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Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer—Part 1
S.M. Sagar MD,* D. Yance MH,† and R.K. Wong MD*
An integrative approach for managing a patient with cancer should target the multiple biochemical and physiologic pathways thatsupport tumour development and minimize normal-tissue toxicity. Angiogenesis is a key process in the promotion of cancer. Many natural health products that inhibit angiogenesis also manifest other anticancer activities. The present article focuses on products that have a high degree of anti-angiogenic activity, but it also describes some of the many other actions of these agents that can inhibittumour progression and reduce the risk of metastasis. Natural health products target molecular pathways other than angiogenesis, including epidermal growth factor receptor, the HER2/neu gene, the cyclooxygenase-2 enzyme, the nuclear factor kappa-B transcription factor, the protein kinases, the Bcl-2 protein, and coagulation pathways. The herbs that are traditionally used for anticancer treatmentand that are antiangiogenic through multiple interdependent processes (including effects on gene expression, signal processing, and enzyme activities) include Artemisia annua (Chinese wormwood), Viscum album (European mistletoe), Curcuma longa (curcumin), Scutellaria baicalensis (Chinese skullcap), resveratrol and proanthocyanidin (grape seed extract), Magnolia officinalis (Chinese magnolia tree),Camellia sinensis (green tea), Ginkgo biloba, quercetin, Poria cocos, Zingiber officinalis (ginger), Panax ginseng, Rabdosia rubescens hora (Rabdosia), and Chinese destagnation herbs. Quality assurance of appropriate extracts is essential prior to embarking upon clinical trials. More data are required on dose–response, appropriate combinations, and potential toxicities. Given the multiple effectsof these agents, their future use for cancer therapy probably lies in synergistic combinations. During active cancer therapy, they should generally be evaluated in combination with chemotherapy and radiation. In this role, they act as modifiers of biologic response or as adaptogens, potentially enhancing the efficacy of the conventional therapies.
Angiogenesis, anti-angiogenic,natural health products, herbal medicine, anticancer, clinical trials, integrative, molecular biology
To progress, cancers require a source of nutrition and oxygen. Tumours that outgrow their oxygen supply cannot form masses greater than 1–2 mm without developing central necrosis. Neoplasms are genetically plastic and often adapt by switching on genes that increase their ability toinvade and metastasize. A critical part of this process is the induction of local small blood vessels, termed “angiogenesis” 1,2. Tumours do not grow progressively unless they induce a blood supply from the surrounding stroma. Cancers that lack angiogenesis remain dormant. Rapid logarithmic growth follows the acquisition of a blood supply. The tumour angiogenic switch seems to be activated when thebalance shifts from angiogenic inhibitors to angiogenic stimulators. The process of neovascularization is subtly controlled in normal tissues by a sequence of endogenous polypeptides that are secreted during growth, healing, and tissue renewal (Table I). Neoplasms are able to synthesize or induce some of these polypeptides, an activity that is partly achieved by the secretion of vascularendothelial growth factor ( VEGF ) and angiopoietins (APNs). Hypoxia stimulates these peptides; the result is a sprouting of endothelial cords. This sprouting creates profuse but immature networks of thin endothelial-lined channels, essential for tumour oxygenation. Although these networks permit progressive tumour growth, they are less efficient than the vascular supply to normal tissues. The APNs...