Angiogenesis is central to tumor development and metastasis because it facilitates oxygen and nutrient supplies to cancer cells. Inhibiting angiogenic pathways is a commonly used strategy in the treatment of cancer, usually through inhibitory actions that first determine targeted apoptosis of the key proangiogenic factor, vascular endothelial growth factor (VEGF), and its upstream regulator, hypoxia-inducible factor 1-alpha (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 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 (FGF) and platelet-derived growth factor (PDGF), which impact endothelial cell proliferation and pericyte recruitment. Emodin can facilitate vessel destabilization by acting on several angiopoietins, causing the function of the tumor vasculature to be disrupted. Molecular docking studies have shown emodin can bind the ATP-binding pocket of VEGFR-2 and the degradation domain of HIF-1α, acting as a multi-target inhibitory compound. These mechanisms collectively obstruct tumor vascularization, deprive tumor cells of vital nutrients, and prevent cancer progression. Pre-clinical studies to date have determined it to be a significant anti-angiogenic agent and a synergistic agent in combination with chemotherapy and/or targeted therapies that can be given to patients. Future studies will address bioavailability issues, target the associated resistance mechanisms, and explore ways to increase its efficacy as an adjuvant in cancer treatment.

Angiogenesis is central to tumor development and metastasis because it facilitates oxygen and nutrient supplies to cancer cells. Inhibiting angiogenic pathways is a commonly used strategy in the treatment of cancer, usually through inhibitory actions that first determine targeted apoptosis of the key proangiogenic factor, vascular endothelial growth factor (VEGF), and its upstream regulator, hypoxia-inducible factor 1-alpha (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 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 (FGF) and platelet-derived growth factor (PDGF), which impact endothelial cell proliferation and pericyte recruitment. Emodin can facilitate vessel destabilization by acting on several angiopoietins, causing the function of the tumor vasculature to be disrupted. Molecular docking studies have shown emodin can bind the ATP-binding pocket of VEGFR-2 and the degradation domain of HIF-1α, acting as a multi-target inhibitory compound. These mechanisms collectively obstruct tumor vascularization, deprive tumor cells of vital nutrients, and prevent cancer progression. Pre-clinical studies to date have determined it to be a significant anti-angiogenic agent and a synergistic agent in combination with chemotherapy and/or targeted therapies that can be given to patients. Future studies will address bioavailability issues, target the associated resistance mechanisms, and explore ways to increase its efficacy as an adjuvant in cancer treatment.

Emodin is a naturally occurring anthraquinone and has been of great interest as a multi-target anticancer agent with potential anti-metastatic effects. There is a growing body of evidence that emodin inhibits the progression of cancer by regulating essential events of epithelial–mesenchymal transition (EMT) and extracellular matrix remodeling. It suppresses matrix metalloproteinases and other associated proteolytic enzymes, thus hindering tumor invasion and metastatic spread. Emodin also suppresses key EMT-related transcription factors, such as Snail, Slug and Twist resulting in lower expression of mesenchymal markers, recovery of epithelial phenotype and lack of cellular motility. These effects are mechanistically mediated by disrupting central oncogenic pathways including transforming growth factor-β (TGF-β)/Smad, Akt/mTOR, MAPK and other signaling pathways that promote EMT plasticity. Recent research also indicates that emodin has a role in regulating cytoskeletal organization, ROS signal, and interactions with the tumor microenvironment that promote metastatic behavior. Although there is strong preclinical evidence, there are still a number of translational gaps. This limits its possible therapeutic use due to low bioavailability, low stability, and inconsistent tumor responsiveness. Possible resistance mechanisms, such as the compensatory activation of other pathways such as Wnt/ β-catenin and survival signaling cascades, are not sufficiently characterized. There is also lack of clinical validation with few controlled trials assessing safety and anti-metastatic efficacy across different types of cancer. The future directions are to focus on optimization of formulation and delivery, improvement of the pharmacokinetics, patient stratification, biomarker-based guided, and rigorous comparisons of combination regimens with chemotherapy, radiotherapy, and targeted agents. These approaches can be used to achieve the full potential of emodin as a therapeutic candidate, which is a metastasis-modulating agent.