• Erin Bannink, DVM, DACVIM

Biomedical Basis for Herbs as Anti-angiogenic Agents: Chinese Herbal Medicine in Cancer Care

Updated: Jun 21, 2019

The interest in "natural" treatments for cancer is increasing. But are they effective? And how might they work? Classical Chinese Herbal medicine contains many herbal formulas used for management of patients diagnosed with cancer. When the goal of herbal therapy interventions is to assist in tumor control, herbs may be helpful in strategies aimed at starving the tumor of its blood supply. This is called "Antiangiogenic therapy". Antiangiogenic therapy is typically considered an appropriate treatment approach when the goal is to slow or halt tumor growth or prevent metastasis, maintaining good quality life. Read on for the science behind antiangiogenic mechanisms of herbs.




An integrative approach to cancer treatment should target many pathways of tumor progression from a physiological and biochemical standpoint while minimizing normal tissue toxicity and supporting overall well-being. Cancer development and progression requires a complex cascade of events. Each of these pathways is a potential target for anti-cancer therapy. Targeting one of these pathways is unlikely to result in significant tumor control. The potential benefit of herbal therapies in anti-cancer strategies stems from the ability of many herbs to target multiple pathways of tumor progression while causing minimal normal tissue toxicity.


WHAT IS ANTIANGIOGENIC THERAPY?

Angiogenesis is the process of new blood vessel formation. Angiogenesis is important in both local tumor progression and the ability for cancer cells to spread and develop into tumors at distant sites, a process called "metastasis".


Antiangiogenic therapy targets tumor blood vessels to halt tumor growth and prevent tumor metastasis. It is a popular topic in the forefront of current cancer therapy and much research is being done on targeted therapies designed to inhibit the ability of tumors to form their own blood supply.


A tumor less than 1 mm in diameter can receive oxygen and nutrients by diffusion but any increase results in the need for the tumor to form its own blood supply. Without the ability to form its own blood supply, a tumor cannot grow larger than about 2mm. Tumors this small would be unlikely to cause clinical problems in a patient. If angiogenesis to spreading tumor cells could be stopped, death from tumor metastasis could theoretically be prevented.



The process of "angiogenesis" requires a number of different steps:

1) recruitment of circulating endothelial cells - these are the cells that will eventually form the structure of the blood vessels

2) survival signals to allow these recruited cells to survive at the tumor site

3) formation of these recruited endothelial cells into vascular tubes

4) reorganization to sustain blood flow through these newly formed blood vessel tubes



The normal balance of the processes promoting angiogenesis (pro-angiogenic signals) and inhibiting angiogenesis (anti-angiogenic signals) in tissues is disturbed in tumors due to increased stimuli. These stimuli include hypoxia (low oxygen), low pH (acidic microenvironment), hypoglycemia (low glucose), cytokines, growth factors, and inflammatory mediators such as COX-2 and prostaglandins. Tumor or host cells secrete "pro-angiogenic" molecules in the local tissue microenvironment which bind to receptors on endothelial cells, leading to endothelial cell proliferation, migration, invasion and capillary tube formation.



Antiangiogenic anticancer therapy has a number of promising benefits.

1) There is the potential for a broad spectrum of antitumor activity as the process of angiogenesis is the same across tumor types.


2) Inhibition of tumor vasculature may be targeted without affecting vascularization of normal tissues due to the fact that tumor vasculature has different characteristics than vasculature in normal tissues.


3) Because endothelial cells are not genetically unstable like tumor cells, they are unable to form resistant clones. Targeting endothelial cells may, therefore, be one way to combat the problem of drug resistance in cancer.


4) Because the target (endothelial cells) and goal (cytostatic - or halting growth) of antiangiogenic therapy is different than maximum-tolerated-dose-chemotherapy (MTD Chemotherapy), which generally aims to induce tumor cell suicide (apoptosis) by damaging the tumor cells’ DNA, synergistic activity may be achievable with the combination of these two treatment modalities.



