Promising Anticancer Potentials of Natural Chalcones as Inhibitors of Angiogenesis
ABSTRACT
This chapter focuses on the budding perspective of chalcone (prop-2- ene-l-one)-based natural inhibitors (isoliquiretigenin, butein, garcinol, hydroxysafflor yellow A, broussochalcone A, 2,4-dihydroxy-6-methoxy- 3,5-dimethylchalcone, 4'-hydroxy chalcone, and Parasiticin-A, -B, and -C) and synthetic inhibitors (4-(p-toluenesulfonylamino)-4'-hydroxy chalcone, 4-maleamide peptidyl chalcone, and quinolyl-thienyl chalcone) that will prevent angiogenic switching (fibroblast growth factor angiogenin, TGF-(3) by directly inhibiting the three vital therapeutic targets: vascular endothelial growth factor, vascular endothelial growth factor receptor-2, and matrix metalloproteinases-2/9, which will block neovascularization, vascular formation, and network formation by completely depriving the cells from the required nutrients, fluid, signaling molecules, and oxygen. The highlighted studies will positively motivate young minds, medicinal chemists, future researchers, and allied scientists for developing or exploring potential angiogenic inhibitors for the treatment of cancer with better pharmacodynamics attributes and less side or adverse effects.
INTRODUCTION
Angiogenesis is a vital process in the human body that leads to the fonnation and maintenance of blood vessel network (Breier, 2000). This imperative process, however, leads to the precipitation of several diseases like cancer and inflammation. With the advancement in medical research, numerous signaling molecules, such as the Delta-Notch system, ephrin-Eph receptors, vascular endothelial growth factors-vascular endothelial growth factor receptors (VEGF-VEGFRs), and angiopoietin-Tie, have been known to involve in the angiogenesis process (Weidner, 1993). The VEGF-VEGFRs play a pivotal role in the process of new blood vessel formation from the precursors in early life stages, vasculogenesis, and angiogenesis (Sridhar and Shepherd, 2003). Blood vessels play a crucial role in the supply of oxygen, nutrients, signaling molecules, fluids, etc. along with access to immune supervision. The endothelial cells, which constitute the inner surface of the blood vessels, are repaired by several angiogenic processes (Wilting and Christ, 1996). The capillary walls and vessels of fine dimensions consist of pericytes (a single cell layer), which largely contrast with the constitution of arteries and veins that are formed largely by smooth muscle cells. However, in adults, the formation of the blood vessels is mediated under a veiy strict process because both disproportionately high amount of neovascularization and their scarce formation will lead to several pathogenic conditions (Battegay, 1995).
During the process of vasculogenesis along with the primary vascular plexus, the formation of the vascular net (capillaries fuse into vessels, arteries, and veins) results from the already existing condition/system (Auerbach and Auerbach, 1994). During the angiogenesis progression, further transformations occur, primarily the vascular plexus expands notably due to acute branching of the capillary and formation of the highly organized network (Ribatti, 2009). The whole procedure involves commencement of the process from the nearby destructed pre-existing blood vessels, followed by the initiation of endothelial cell proliferation, and finally the migration process. The situated endothelial cells are bringing together in tubular structures followed by the fonnation of blood vessels around them (Otrock et al., 2007).
In the pathogenesis of tumor development, the activation of angiogenesis is a crucial phenomenon as it provides developmental support to the cancer cells by promoting easy access to food, nutrients, oxygen, and several other growth-promoting factors (Ribatti, 2008). Without these factors, a tumor nodule cannot grow more than 4 cm3 due to prevailing hypoxia and in the due course will lead to death of cells (Shahi and Pineda, 2008). Various factors, such as fibroblast growth factor (FGF), VEGF-VEGFRs, angiogenin, TGF-p, etc., promote tumor growth by enhancing blood vessel networking in the cancer cells. The inhibition of such factors will lead to containment of “angiogenic switching” and therefore will lead to inactivation of pro-angiogenic factors, and ultimately, the progression/proliferation will halt (Tahergorabi and Khazaei, 2012).
Several natural products, such as chalcones, aurones, flavonoids. flavones, flavonols, flavanones, isoflavones, anthocyanidine, flavan-3-ols, proanthocy- anidins, etc., are regarded as potential antiangiogenic compounds (Mahapatra et al., 2015a). Chalcones (prop-2-ene-l-one) are the class of natural products having a composition of two aromatic rings bound by an a,p unsaturated carbonyl bridge (Mahapatra et al., 2015b). They are the chromophoric compounds first synthesized in the 19th century by Tarnbor and Kostanecki (Mahapatra et al., 2015c). They are regarded as open-chain intermediates in the flavonoid synthesis in the aurone pathway (Mahapatra and Bharti, 2016). The chalcone scaffold-bearing compounds are known to have antibacterial, anti-inflammatory, anticancer, antifungal, hypnotic, antiviral, sedative, anticonvulsant, antimalarial, antileishmanial, antitrypanosomal, antiretroviral, antiplatelet, antihypertensive, antihyperlipidemic, antiarrhythmic, antigout, analgesic, antidiabetic, antiobesity, etc. properties (Mahapatra et al., 2017; Mahapatra et al., 2019a, 2019b). This chapter highlights the antiangiogenic perspectives of natural chalcones.
