Abstract
Natural products comprise a major source of small molecular weight angiogenesis inhibitors. We have used the transformed endothelial cell line SVR as an effective screen of natural product extracts to isolate anti-angiogenesis and anti-tumor compounds. Aqueous extracts of Magnolia grandiflora exhibit potent activity in our SVR proliferation assays. We found that the small molecular weight compound honokiol is the active principle of magnolia extract. Honokiol exhibited potent anti-proliferative activity against SVR cells in vitro. In addition, honokiol demonstrated preferential inhibition of primary human endothelial cells compared with fibroblasts and this inhibition was antagonized by antibodies against TNF alpha-related apoptosis-inducing ligand. In vivo, honokiol was highly effective against angiosarcoma in nude mice. Our preclinical data suggests that honokiol is a systemically available and non-toxic inhibitor of angiogenesis and should be further evaluated as a potential chemotherapeutic agent.
Highlights
Regulate the synthesis of VEGF (4 –9)
Effect of Purified Magnolia Compounds on SVR Proliferation—Given the potential importance of natural products as anti-tumor and anti-angiogenesis agents, honokiol and magnolol were tested for their effects on the survival and proliferation of SVR cells and a steep decline in cell number was seen between 4 and 8 g/ml honokiol (Fig. 1A)
Because we have previously demonstrated that reactive oxygen species are involved in VEGF-induced KDR autophosphorylation in endothelial cells [26], we examined the effect of honokiol on this response in cultured HUVEC
Summary
Regulate the synthesis of VEGF (4 –9). Genistein and resveratrol are broad spectrum protein kinase inhibitors that inhibit tumor promotion [1, 2, 10, 11]. Honokiol inhibits the growth of transformed epithelial cells in vitro, demonstrating that it has both antiangiogenic and anti-tumor activity. TRAIL Inhibition Studies (Endothelial Proliferation, VEGFR2 Phosphorylation, and Rac Activation)—Human dermal microvascular endothelial cells (Emory Skin Disease Research Center) were cultured in 24-well plates with 10,000 cells/well for 24 h.
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