Angiogenesis is a double-edged sword; it is a mechanism that defines the boundary between health and disease. In spite of its central role in physiological homeostasis, it provides the oxygen and nutrition needed by tumor cells to proceed from dormancy if pro-angiogenic factors tip the balance in favor of tumor angiogenesis. Among pro-angiogenic factors, vascular endothelial growth factor (VEGF) is a prominent target in therapeutic methods due to its strategic involvement in the formation of anomalous tumor vasculature. In addition, VEGF exhibits immune-regulatory properties which suppress immune cell antitumor activity. VEGF signaling through its receptors is an integral part of tumoral angiogenic approaches. A wide variety of medicines have been designed to target the ligands and receptors of this pro-angiogenic superfamily. Herein, we summarize the direct and indirect molecular mechanisms of VEGF to demonstrate its versatile role in the context of cancer angiogenesis and current transformative VEGF-targeted strategies interfering with tumor growth.

Fingolimod is a well-tolerated, highly effective disease-modifying therapy successfully utilized in the management of multiple sclerosis. The active metabolite, fingolimod-phosphate, acts on sphingosine-1-phosphate receptors (S1PRs) to bring about an array of pharmacological effects. While being initially recognized as a novel agent that can profoundly reduce T-cell numbers in circulation and the CNS, thereby suppressing inflammation and MS, there is now rapidly increasing knowledge on its previously unrecognized molecular and potential therapeutic effects in diverse pathological conditions. In addition to exerting inhibitory effects on sphingolipid pathway enzymes, fingolimod also inhibits histone deacetylases, transient receptor potential cation channel subfamily M member 7 (TRMP7), cytosolic phospholipase A2α (cPLA2α), reduces lysophosphatidic acid (LPA) plasma levels, and activates protein phosphatase 2A (PP2A). Furthermore, fingolimod induces apoptosis, autophagy, cell cycle arrest, epigenetic regulations, macrophages M1/M2 shift and enhances BDNF expression. According to recent evidence, fingolimod modulates a range of other molecular pathways deeply rooted in disease initiation or progression. Experimental reports have firmly associated the drug with potentially beneficial therapeutic effects in immunomodulatory diseases, CNS injuries, and diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), epilepsy, and even cancer. Attractive pharmacological effects, relative safety, favorable pharmacokinetics, and positive experimental data have collectively led to its testing in clinical trials. Based on the recent reports, fingolimod may soon find its way as an adjunct therapy in various disparate pathological conditions. This review summarizes the up-to-date knowledge about molecular pharmacology and potential therapeutic uses of fingolimod.

As a complicated process of forming new blood vessels from the present vasculature endothelium, angiogenesis plays a critical role in the progression of cancer, through developing new blood vessels in tumor cells. Angiogenesis is regulated by proteins known as inhibitor or activator molecules, affected by different medicinal herbs and small molecules. In the present review, the molecular mechanisms of tumor angiogenesis are outlined, focusing on the pharmacological aspects and molecular mechanisms of natural compounds used in chemotherapy and their effects on angiogenesis, focusing on vascular endothelial growth factor (VEGF). Our findings show that a significant number of drugs used in the treatment of cancer are antiangiogenic small molecules and phytochemicals which inhibit VEGF and angiogenesis. Besides, medicinal herbs are potential multi-target agents with more covering mechanisms, lower costs and lower toxicity to develop novel anticancer drugs through targeting the VEGF signaling pathway and receptor tyrosine kinases (RTKs) in the angiogenesis. For this reason, herbal anti-VEGF agents are considered as imperative targets to be used for cancer treatment in clinical applications. The findings reveal a promising perspective for medicinal herbs and natural compounds acting on VEGF and angiogenesis to find new targets and potential therapeutic use in the treatment of cancer.

Glioblastoma multiforme (GBM) is the most prevalent primary brain tumor with extreme aggressiveness, poor prognosis, and a high mortality rate. To maintain a high rate of proliferation and invasion, GBM cells manipulate many biological processes within the cell and the tumor microenvironment, including intracellular signaling pathways. One of the main signaling pathways with proven roles in GBM pathology is the PI3K/AKT/mTOR signaling pathway, with its molecular alterations considered a hallmark of GBM. Through integrating with various upstream signals from growth factors, nutrients, and energy status, regulatory feedback mechanisms with other signaling pathways, manipulation of glioma stem cells, and epigenetic regulations, this pathway contributes to GBM cell proliferation, growth, angiogenesis, and metastasis, and more importantly escape the effects of available therapies. The extent of involvement of the PI3K/AKT/mTOR signaling pathway grants a more delicate and detailed understanding of this pathway. This review provides a deep insight into the mTOR pathway in GBM, revealing its modulators and interactions with upstream and downstream regulators. It also provides comprehensive information on the latest mTOR-targeted therapies and resistance mechanisms.