Fighting angiogenesis with natural compounds backed by science

Angiogenesis, the induction of local small blood vessels (neo-vascularisation) is a key process in the promotion of all cancers, since they require a source of nutrition and oxygen.

In general, neo-vascularisation in normal tissues (embryonic development, placenta formation and wound healing) is controlled by a sequence of endogenous polypeptides that are secreted during growth, healing and tissue renewal, and these peptides are (source, table 1):

Activator protein 1, Angiogenin, Angiotropin, Angiopoietin, Basic fibroblast growth factor , Cyclooxygenase, Lipoxygenase, Granulocyte-colony stimulating factor, Hepatocyte growth factor, Insulin-like growth factors 1 and 2, Interleukin-8, Nuclear factor kappa B , Placental growth factor, Platelet-derived endothelial cell growth factor, Pleiotrophin , Proliferin Thrombospondin-1, Transforming growth factor alpha and beta , Tumour necrosis factor alpha, Vascular endothelial growth factor and Vascular permeability factor.

Unfortunately, cancers also have the ability to synthesise or induce some of these peptides, and this is partly achieved by the secretion of: 1) the vascular endothelial growth factor (VEGF), a signal protein produced by many cells that stimulates the formation of blood vessels, and 2) angiopoietins (APNs), a family of vascular growth factors that play a role in embryonic and postnatal angiogenesis. Additionally, hypoxia in the cancer area also stimulates these peptides, and promotes vessel growth by up-regulating multiple pro-angiogenic pathways.

As a consequence, we have the sprouting of endothelial cords in the cancerous tissue, that creates something like immature networks of thin endothelial-lined channels, essential for tumour oxygenation, but in any case less efficient than the vascular supply that is formed in normal tissues.

Hopefully, many natural health products have been identified that can inhibit the process of angiogenesis or neo-vascularisation in the cancer area, and can also manifest other anticancer activities, by targeting molecular pathways other than angiogenesis related pathways.

This article,

"Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer—Part 1"

by S.M. Sagar MD, D. Yance MH and R.K. Wong MD,

is an overview of herbs that have been traditionally used for anti-angiogenic anticancer treatment in synergistic herbal combinations and in combination with chemotherapy, monoclonal antibodies and radiation. (please always check the original studies in the review)

Some of these anti-angiogenic herbs and phytochemicals are:

Artemisia annua (Chinese Wormwood)

Artemisinin (the active constituent extracted from the plant Artemisia annua) has been clinically used as an anti-malaria drug, but more recently it was shown to be cytotoxic to cancer cells (induction of apoptosis).

Additionally, Artesunate (a semi-synthetic derivative of artemisinin) when tested in vitro in a cell model of angiogenesis, significantly inhibited angiogenesis in a dose-dependent manner. The anti-angiogenic effect of artemisinin was tested also in vivo in nude mice, and again the results indicated that treatment with artemisinin significantly reduced the tumour growth and microvessel density (lowered VEGF, VEGFR levels) without any toxicity to the host animals.

VEGF or Vascular endothelial growth factor is a key regulator of physiological angiogenesis during embryogenesis, skeletal growth and reproductive functions and has also been implicated in pathological angiogenesis associated with tumours and intraocular neovascular disorders.

Artemisinin also has anticancer activity through other pathways, since it inhibits the activation of nuclear factor kappa-B (NF-κB), an important protein in cancer development and progression. (Source: Can Artemisinin Treat Cancer?)

The transcription factor NF-κB plays a key role in regulating the immune response to infection and its incorrect regulation has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection and improper immune development.

As of 2018, only preliminary clinical research has been conducted using artemisininin derivatives in various cancers.

Viscum album (European Mistletoe)

Viscum album, also known as Iscador or Mistletoe (called also helixor and isorel), grows on trees such as apple, pine, oak and elm, and researchers believe that viscotoxins, polysaccharide and lectins are the active ingredients in mistletoe extract that:

• have been shown to have anti-angiogenic activity by down-regulating VEGF,
• induce apoptosis of cancer cells,
• boost the immune system by increasing the number of white blood cells, and
• reduce the side effects of chemotherapy and radiation therapy and improve quality of life.

A clinical trial in human subjects showed an increase in survival in a variety of cancers, but the study was poorly controlled and no definitive conclusions could be drawn.

Curcuma longa (Curcumin)

Curcumin is the most active curcuminoid in turmeric, and interacts with cancer cells at a number of levels and can enhance the efficacy of chemotherapy and radiotherapy.

