Nutritional and Botanical Considerations in the Systemic Treatment of Cancer: 2006, 2010 Update

Dana Myatt, N.M.D. and Mark Ziemann, R.N.

Overview 

Some types of cancer are consistently responsive to conventional medical treatment, especially those amenable to surgical intervention when diagnosed early. Cytotoxic therapy is helpful in selected instances. For most cancers, especially those advanced beyond Stage I or II, conventional treatments that evoke durable remissions are elusive and inconsistent. In many instances, cytotoxic and radiation therapies end a patient’s life sooner than the natural course of the disease would be expected to.

Alternative cancer therapies, while typically gentler and less inherently dangerous, have also proven inconsistent for evoking durable remissions. However, instances can be found where durable remissions and event apparent cure have been obtained by unconventional and alternative treatments used as stand-alone therapy. When used in conjunction with conventional treatments, alternative therapies can sometimes potentiate the positive effects of conventional therapy, mitigate the negative effects, or both.

The questions we will examine in this presentation include: 

I.)               Which alternative treatments are most effective as the sole treatment for malignancy and when should they be used?

II.)             Which alternative treatments are most effective as adjuncts to conventional therapy?

III.)            Which alternative treatments may be contraindicated for adjunct cancer therapy? 

A careful review of the medical literature reveals that there are in fact specific modes of action to explain when and why alternative treatments are effective and when such treatments fail.

Cancer Cell Characteristics: Understanding the Enemy

Developing a cohesive and effective treatment strategy requires an understanding of the behavior and biology of cancer cells. Although various cancer types display unique behaviors, there are a number of characteristics common to all solid tissue malignancies: 

1.                Altered interactions with neighboring cells. Unlike normal cells whose division stops when neighboring cells are encountered, cancer cells continue to multiply with uncontrolled growth. This trait is known as lack of contact inhibition. 

Normal cells require a solid substrate (basement membrane) upon which to grow. This is known as anchorage-dependent growth. Cancer cells are anchorage-independent, growing in circumstances where they are deprived of substrate. 

2.                Altered cellular metabolism. Cancer cells demonstrate a greatly increased rate of glucose transport. Anaerobic glycolysis is the predominant energy pathway of cancer cells, even in the presence of adequate oxygen. This may partly explain the large amount of metabolic acids produced by cancer cells. 

Tumor cells have reduced growth requirements and will proliferate in culture media (less than 1% serum) that halt cell growth and division of normal cells. 

3.                Vascularization. Tumor cells secrete angiogenic growth factors which cause non-neoplastic blood vessels to grow from surrounding normal tissue. Research indicates that associated fibrin deposits many be necessary for angiogenesis. ^(1,2) 

4.                Invasion and metastasis. Multiple characteristics allow for local invasion and distant metastasis. 

Cancer cells often secrete enzymes including collagenase, heparinase and stromolysin which are capable of degrading basement membrane and allowing invasion of tumor into adjacent tissues and general circulation. 

Inflammation is caused by cellular substances, high acid cellular waste, and tumor pressure on adjacent normal tissue which produces histamine, leukotrienes and prostaglandins of the 2 series, increasing capillary permeability. 

Anchorage independence (discussed above) allows cancer cells to travel through the blood stream without substrate. Normal cells do not have this ability. Once a clump of cancerous sells has made its way into general circulation, aggregates of platelets and/or fibrin encasement may serve as protection from the immune system. 

Cancer cells have affinity for metastasis to certain and predictable locations not related to obvious blood flow patterns. Unidentified tissue chemotactic factors or lectin binding sites may account for this attraction. ⁽³⁾ 

5.                Escape from immune surveillance. Carcinogenic burden may simply overwhelm available immune surveillance, especially in the immunocompromised host. 

Many cancer patients have apparently intact immune systems, however, and it is felt that cancer cells may secrete substances which circumvent the host’s immune response. Such immune-eluding substances include prostaglandins and other inflammatory substances. Fibrin and platelet aggregation may also serve to assist in protection from host immune response. 

