenesis. Moreover, the role of GSCs in forming new vascular structures through transdifferentiation further complicates treatment, enabling the tumor to maintain its blood supply even when VEGF pathways are blocked.

This review highlights the necessity for comprehensive and targeted treatment strategies that encompass the full spectrum of neovascular mechanisms in GBM. Such strategies are crucial for developing more effective therapies that can extend patient survival and improve overall treatment outcomes.

To address the challenge of understanding tumor angiogenesis and ways to inhibit it, there is a growing consensus on the need for multifaceted therapeutic strategies that not only suppress angiogenesis but also disrupt alternative neovascular mechanisms. The most successfull approaches include the use of antiangiogenic drugs in combination with agents targeting pathways such as the neurogenic locus of the notch homolog protein (NOTCH), Wnt, and C-X-C receptor chemokine motif 4 (CXCR4)/stromal cell-derived factor 1 alpha (SDF-1α) aiming to inhibit vessel co-option, VM, and GSC transdifferentiation.

Disorders of mood and post-traumatic stress disorder (PTSD) are common after major trauma, and one of the treatments used is Tricyclic Antidepressants (TCA). These medications work by inhibiting the re-uptake of neurotransmitters like serotonin and noradrenaline. Serotonin is known to have measurable effects on bone tissue due to the presence of specific receptors on bone cells. However, there are conflicting reports about how serotonin signaling affects bone tissue and the process of fracture healing. This study aimed to evaluate the effect of TCAs on fracture healing.

Twelve skeletally mature Wistar rats were used in the study. All rats underwent intra-medullary pinning of the right tibia, and a complete mid-diaphyseal fracture was created. The rats were then randomly split into two groups: a control group and a study group. For twenty-eight days, the study group received a daily dose of 10 mg/kg of amitriptyline via intraperitoneal infusion, while the control group received an equal volume of plain saline via the same route. On day twenty-eight, five hours after the final dose, all rats were euthanized to assess fracture healing using radiological, microscopic, and histological methods.

The study found a significant difference in the total volume of new bone formation between the two groups on day twenty-eight. The control group had a mean bone formation volume of 1.077 mm³, whereas the amitriptyline-treated group had a significantly higher mean volume of 1.824 mm³ (p<0.01).

The results suggest that TCAs positively influence the early phases of fracture healing. The increased new bone formation observed in the amitriptyline group indicates a potential therapeutic benefit beyond their known psychiatric effects. This finding adds to the existing literature on the complex relationship between serotonin signaling and bone metabolism, providing evidence that this class of antidepressants may enhance the process of bone repair.

Tricyclic Antidepressants, specifically amitriptyline, significantly increase new bone formation in the early stages of fracture healing in Wistar rats.