Curcumin can: 1) inhibit the transcription of two major angiogenesis factors VEGF and bFGF (or basic fibroblast growth factor that has broad mitogenic and cell survival activities, and is involved in embryonic development, cell growth, morphogenesis, tissue repair, tumour growth and invasion), and 2) interacts with VEGF- and nitric oxide–mediated angiogenesis in tumours, reducing nitric oxide generation in endothelial cells. This is important because elevated levels of nitric oxide correlate with tumour growth. Curcumin inhibits also the growth factor receptor EGFR (epidermal growth factor receptor) that induces cell differentiation and proliferation.

Curcumin also binds to membrane-bound enzyme CD13 (aminopeptidase N), found in blood vessels undergoing active angiogenesis, and blocks its activity, thereby inhibiting angiogenesis and invasion by tumour cells.

Curcumin also down-regulates the expression of the Matrix Metallopeptidase 9 (MMP9) genes that are associated with angiogenesis. In particular, demethoxycurcumin is a structural analogue of curcumin isolated from Curcuma aromatica, that specifically inhibits the expression of the protein MMP9, thereby reducing the degradation of the extracellular matrix (ECM), degradation that allows tumour growth and facilitate tissue remodelling. Apart MMP9, curcumin can interfere with the activity of both MMP2 and MMP9, the basis of the angiogenic switch, thereby reducing degradation of the ECM.

Curcumin's anti-invasive effects are partly also mediated by up-regulation of the tissue inhibitor of metalloproteinase-1 (TIMP1), involved in the regulation of tumour cell invasion.

A phase I study with curcumin found no treatment-related toxicity at doses up to 8000 mg daily, therefore the study suggested that curcumin may prevent cancer progression.

Scutellaria baicalensis (Chinese Skullcap)

Baicalin and baicalein, are the main derivatives of the Chinese skullcap herb or Scutellaria baicalensis, and they are potent anti-angiogenic compounds that reduce VEGF, bFGF, 12-lipoxygenase activity (promotes tumour angiogenesis and growth in vivo) and MMP.

Scutellaria baicalensis is one of the herbs found in PC-SPES, a complex of Chinese herbs that is clinically active against advanced prostate cancer.

Resveratrol and Proanthocyanidin (Grape Seed Extract)

Resveratrol is a phytoalexin found in grapes and wine, but also in blueberries, raspberries, mulberries and peanuts.

It has demonstrated anti-angiogenic activity by its ability to inhibit division in human umbilical vein endothelial cells (HUVECs) and by its ability to decrease the lytic activity of MMP-2. Resveratrol also inhibits VEGF- induced angiogenesis.

For example, edible berries contain high concentrations of proanthocyanidin (chemical compounds that give the fruits or flowers of many plants their red, blue or purple colours, such as cranberries, blueberries and grape seeds), that inhibit VEGF expression induced by tumour necrosis factor alpha (TNFα). In particular, feeding proanthocyanidins to mice with tumour xenografts reduced VEGF secretion, which resulted in reduced intra-tumoral microvasculature.

On the other hand, one study showed that grape seed extract may up-regulate oxidant-induced VEGF expression, suggesting that proanthocyanidin can induce angiogenesis as part of normal tissue healing.

Magnolia officinalis (Chinese Magnolia Tree)

The seed cones of the Chinese magnolia tree contain substances that inhibit the growth of new blood vessels. For example, honokiol is an active ingredient that it may partly reduce angiogenesis through the regulation of platelet-derived endothelial cell growth factor and transforming growth factor beta (TGFβ) expression. And it also inhibits nitric oxide synthesis, and TNFα expression. TNFα often called tumour necrosis factor alpha, is an adipokine and a cytokine and its primary role is in the regulation of immune cells. TNF is able to induce fever, apoptotic cell death, cachexia and inflammation, inhibit tumorigenesis and viral replication. Deregulation of TNF has been implicated in Alzheimer's disease, cancer, major depression, psoriasis and inflammatory bowel disease.

In animal experiments, honokiol suppressed proliferation in blood vessel endothelial cells more than in other types of cells and thereby reduced tumour growth.

Silybum marianum (Milk Thistle)

Silibinin and silymarin are polyphenolic flavonoids isolated from the fruits or seeds of Silybum marianum.

In particular, silymarin demonstrated in the laboratory strong activity against a variety of tumours by down-regulation of VEGF and EGFR.

Camellia sinensis (Green Tea)

Green tea contains many polyphenols and catechins, such as epigallocatechin-3 gallate (EGCG) namely the active and major constituent of green tea (Camellia sinensis).

So far, these polyphenols and catechins have successfully inhibited proliferation of breast cancer cells and HUVECs, and in rodent studies also suppressed breast cancer xenograft growth and reduced the density of tumour vessels. This activity was associated with a decrease in VEGF expression.