Tumor cells also appear to escape host immunity by down-regulation of Human Leukocytic Antigen (HLA) expression. HLA assists lymphocyte recognition of target cells. 

Causes of Cancer 

Understanding the causes of a particular cancer gives valuable clues to vulnerabilities and points of attack. Immune system dysfunction has long been considered a primary cause and point of treatment in alternative cancer treatment. However, there is significant evidence to suggest that immune dysfunction is only one of a number of causative factors and certainly NOT the most important one. 

It appears that very few cancers have a single cause or "initiator." Instead, most cancers may begin as a series of combination of events that lead to mutation. Tumor initiation begins when DNA in a cell or population of cells is damaged by exposure to exogenous or endogenous carcinogens. This alone is not sufficient to give rise to cancer. Damage at this point can be repaired. If DNA damage is not repaired or damaged cells eliminated, and if the microenvironment of the damaged calls are suitable to contribute to cell growth, then the process continues to the "promotion" phase. ^{(48,49,50,51,52)} 

Known initiators of cancer include: 

1.                Genetic factors. A number of genetic factors may play a role in susceptibility to cancer, although study of this aspect of malignancy is a newly emerging field. ⁽⁴⁷⁾ Such genetic factors include APC/MCC ^(45,46), RAS, DCC, p53 mutations and/or allelic losses, hyperexpression of c-MYC and RB genes. ⁽¹⁰⁾ 

Mutation of the p53 tumor suppressor gene is the most frequently observed genetic lesion in human cancer; more than 50% of all human tumors examined to date have identifiable p53 gene point mutations or deletions. ^(4,5,6,7,14)   While some p53 gene mutation is heritable, the majority of tumor suppressor gene mutation appears inducible, primarily by environmental factors. ^{(8,9,11,12,13,15,16,17)} 

Although genetics undoubtedly play a role in susceptibility to cancer, it is estimated that less than 25% of all cancers are genetically related. ⁽⁵⁸⁾ 

2.                2.) Chronic viral infections. Chronic infections of Epstein-Barr(EBV) ^{(18,19,20,21,32)} ,Human Papilloma (HPV) ^{(22,23,24,25)}, Hepatitis C (HCV) ⁽²⁶⁾, Hepatitis B (HBV) ⁽²⁷⁾, Cytomegalovirus (CMV) ^(28,29,30), human polyomaviruses JC(JCV) and BK (BKV) ⁽³¹⁾, and others predispose to cancer development. 

3.                3.) Chronic inflammation.^{(32,33,34,35,36,37,38,39,40,41,42,43,44,47)} 

4.                4.) Toxins, both endogenous and exogenous, can initiate cancer by causing ROS which in turn damage DNA. A number of exogenous and endogenous chemicals are considered carcinogenic, although the rate and degree of internal detoxification, especially phase II liver enzymes, are an important part of the initiation process. Few substances are carcinogenic per se without contribution from faulty or under-functioning internal detoxification systems. ^{(53,54,55,56,57,58,59)} 

5.                5.) Ionizing radiation. X-rays and other sources of ionizing radiation are known to cause DNA mutations consistent with cancer initiation. ⁽⁶⁰⁾ 

Cancer Promoters 

DNA damage alone is usually insufficient to initiate tumor development. If the DNA damage is repaired or the damaged cell is eliminated, the multi-step process of cancer development will be thwarted. If, however, mutagenic damage is not repaired and/or the damaged cell is not eliminated, and if the cellular environment is conducive to cell growth, then damaged cells can multiply. This stage is known as "progression" and it is a necessary step for the development of malignancy. Factors which promote malignant cell growth include: 

1.)    Nutritional deficiencies. Certain vitamins, minerals, trace minerals and phytonutrients act in a number of ways to thwart malignant cell promotion. The mechanisms of actions are many and varied but include ROS inactivation, upregulation of detoxification pathways, esp. phase II liver enzyme pathways, direct decrease or neutralization of carcinogenic compounds, and immune system enhancement. Deficiencies of any one of the nutrients involved in these protective processes can leave the organism vulnerable to the promotion phase of cancer development.^{(61,62,63,64,65,66,67,68,69,70,71)} 