Successful antiangiogenic therapy has the potential to prevent tumor metastasis from overwhelming the body, prolonging survival times in cancer patients. Because angiogenesis is a multistep process, a successful antiangiogenic protocol targets multiple pathways in blood vessel formation in order to induce a clinical response. Vascular endothelial growth factor (VEGF), nuclear factor-kB (NF-kB) and cyclooxygenase-2 (COX-2) are some of the many angiogenic polypeptides that are involved in cancer angiogenesis and are all potential therapeutic targets in antiangiogenic therapy.


METRONOMIC CHEMOTHERAPY: ANTIANGIONGENIC THERAPY WITH DRUGS

Metronomic chemotherapy, is a strategy of chemotherapy administration which uses low doses of oral chemotherapy agents at regular intervals, often daily. This type of treatment aims to inhibit the process of new blood vessel formation, or angiogenesis, that tumors need in order to supply nutrients needed to grow. This treatment can also make it harder for the tumor to hide from the immune system by changing certain immune responses involved in protecting tumor cells from immune system attack.



ANTIANGIOGENIC THERAPY WITH HERBS: Biomedical Rationale and Research

COX-2 INHIBITION

Overexpression of COX-2 has been demonstrated in a variety of veterinary tumors: transitional cell carcinoma, osteosarcoma, melanoma, prostate adenocarcinoma, canine oral squamous cell carcinoma, canine renal carcinoma, canine nasal carcinoma, canine mammary carcinoma, and feline mammary carcinoma. Canine tumor types shown to lack COX-2 expression are hemangiosarcoma, histiocytic sarcoma, and mast cell tumors. COX-2 converts arachadonic acid into Prostaglandins (PGE) and thromboxanes. PGE2 contributes to tumor cell growth, immunosuppression and angiogenesis. It stimulates angiogenesis and vasodilation. COX-2 also stimulates synthesis of a signaling molecule called vascular endothelial growth factor (VEGF) which is important in the angiogenic process.


Many herbs that inhibit COX-2 do so by blocking the amplified activity of NF-kB (a COX-2 transcription factor) without affecting normal function.


Some Chinese Herbs that have been shown to inhibit COX-2

Ginger (Sheng Jiang, Gan Jiang)

Licorice (Gan Cao)

Chinese skullcap (Huang Qin; Scuttelaria)

Boswellia (Ru Xiang; Frankincense)

Ginseng (Ren Shen; Panax Ginseng)

Turmeric (Yin Zhu, E Zhu, Jiang Huang; Curcuma)


Of particular interest are panax ginseng and curcumin which are adaptogens whose antiangiogenic activity is at least in part due to COX-2 inhibition via inactivation of NF-kB (see below).


Other herbs which have shown ability to inhibit COX-2 are bilberry, aloe vera, green tea, and milk thistle.


VEGF INHIBITION

Vascular Endothelial Growth Factor (VEGF) stimulates angiogenesis, permeability, leukocyte adhesion, and integrates angiogenic and survival signals. It is an important player in what is called the "angiogenic switch". The angiogenic switch refers to conversion of non-angiogenic tumor cells to angiogenesis inducers by way of release of angiogenic factors. Hypoxia (low oxygen) is one of the primary triggers of VEGF activation. Other triggering factors include COX-2 and growth factors such as EGF, bFGF, IL-1, IL-6, and TGF. VEGF binds to its receptors which trigger downstream signals that lead to inhibition of apoptosis (programmed cell suicide), stimulation of cell division, and degradation of the extracellular matrix which is required for blood vessel formation and also for tumor cells to escape to other areas of the body.


VEGF stimulates proliferation and migration of endothelial cells. It has been shown to stimulate vascular growth, enhancing tumor growth and metastasis is several animal models. VEGF is commonly over-expressed by cancer cells and has been associated with poor prognosis in many malignancies. Higher VEGF levels have been associated with more aggressive tumors and shorter time to radiation treatment failure in dogs with spontaneously arising cancers. In veterinary medicine, VEGF expression has been associated with canine and feline mammary carcinoma, osteosarcoma metastasis, hemangiosarcoma, and canine meningioma, canine nasal tumors, mast cell tumors, canine cutaneous and digital squamous cell carcinoma, canine lymphoma, soft tissue sarcomas, and various intracranial tumors.

