Abstract
The hypoxia-inducible factor-1α (HIF-1α) plays a critical role in tumor angiogenesis. It has been reported that the acetone extract of Angelica sinensis (AE-AS) rich in phthalides is able to inhibit cancer cell proliferation. However, whether AE-AS reduces cancer angiogenesis remains unknown. In this study, we demonstrated that AE-AS significantly inhibited the angiogenesis in vitro and in vivo evidenced by attenuation of the tube formation in hypoxic human umbilical vascular endothelial cells (HUVECs), and the vasculature generation in Matrigel plug, the chicken chorioallantoic membrane, and tumors. Treatment with AE-AS markedly decreased the protein accumulation and transcriptional activity of HIF-1α, vascular endothelial growth factor (VEGF) expression/secretion, and VEGFR2 phosphorylation in hypoxic human bladder cancer (T24) cells and tumor tissues accompanied by a reduction of tumor growth. Notably, AE-AS-induced HIF-1α protein degradation may, at least partly, attribute to inhibition of WSB-1-dependent pVHL degradation. Moreover, VEGFR2-activated PI3K/AKT/mTOR signaling pathway in hypoxic T24 cells was greatly inhibited by AE-AS. Collectively, AE-AS may be a potential anticancer agent by attenuating cancer angiogenesis via suppression of WSB-1/pVHL/HIF-1α/VEGF/VEGFR2 cascade.
Highlights
The intratumoral hypoxia (0.05–5% O2) is a common characteristic of most advanced solid tumors, leading to a resistance to radiotherapy and chemotherapeutic drugs, which causes a poor outcome of cancers due to induction of angiogenic and metastatic phenotypes[1, 2]
The data obtained from HPLC analysis revealed that z-ligustilide and n-butylidenephthalide are major components accounting for 39% and 5% in the Angelica sinensis (AE-Angelica sinensis (AS)), respectively (Fig. 1A)
A marked increase of nuclear hypoxia-inducible factor-1α (HIF-1α) protein level in T24 cells caused by deferoxamine (DFO), an iron chelating agent acting as a hypoxia mimetic agent, was inhibited by AE-AS (Fig. 2B)
Summary
The intratumoral hypoxia (0.05–5% O2) is a common characteristic of most advanced solid tumors, leading to a resistance to radiotherapy and chemotherapeutic drugs, which causes a poor outcome of cancers due to induction of angiogenic and metastatic phenotypes[1, 2]. Attenuating HIF-1α-induced tumor angiogenesis is a potential strategy for cancer treatment. The RAS extracts have a variety of biological functions, including anticancer, neuroprotective, immunoregulatory, antioxidant, and hematopoietic activities[12]. The acetone extract of RAS (AE-AS) has been reported to inhibit A549 human lung adenocarcinoma cell proliferation by inducing apoptosis[14]. Whether AE-AS inhibits hypoxia-evoked cancer angiogenesis and the involvement of HIF-1α-regulated processes remain unknown. We demonstrated that AE-AS is able to inhibit the angiogenesis in bladder cancer through suppressing HIF-1α induction and its-regulated pro-angiogenic signaling pathway
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