2.)    Extracellular milieu. Blood glucose, insulin, cortisol, and arachadonic-derived prostatglandins (especially PGE2) act as promoters. In hormone-responsive cancers, estrogens, testosterone, prolactin and sex hormone metabolites and mimickers can also promote cell growth. The metabolic state of the organism therefore plays a major role in the promotion of cancer. ^{(72,73,74,75,76,77)} 

^3.)         Inflammation. In addition to being an initiator of cancer, inflammation also acts to promote cancer in several ways, primarily by altering the cell-to-cell communication and delaying local detoxification. ^{(32,33,34,35,37,38,39,40)} 

Treatment Strategies 

Treatment strategies involve interfering with cancer progression at any phase of development, but initiation and promotion stages present the greatest opportunity for intervention.

To prevent the DNA damage which occurs during initiation, steps can be taken to mitigate sources of mutation, as follows: 

            I.) Genetic factors. While this aspect of initiation might seem the hardest to compensate for, it must be remembered that genetic mutation represents only weakness, not a forgone conclusion that cancer will develop. Minimizing other predispositions to initiation, such as nutrient deficiencies and carcinogenic exposure, can be sufficient to overcome heritable weaknesses. Further, dietary fasting, calorie restriction (CR) or a ketogenic diet (KD) have been shown to suppress the p53 oncogene, rendering this most common genetic factor less relevant. ⁽⁷⁸⁾

            II.) Chronic viral infections. As with genetic factors, the presence of a chronic viral infection does not, by itself, mean an initiating certainly. Immune-enhancing strategies, anti-viral therapies and avoidance of other known initiators may be sufficient to prevent virally-caused mutagenesis.    

            III.) Chronic inflammation. Now known as a risk factor for heart disease, rheumatic disease and cancer, even subtle levels of inflammation, as measured by an hs-CRP blood test, can elevate risk of initiation. Fortunately, such inflammatory conditions respond well to nutritional, botanical and dietary modification. CR and KD have both been shown to reduce inflammation. Bromelain, curcumin and other anti-cancer drugs are, perhaps not coincidentally, also potent anti-inflammatory substances.

            IV.) Toxins and radiation. Minimization of exposure and optimal dietary antioxidants can help offset the effects of environmental toxins, whether chemicals or ionizing radiation. Avoidance of exposure is also an obvious but often-overlooked preventive measure. 

The Most Potent Anti-Cancer Strategy Known 

"Attack by stratagem: hence, to fight and conquer in all your battles is not supreme excellence; supreme excellence consists in breaking the enemy's resistance without fighting"    ---Sun Tzu, "The Art of War" 

Nutritional and botanical factors can have profound positive effects in cancer treatment, either alone or as adjuncts to conventional treatment. 

The single most potent anti-cancer strategy documented in the medical literature is to strike at the core of cancer's metabolism: anaerobic glycolysis. Numerous animal and human studies have demonstrated that the glycolytic pathway of cancer cells can be confounded by the metabolic state of ketosis, often with profound apoptotic effects on cancer cells but without consequence to normal cells. In fact, the metabolic state of ketosis may curtail cancer growth by a number of different mechanisms: 

            I.) Greatly decreasing the glucose substrate required for cancer cell metabolism. Most tumors express abnormalities in the number and function of their mitochondria ^{(80,81,88,89)}. Such abnormalities would prevent the bioenergetic utilization of ketone bodies, which require functional mitochondria for their oxidation.

            II.) Decreasing insulin, a secondary growth factor for cancer cells.

            III.) Decreasing inflammation (metabolic ketosis has anti-inflammatory effects). ^(85,86,87)

            IV.) Decreasing ROS production. ^(82,83,84) 

As one author pointed out, why would we believe that cells damaged by mutation are more resilient than normal cells? The answer is: they are not. Malignant cells are largely incapable of the metabolic flexibility displayed by normal cells, and therein lies their weakness and the potential for a gentle but highly effective point of attack. 

