Emodin as a multi‑target modulator of tumor angiogenesis: Mechanisms, microenvironment and therapeutic potential (Review)

Angiogenesis is central to tumor development and metastasis as it facilitates oxygen and nutrient supplies to cancer cells. The inhibition of angiogenic pathways is a commonly used strategy in the treatment of cancer, usually through inhibitory actions that first lead to the targeted suppression of the key pro‑angiogenic factor, vascular endothelial growth factor (VEGF), and its upstream regulator, hypoxia‑inducible factor 1α (HIF‑1α). Emodin, a common anthraquinone derivative of natural origins, has a variety of actions to inhibit angiogenesis, which include the ability to inhibit the expression of VEGF, as well as the ability to reverse the stabilization of HIF‑1α and inhibit tumor microvessel branching. Moreover, emodin is recognized for pathways other than those involving VEGF, such as fibroblast growth factor and platelet‑derived growth factor, which affect endothelial cell proliferation and pericyte recruitment. Emodin can facilitate vessel destabilization by acting on several angiopoietins, leading to the disruption of the function of the tumor vasculature. These mechanisms collectively obstruct tumor vascularization, deprive tumor cells of vital nutrients and prevent cancer progression. In silico molecular docking analyses suggest that emodin may interact with the ATP‑binding pocket of VEGFR‑2 and the oxygen‑dependent degradation domain of HIF‑1α. Although these findings support a plausible multi‑target inhibitory profile for emodin, direct biochemical and structural validation of these interactions remains limited. Pre‑clinical studies to date have determined it to be a critical anti‑angiogenic agent and a synergistic agent in combination with chemotherapy and/or targeted therapies that can be administered to patients. Future studies are required to address bioavailability issues, target the associated resistance mechanisms, and explore mechanisms with which to increase its efficacy as an adjuvant in the treatment of cancer.