Natural compounds present in medicinal

Natural compounds, present in medicinal and/or nutritional plants as well as in macrofungi sources, have stimulated a great interest from the pharmaceutical industry. Different natural compounds such as phenolic compounds, alkaloids, terpenoids among others, have shown strong antiangiogenic effects and can be considered as viable options to develop new strategies or drugs for targeting pathological angiogenesis. The low or even absent toxicity of these active compounds, make them an attractive alternative for human health maintenance. Chemoprevention is a promising anticancer approach with reduced secondary effects in comparison with synthetic drugs [18]. Chemoprevention consists in using other active molecules, such as naturally occurring anticancer agents, to inhibit or reverse some processes of carcinogenesis, including pathological angiogenesis [19]. The advent of diseases can thus be substantially prevented through new dietary habits, and the increased consumption of natural products have long been known to have a chemopreventive effect. In the next section (Section 2) a survey of selected angiogenesis pathways and therapeutic targets will be presented, with emphasis on molecular mechanisms that have been targeted by natural molecules or natural sources. Section 3 will then review the current status of drugs used against angiogenesis, while Section 4 will provide an extensive review on the state of the art of known natural sources with antiangiogenic activity. Finally, Section 5 will focus on the challenges that natural products face to be used at a wider scale for medicinal purposes, thus as potential substitutes for the existing drugs.
Angiogenesis molecular pathways and therapeutic targets The formation of new blood vessels is controlled by various angiogenic factors that act by triggering the signaling pathways leading to blood vessels formation and repairing. Other angiogenic factors may act by promoting the inhibition of angiogenesis, thus interfering with the formation of new blood vessels. The activation and inhibition effects of these angiogenetic factors are normally balanced so that blood vessels only form when needed by the organism. These angiogenic factors may be classified in different groups including growth factors, matrix metalloproteinases (MMP-2 and MMP-9), cytokines, transcription factors, arachidonic perindopril erbumine synthesis derivatives and cell cycle related proteins, among others [1]. All of these angiogenic factors may be regarded as potential therapeutic targets, for treatment of conditions involving pathological angiogenesis. Some of the most widely studied angiogenic factors, as potential therapeutic targets, include vascular endothelial growth factor (VEGF), fibroblast growth factors (FGF), platelet derived growth factor (PDGF), matrix metalloproteinases, tumor necrosis factor alpha (TNF-α) and hypoxia-inducible factor (HIF-1), just to name a few [20]. Therapeutic treatments that target angiogenic factors have in fact already been developed, with the notable example of antibodies and small TKIs against VEGF and respective receptors (Table 1). A brief description of some of the most studied angiogenic factors, and the respective molecular pathway, will be presented, highlighting the pathways that have already been targeted by natural compounds and sources. Fig. 1 presents an overview of the signaling pathways involved in angiogenesis, which were targeted by different natural molecules.
Antiangiogenic drugs The development of drugs that act as angiogenic inhibitors has become essential for the treatment of various types of cancer (Table 1). The main objective of these antiangiogenic drugs is to deprive tumor cells of oxygen and nutrients, thus preventing the formation of new blood vessels and therefore limiting tumor growth [104]. An extensive, yet non-exhaustive, account of angiogenesis molecular pathways and targets was presented in chapter 2 (Fig. 1). Still, the majority of drugs in clinical use where developed, either as RTK inhibitors or as growth factor inhibitors, that activates the respective RTK (Fig. 2) [104], [105]. The explanation for this lack of therapeutic targets diversity is probably due to the fact that antiangiogenic drugs in clinical use are relatively recent. In fact, it was only in 2004 that bevacizumab (Avastin) was approved as the first antiangiogenic drug cancer treatment, by the USA Food and Drug Administration (FDA) [106], [107]. Bevacizumab is a monoclonal antibody that specifically binds to VEGF, thus preventing it to interact and activate their RTK receptors [108]. Initially it was approved as a first-line treatment in metastatic colorectal cancer (CRC) and subsequently for treatment in cervical, non-small cell lung (NSCL), renal cell and glioblastoma cancers [106], [109], [110]. With the increased interest in antiangiogenic drugs, other compounds were developed over the years (Table 1). These compounds can be essentially divided in three families: antibodies targeting VEGF or his membrane RTKs (Bevacizumab and Ramucirumab); small molecule inhibitors of RTKs (Cabozatinib, Pazopanib, Regorafenib, Sorafenib, Sunitinib and Vandetanib) and small molecule inhibitors targeting proteins involved in angiogenesis signaling pathways, downstream membrane RTKs activation, either directly or by inhibiting its expression (Lenalidomide and Thalidomide) [104], [106].