Usnic acid inhibits breast tumor angiogenesis and growth by suppressing VEGFR2-mediated AKT and ERK1/2 signaling pathways

Abstract

Tumor growth depends on angiogenesis and inducing angiogenesis is one of the most important hallmarks in the cancer development. Treatment with small molecules that inhibit angiogenesis has been an effective strategy for anti-cancer therapy. Some anti-angiogenic factors are derived from traditional Chinese herbs. Usnic acid (UA), an active compound mainly found in lichens, has shown some biological and physiological activities. However, the role and mechanism of UA in tumor angiogenesis are still unknown. The aim of this study was to assess the effects of UA on tumor angiogenesis. In this study, we demonstrated that UA strongly inhibited in vivo angiogenesis in a chick embryo chorioallantoic membrane assay and vascular endothelial growth factor-induced mouse corneal angiogenesis model. In a mouse xenograft tumor model, UA suppressed Bcap-37 breast tumor growth and angiogenesis without affecting mice body weight. In an in vitro assay, UA not only significantly inhibited endothelial cell proliferation, migration and tube formation, but also induced morphological changes and apoptosis in endothelial cells. In addition, UA inhibited Bcap-37 tumor cell proliferation. Moreover, western blot analysis of cell signaling molecules indicated that UA blocked vascular endothelial growth factor receptor (VEGFR) 2 mediated Extracellular signal-regulated protein kinases 1 and 2(ERK1/2) and AKT/P70S6K signaling pathways in endothelial cells. These results provided the first evidence of the biological function and molecular mechanism of UA in tumor angiogenesis.

Secalonic Acid-D Represses HIF1α/VEGF-Mediated Angiogenesis by Regulating the Akt/mTOR/p70S6K Signaling Cascade

“…The wound-healing migration assay was performed as described previously (22). Briefly, HUVECs were treated with mitomycin-C to inactivate cell proliferation, wounded by a microtip, washed with PBS, supplemented with fresh medium with or without VEGF (20 ng/mL) and treated with SAD.…”

Orally Administered Mucolytic Drug l-Carbocisteine Inhibits Angiogenesis and Tumor Growth in Mice

“…VEGFR2-mediated activation of Akt, ERK, JNK, and p38 MAP kinase contributes to VEGF-induced survival, proliferation, migration, and tubular-network formation of endothelial cells (Zachary and Gliki, 2001;Wu et al, 2006;Dellinger and Brekken, 2011;Song et al, 2012). Our data showed that L-carbocisteine significantly abrogated ERK activation specifically in endothelial cells; no effect was observed in epidermal cells (Figs.…”

“…To evaluate the molecular mechanisms associated with L-carbocisteine-induced inhibition of VEGF-dependent angiogenesis, we measured by Western blotting the phosphorylation of key proteins downstream of VEGFR2 activation: Akt, ERK1/2, JNK, and p38 MAP kinase (Wu et al, 2006;Dellinger and Brekken, 2011;Song et al, 2012;). L-Carbocisteine (100 mM) potently suppressed VEGF-induced ERK1/2 activation in HUVECs but had no effect on activation of Akt, JNK, or p38 MAP kinase (Fig.…”

Changes in apoptosis-related gene expression profiles in cancer cell lines exposed to usnic acid lichen secondary metabolite

“…The study by Zu et al and our study provide similar results of alternative source-induced apoptosis of cancer cells. Song et al found that treatment with usnic acid significantly suppresses mouse corneal neovascularization via inhibiting vascular endothelial growth factor (VEGF)-activated VEGFR2 phosphorylation (Song et al, 2012). It was determined that usnic acid functions as a tumor angiogenesis inhibitor by suppressing VEGFR2-mediated AKT and extracellular signal-regulated kinase (ERK 1/2) signaling pathways.…”