Traditional Chinese Medicine Herbs That Inhibit VEGF:

Chinese Skullcap (Huang Qin; Scuttelaria baicalensis )

Scrophularia (Xuan Shen; Scrophularia ningpoensis )

Coptis (Huang Lian; Coptis chinensis )

Turmeric (Jiang Huang; Curcuma longa )

Angelica root (Dang Gui Shen, Angelica sinensis )

Magnolia bark (Huo Po; Magnolia obovata)

Ginger (Sheng Jiang and Gan Jiang; Zingiber officianale )

Chinese Wormwood (Qing Hao; Artemesia annua)



NF-kB IN CANCER PROGRESSION AND CHEMOTHERAPY RESISTANCE

Nuclear Factor-kB (NF-kB) is one of the primary transcription factors in the cell survival pathway. It is activated by various cytokines, including TNF-a (tumor necrosis factor-alpha). Activation of NF-kB suppresses apoptosis (cell suicide). Inhibition of NF-kB results in enhanced apoptosis. NF-kB does much more than modulate the process of cell death, however. It regulates the expression of over 400 genes involved in inflammation, cell survival, proliferation, angiogenesis and immune responses. NF-kB is involved in the upregulation of multidrug resistance and blocks apoptosis induced by cytotoxic agents such as chemotherapy, radiation and oxidative damage. Of particular importance in antiangiogenic therapy, VEGF and COX-2 activation are induced by NF-kb.


Inflammation via the NF-kB pathway has been linked to the development of cancer in many studies. NF-kB suppression was shown to prevent liver cancer progression in a mouse model. Similarly, suppression of NF-kB signaling prevented development of liver carcinoma (HCC) in the established HCC model mdr2-knockout mouse. Rapid tumor development occurred with reactivation of NF-kb.


NF-kB is activated by radiation therapy and has been linked to radiation resistance in many tumors. More specifically, NF-kB activation has been linked to development of radiation and chemotherapy resistance in solid tumors and its expression is induced in response to radiation and many chemotherapy drugs. Inhibition of NF-kB, therefore, becomes an interesting method by which development of chemotherapy resistance may be limited, or by which chemotherapy sensitivity may be enhanced.


Within earlier literature, there exists concern that inhibition of NF-kB or other antioxidant therapies may reduce the effectiveness of chemotherapeutic agents. In particular, it has been proposed that some of Adriamycin’s cytotoxic activity is through activation of NF-kB. While there are studies showing that NF-kB can inhibit the expression of certain anti-apoptotic genes, these reports do not examine the overall effects of NF-kB inhibition on Adriamycin sensitivity and there is little evidence that NF-kB inhibition actually decreases the effectiveness of chemotherapy.


On the contrary, NF-kB inhibition (using a small molecule inhibitor of IKKb) was specifically proven in one study to actually enhance the cell killing ability of Adriamycin chemotherapy. This study evaluated whether NF-kB proved to be pro-apoptotic or anti-apoptotic in Adriamycin-treated osteosarcoma cells. The study showed that the ability of Adriamycin to inhibit expression of anti-apoptotic (survival) genes such as Survivin, Bcl-2 and Bcl-xL was through mechanisms other than NF-kB. Additionally, Adriamycin-induced NF-kB expression was actually shown to decrease the apoptotic activity of Adriamcyin and NF-kB inhibition improved apoptotic cell death in Adriamycin-treated osteosarcoma cells. NF-kB expression was linked with the ability of osteosarcoma cells to resist the cytotoxic effects of Adriamycin. With the combination therapy, equivalent cytotoxicity was able to be achieved using 75% less Adriamycin.


Chinese Herbs that inhibit NF-kB include

Turmeric (Jiang Huang, Yin Zhu, E Zhu; Curcuma)

Ginger (Sheng Jiang, Gan Jiang)

Ginseng (Ren Shen; Panax Ginseng)

Chinese wormwood (Qing Hao; Artemesia annua)

Other: resveratrol, green tea, holy basil




CHINESE HERBAL FORMULAS: Compounds with Research on Angiogenic Action

Xiao Chai Hu Tang

Panax ginseng (Ren Shen) contains saponins, or ginsenosides, which have been shown to have antiangiogenic action and induce apoptosis in cancer cells. Ginseng was shown to inhibit NF-kB and enhance the susceptibility of colon cancer cells to chemotherapy in vitro when compared to chemotherapy alone. It has shown anti-proliferative effects on hepatocellular carcinoma cells. It was also shown to have synergistic activity when used with gemcitabine against lung carcinoma in mice and decreased tumor VEGF expression.