In addition, EGCG can suppress protein kinase C (PKC), that is another VEGF transcription modulator, promoting in this way the anti-angiogenic effects of green tea that may contribute to its potential use for cancer treatment.

EGCG may be administered as a powdered extract of green tea (each gram of this extract provides 400–500 mg of EGCG), and an appropriate dose has been extrapolated from anti-angiogenic activity in rodent experiments as well as from a phase I study in humans. In practice, lower total daily doses of 2–4 g standardized green tea extract (95% polyphenols and 60% catechins) are usually prescribed, and 250 ml of brewed green tea typically contains about 50–100 mg of EGCG.

However, daily intakes equal to or above 800 mg of EGCG per day increase the blood levels of transaminases, an indicator of liver damage, so a safe intake level of 338 mg of EGCG per day has been recommended. In general, you should be very cautious if you’re considering taking this supplement.

Ginkgo biloba

Ginkgo biloba extract has anticancer effects that are related to its gene-regulatory and anti-angiogenic properties.

In particular, the Ginkgo biloba extract used in most research is EGb 761, which contains about 25% flavonoids (ginkgo-flavone glycosides) and about 5% terpenoids (ginkgolides and bilobalides). The most potent flavonoid is ginkgolide B, that has been studied for its potential to act as a platelet-activating factor receptor antagonist.

In fact, the ginko biloba extract inhibits angiogenesis by down-regulating VEGF.

Quercetin

Quercetin is a flavone found in apples, onions, raspberries, red grapes, citrus fruit, cherries, broccoli and leafy greens. Among vegetables and fruits, quercetin content is highest in onions, while quercetin conjugates are found exclusively in the peel of the apples.

Quercetin inhibits angiogenesis through multiple mechanisms, including interaction with 1) the COX-2 enzyme (or Cyclooxygenase 2 also known as prostaglandin endoperoxide synthase, that its pharmaceutical inhibition can provide relief from the symptoms of inflammation and pain), 2) lipoxygenase-5 enzyme (Arachidonate 5-lipoxygenase, also known as ALOX5, 5-lipoxygenase expressed primarily by cells involved in regulating inflammation, allergy and other immune responses), 3) EGFR, 4) the HER2 intracellular signalling pathway (Receptor tyrosine-protein kinase erbB-2, also known as CD340, proto-oncogene Neu, Erbb2, or ERBB2, is a protein that helps breast cancer cells grow quickly) and 5) the NF-κB nuclear transcription protein.

Finally, quercetin may enhance the anticancer effect of tamoxifen through anti-angiogenesis.

Poria cocos

Poria cocos, also known as China root, China tuckahoe, Fu ling, Hoelen and Matsuhodo, is a mushroom extract that has anticancer activity. In particular, it inhibits platelet aggregation and appears to be anti-angiogenic by down-regulating NF-κB.

Panax Ginseng

The lipophilic constituents of ginseng are called saponins (or ginsenosides). These extracts have anticancer activities in tumours that include anti-angiogenesis and induction of tumour cell apoptosis.

Rabdosia rubescens Hara (Rabdosia)

Rabdosia is used in certain traditions to treat cancer and contains ponicidin and oridonin, two diterpenoids that possess significant anti-angiogenic activity.

Extracts of Chinese Medicinal Herbs

Other herbs that are used in China as anticancer agents and have been screened for their anti-angiogenic activity are (that exhibit more than 20% inhibition at 0.2 g herb/mL): Berberis paraspecta, Catharanthus roseus, Coptis chinensis, Scrophularia ningpoensis, Polygonum cuspidatum and Taxus chinensis.

Aromatic herbs that have inhibitory effects on lipid peroxidation or protein oxidative modification by copper

Some cancers are associated with high serum levels of copper, that is essential for the function of many angiogenic growth factors such as bFGF, VEGF, TNFα, and IL-1 (The Interleukin-1 family is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses). Therefore, copper chelation with tetrathiomolybdate (a copper chelator) is a promising therapy for tumour control, since tetrathiomolybdate inhibits multiple angiogenic cytokines. Part of this effect appears to stem from inhibition of NF-κB, which in turn controls transcription of many angiogenic factors and other cytokines.

Finally, several aromatic herbs — such as Caryophylli flos (clove), Cinnamomi cortex (cinnamon), Foeniculi fructus (fennel) and Zedoariae rhizoma (made from the dried rhizome of Curcuma zedoaria Roscoe) — they all have inhibitory effects on lipid peroxidation or protein oxidative modification by copper, and they might have a role to play in anti-angiogenesis.

Thank you for reading 👓💙

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