Caffeic acid and its synthetic derivative CADPE suppress tumor angiogenesis by blocking STAT3-mediated VEGF expression in human renal carcinoma cells

Abstract

Tumor angiogenesis is required for tumor development and is stimulated by angiogenic inducers like VEGF (vascular endothelial growth factor). Our previous study demonstrated that STAT3 (signal transducer and activator of transcription 3) up-regulates HIF-1alpha (hypoxia inducible factor-1alpha) protein stability and enhances HIF-1-mediated VEGF expression in hypoxic solid tumor cells, thus suggesting that the inhibition of STAT3 signaling may have clinical applications. In this study, we examined in vitro and in vivo, whether caffeic acid (CA) or its derivative CADPE [3-(3,4-dihydroxy-phenyl)-acrylic acid 2-(3,4-dihydroxy-phenyl)-ethyl ester] exert anticancer activity by targeting STAT3. It was found that CA or CADPE significantly inhibit STAT3 activity, and that this in turn down-regulates HIF-1alpha activity. Consequently, sequential blockade of STAT3 and HIF-1alpha resulted in the down-regulation of VEGF by inhibiting their recruitment to the VEGF promoter. In mice bearing a Caki-I carcinoma, both CA and CADPE retarded tumor growth and suppressed STAT3 phosphorylation, HIF-1alpha expression, vascularization and STAT3-inducible VEGF gene expression in tumors. Taken together, our results demonstrate that CA and CADPE are potential inhibitors of STAT3 and that they suppress tumor angiogenesis by inhibiting the activity of STAT3, the expression of HIF-1alpha and VEGF.

Caffeic acid 3,4-dihydroxy-phenethyl ester suppresses receptor activator of NF-κB ligand–induced osteoclastogenesis and prevents ovariectomy-induced bone loss through inhibition of mitogen-activated protein kinase/activator protein 1 and Ca2+–nuclear factor of activated T-cells cytoplasmic 1 signaling pathways

“…S6), Moreover, in the CADPE-treated groups, CADPE had little effect on body weight at the concentrations tested at 3 months (Fig. 4F), which is consistent with a previous report, (24) suggesting little toxicity of CADPE at the tested concentration.…”

“…(39) CADPE has been demonstrated to be effective in inducing tumor cell senescence and suppression of tumor growth, invasion, and angiogenesis. (23,24) However, its inhibitory effect on osteoclastogenesis and the molecular mechanism(s) are unknown. In this report, we demonstrated that CADPE Fig.…”

“…(20) NFATc1 then translocates to the nucleus and activates the expression of multiple osteoclastogenesis-related genes, such as tartrate-resistant acid phosphatase (TRAP), latent transforming growth factor beta binding protein3 (LTBP3), chloride channel (ClC7), MMP9, calcitonin receptor (CTR), cathepsin K, and c-Src. (21) Caffeic acid 3,4-dihydroxy-phenethyl ester (CADPE), a compound originally isolated from medicinal plants Sarcandra glabra and Teucrium pilosum, (22) has attracted much interest due to its proven pharmacologic safety and its many biologic activities, such as induction of cancer senescence, (23) inhibition of tumor angiogenesis, (24) suppression of hepatocellular carcinoma growth, (25) and gastric carcinoma cell migration. (26) In the present study, we investigated the effects of CADPE on osteoclastogenesis both in vitro and in vivo, and elucidated the underlying molecular mechanisms.…”

Inhibition of STAT3 Signaling Pathway by Nitidine Chloride Suppressed the Angiogenesis and Growth of Human Gastric Cancer

“…Considering the critical roles of STAT3 signaling in the angiogenic and neoplastic process (20,21), we screened a number of natural compounds and found that nitidine chloride exerted its antiangiogenic and antitumor property through the suppression of STAT3 pathway. We provide evidence that nitidine chloride dose dependently suppresses the activation of STAT3, its DNA-binding activity, and its transcriptional activity in both human endothelial cells and gastric cancer cells.…”

Angiogenesis inhibition by green propolis and the angiogenic effect of L-lysine on bladder cancer in rats

“…The discovery of the anticarcinogenic effects of propolis encouraged efforts to identify, isolate and synthesize constituents of propolis and to study their effects and mechanisms of action, including artepillin C 11 , caffeic acid 12 , caffeic acid phenethyl ester 13 , and in the present study, we used an in vivo model to evaluate the effect of intragastric administration of green propolis (in the form of WSDP) on angiogenesis in BBN-induced rat bladder cancer.…”