Abstract
BackgroundHonokiol, a small-molecular weight natural product, has previously been reported to activate apoptosis and inhibit gastric tumorigenesis. Whether honokiol inhibits the angiogenesis and metastasis of gastric cancer cells remains unknown.Methodology/Principal FindingsWe tested the effects of honokiol on angiogenic activity and peritoneal dissemination using in vivo, ex vivo and in vitro assay systems. The signaling responses in human gastric cancer cells, human umbilical vascular endothelial cells (HUVECs), and isolated tumors were detected and analyzed. In a xenograft gastric tumor mouse model, honokiol significantly inhibited the peritoneal dissemination detected by PET/CT technique. Honokiol also effectively attenuated the angiogenesis detected by chick chorioallantoic membrane assay, mouse matrigel plug assay, rat aortic ring endothelial cell sprouting assay, and endothelial cell tube formation assay. Furthermore, honokiol effectively enhanced signal transducer and activator of transcription (STAT-3) dephosphorylation and inhibited STAT-3 DNA binding activity in human gastric cancer cells and HUVECs, which was correlated with the up-regulation of the activity and protein expression of Src homology 2 (SH2)-containing tyrosine phosphatase-1 (SHP-1). Calpain-II inhibitor and siRNA transfection significantly reversed the honokiol-induced SHP-1 activity. The decreased STAT-3 phosphorylation and increased SHP-1 expression were also shown in isolated peritoneal metastatic tumors. Honokiol was also capable of inhibiting VEGF generation, which could be reversed by SHP-1 siRNA transfection.Conclusions/SignificanceHonokiol increases expression and activity of SPH-1 that further deactivates STAT3 pathway. These findings also suggest that honokiol is a novel and potent inhibitor of angiogenesis and peritoneal dissemination of gastric cancer cells, providing support for the application potential of honokiol in gastric cancer therapy.
Highlights
The majority of patients (,60%) with gastric cancer are diagnosed with late stage disease
We demonstrated for the first time that honokiol is a potent inhibitor of angiogenesis and peritoneal metastasis of gastric cancer
Our research has focused on the effects and possible mechanisms of honokiol on peritoneal metastasis and angiogenesis using PET/ CT, CAM assay, matrigel plug assay, aortic ring endothelial cell sprouting assay, endothelial cell tube formation assay, and in vitro cell experiments
Summary
The majority of patients (,60%) with gastric cancer are diagnosed with late stage disease. Cancer growth and peritoneal metastasis are angiogenesis dependent, a process which involves several angiogenic factors including vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), basic fibroblast growth factor, prostaglandin E2, interleukin-8, chemokine (C-X-C motif) ligand 1, and the matrix metalloproteinase family [4,5,6]. Several molecular signals, such as signal transducer and activator of transcription-3 (STAT-3), nuclear factor-eB, Akt, mitogen-activated protein kinases, cyclooxygenase-2, lipoxygenase, inducible nitric-oxide synthase, tumor necrosis factor and others, have been shown to be involved in tumor progression and angiogenesis [7,8,9]. Whether honokiol inhibits the angiogenesis and metastasis of gastric cancer cells remains unknown
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