Ginger (Sheng Jiang, Gan Jiang) inhibits VEGF and bFGF and causes cell cycle arrest. At doses lower than cytotoxic levels, it decreased the number of lung metastasis in mice injected with melanoma cells. Ginger also has been shown to inhibit NF-kB.


Chinese Skullcap (Huang Qin; Scuttelaria baicalensis) contains baicalin and baicalein which are potent antiangiogenic compounds via their ability to inhibit VEGF, bFGF, 12-lipoxygenase and MMP.


Rhubarb (Da Huang; Rheum palmatum) contains emodin which reduced angiogenesis and reduced breast carcinoma growth in vivo.


Modified Xue Fu Zhu Yu Tang

Angelica Root (Dang Gui Wei) has been shown to inhibit VEGF in numerous laboratory studies. An in vivo study of transgenic adenocarcinoma in mouse prostate, it was shown to decrease expression of FGF2, decrease expression of genes related to inflammation and angiogenesis, and increase expression of many tumor suppressor genes.


Safflower (Hong Hua; Carthamus tinctorius) contains hydroxysafflor yellow A inhibited angiogenesis in mice bearing hepatoceullar carcinoma through mechanisms involving down regulation of MMP-2 and MMP-9. COX-2 expression was down regulated through inhibition of MAPK signaling pathways. It also inhibits NF-bK.


Turmeric (Jiang Huang, Yin Zhu, E Zhu; Curcuma longa) contains curcumin, which has been shown to enhance cytotoxicity when used in conjunction with chemotherapy and radiation. Curcumin has been shown to suppress NF-kB activation. By this mechanism, it enhances the sensitivity of colorectal cells to fractionated radiation therapy and inhibits angiogenesis. It decreases NF-kB-regulated gene products such as cyclin-D, c-myc, Bcl-2, Bcl-xL, COX-2, MMP-9 and VEGF which are induced by radiation therapy and implicated in development of radiation resistance. Curcumin was shown to potentiate the antitumor effect of gemcitabine in pancreatic cancer cells both in vivo and vitro. This action was attributed to curcumin’s ability to suppress proliferation, angiogenesis, NF- and NF--regulated gene products.


The following antiangiogenic effects have been demonstrated for curcumin: downregulation of MMP-2 and upregulation of TIMP-1, inhibition of VEGF and bFGF transcription, binds to angiopoietin (APN) and blocks its activity, inhibition of MMP-9 and MMP-2 activity, inhibition of growth factor receptors such as VEGFR and EGFR. An in vivo study confirmed biological activity with oral ingestion of dietary curcumin in mice resulting in slowed growth of implanted human pancreatic tumors and measurable decrease in NF-kB and NF-kB-related gene products.



Other Herbs containing Compounds that have Demonstrated Antiangiogenic Action

Magnolia officinalis (Huo Po; chinese magnolia tree) contains the antiangiogenic agent honokiol which alters expression of PDGF, TGF-band TNF-a. Additionally, in animal models, it was shown to decrease tumor growth via inhibition of vascular endothelial cells.


REALISTIC EXPECTATIONS: Hope and Perspective

While there are no "magic bullets" for cancer cure yet, herbal therapies do hold promise as effective tools in our anticancer toolbox. There are many laboratory studies demonstrating the anticancer effects of herbs and providing proof of principle for the use of herbs as antiangiogenic agents in cancer treatment. I have treated many patients with herbal therapies alone and seen cancer remissions. However, not every patients or cancer type will respond to herbal therapies, just like not every patient will respond to chemotherapy. It is important to be well-informed about the pros and cons of herbal treatment in cancer therapy for pets and understand that, while there is substantial biomedical basis for use of herbs in cancer treatment, there are still many unanswered questions. As with any therapy, this course of treatment should be embarked upon with informed consent and proper guidance. If you are interested in herbal medicine, talk with your veterinarian trained in herbal medicine about expected responses and whether your pet may be a candidate for this type of therapy.



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