Antiangiogenic effect of licochalcone A
Graphical abstract
Introduction
Angiogenesis is the development of new blood vessels from pre-existing ones through a complex multistep progression that includes proliferation, migration, and tube formation of endothelial cells [1]. It plays an important role in physiologic and pathologic processes, such as embryonic development, wound healing, tumor growth, metastasis, and various inflammatory disorders [2]. Angiogenesis is crucial for tumor progression and sustains malignant cells with nutrients and oxygen. Inhibition of new blood vessel networks reduces tumor size and metastases [3]. Since angiogenesis is required for tumor development and tumor vasculature is a supreme target for anticancer strategies, antiangiogenic compounds may act as cancer treatment agents or adjuncts to standard chemotherapeutic regimens [4], [5], [6].
One of the most important factors regulating angiogenesis is vascular endothelial growth factor (VEGF) and its endothelial tyrosine kinase receptors, VEGF receptors (VEGFR). VEGF transduces their signals to the nucleus principally through VEGFR-1, -2, and -3 [1], [7], [8]. Of these receptors, VEGFR-2 appears to play a critical role in the regulation of angiogenesis through signal transduction pathways that control proliferation, migration and tube formation of endothelial cells [8], [9], [10]. Phosphorylation of VEGFR-2 is necessary for the activation of AKT, which is vital for following activation of endothelial cell survival, migration as well as proliferation [9] and is also essential for the activation of cSrc, which regulates cell migration [10]. In contrast, VEGFR-1 is poorly autophosphorylated in response to VEGF in endothelial cells and also seems to participate in pathological angiogenesis [8]. VEGFR-3 is responsible for lymphangiogenesis [8]. Several angiogenesis inhibitors, including VEGFR-2 inhibitors, are currently being evaluated in phase I or phase II clinical trials for cancer therapy [11].
Bioactive compounds in traditional spices and herbs can protect and/or prevent cancer development by reducing angiogenesis. These bioactive compounds are generally safe and efficacious, given that they have been consumed by humans for centuries [12]. However, understanding their mechanisms of action as therapeutic modalities is a major challenge for contemporary science.
Licochalcone A (LicA; C21H22O4, MW 338.4, Fig. 1) is the main active compound of the licorice species Glycyrrhiza inflate, and is an estrogenic flavonoid with antitumor and antiparasitic properties [13], [14], [15], [16]. LicA reduces Bcl-2 protein expression and induces apoptosis in several human cancer cell lines [14]. It also interferes with the parasite mitochondrial electron transport chain and energy metabolism [15], [16]. We previously demonstrated that LicA exerts anti-inflammatory effects by suppressing nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) signaling [17]. As inflammation is closely linked to tumor angiogenesis [18], we asked whether LicA inhibits angiogenesis, a central step in tumor growth and metastasis. Here we show that LicA inhibits the migration and tube formation of endothelial cells in vitro and angiogenesis in vivo.
Section snippets
Reagents and cells
LicA was purchased from Calbiochem (San Diego, CA). 40 mM LicA was prepared in DMSO (Sigma–Aldrich, St. Louis, MO), stored at −20 °C, and then diluted as needed with cell culture medium for in vitro experiments or with PBS for animal experiments. Human umbilical vascular endothelial cells (HUVECs) were obtained from Lonza (Walkersville, MD) and cultured in EGM (Lonza). CT-26 colon cancer cells were obtained from the Korean Cell Bank (Seoul, Korea) and cultured in DMEM (Hyclone, Logan, UT)
LicA inhibits migration and tube formation of endothelial cells
Sprouting angiogenesis includes successive phases of microvessel formation, neovessel growth, and neovessel stabilization [21]. These steps require the migration of endothelial cells from the parent vessel toward angiogenic growth factors, proliferation of endothelial cells behind the migration front, and the organization of endothelial cells into capillary-like structures. These multistep processes can be recapitulated with in vitro assays.
We first tested whether LicA treatment affected HUVECs
Discussion
Angiogenesis is one of the hallmarks of cancer, playing a fundamental role in tumor growth, invasion, and metastasis [1], [2], [3]. Persistent upregulated angiogenesis is a common feature in many pathological conditions, including chronic inflammation, diabetic retinopathy, rheumatoid arthritis, and atherosclerosis [22], [27]. Thus, understanding the central importance of angiogenesis and how new blood vessels are formed has led to novel therapies designed to interrupt this process [3], [4], [5]
Acknowledgment
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2007-0055085).
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These authors contributed equally to this work.