Ketosis can be achieved by a high fat, moderate protein, low carbohydrate diet or by a calorie-restricted (CR) diet. Both methods of achieving ketosis have proven to decrease the production of ROS. Calorie restriction (CR) has a long history of experimentation in animals where it has also been seen to increase ROS antioxidant defense systems including superoxide dismutase, catalase, and glutathione peroxidase. ⁽⁹⁰⁾ 

In spite of improved availability of foods containing anti-carcinogenic phytonutrients and vitamins, many types of cancer have not declined as expected. This correlates to the overall calorie increase and overweight condition of our society, a condition which puts us in "constant feast" mode instead of the periodic fasting our ancestors previously experienced. ⁽⁹¹⁾ Many observers feel that our previous occasional fast, which would induce ketosis, was also beneficial for cancer control. It has also been hypothesized that some alternative cancer treatments, such as juice fasting or the use of Coley's toxins, are effective primarily because they induce metabolic ketosis. 

Additional Nutritional and Botanical Interventions 

Although virtually any nutrient or herb can be considered in cancer treatment because of the multiple systems involved in same, only a relatively small handful of specific nutrients and botanicals have been well-studied and consistently proven to benefit the cancer patient. We will confine our discussion to those substances with a long history of use in human malignancy. 

Nutritional Supplementation in the Treatment of Cancer 

Supplements of proven utility in cancer treatment include: 

            I.) Vitamin C: long used for it's dual function of immune up-regulation and direct toxicity to cancer cells, but doses sufficient to achieve the cytotoxic effect are unobtainable via the oral route. For this reason, IV vitamin C should be considered in cancer therapy. ⁽⁹²⁾

            II.) Vitamin D3 (cholecalciferol): vitamin D deficiency is a known risk factor for cancer development.⁽⁹³⁾ D3 induces differentiation, inhibits angiogenesis ^{(94, 95,96)} and shows antitumor activity.^(97,98,99) It may also up-regulate vitamin A receptors.⁽⁹⁴⁾ Vitamin D3 may serve to prevent metastatic bone disease in higher doses, perhaps because it is needed for normal calcification of bone matrix.

            III.) Melatonin: a hormone produced by the pituitary gland which regulates sleep and circadian rhythms. Melatonin is a more potent antioxidant than glutathione or vitamin E ⁽¹⁰¹⁾. In vitro, it demonstrates anti-estrogen activity and immune stimulation. ⁽¹⁰⁰⁾ Recent studies show that melatonin inhibits cell proliferation profoundly in vivo but only weakly in vitro. It is synergistic with IL-2 and increases the effectiveness of IL-2 treatment. ⁽¹⁰²⁾

            IV.) CoQ10 (ubiquinone): this vitamin-like compound is involved in mitochondrial energy production. The heart is a high user of CoQ10 and many chemotherapeutic drugs deplete body stores of this nutrient. CoQ10 has been used successfully to reduce chemotherapy-induced cardio toxicity. In breast cancer patients, a dose of 90mg daily increases late stage survival dramatically. Three cases of complete remission have been documented at higher doses (300-400mg) per day. ⁽¹⁰³⁾

            V.) Selenium: studies show that seleium interferes with the activity of p53 genes that promote the growth of cancer and induces apoptosis ^{(104,105,106)}.

            VI.) Tocotrienols: a member of the Vitamin E family, tocotrienols induce apoptosis and S-phase arrest ^(107,108) and inhibit proliferation. ⁽¹⁰⁹⁾ 

Botanical Considerations in Cancer Treatment 

A HIGHLY SELECTIVE MATERIA MEDICA

Classified by action: 

Natural Killer (NK) Cell Activation

Allium sativum

Astragalus

Echinacea spp.

Eleutherococcus senticosus

Panax ginseng 

T-Cell Activation

Allium sativum

Astragalus

Echinacea spp.

Eleutherococcus 

Anti-tumerogenic

Allium sativum

Berberine derivatives:

Hydrastis canadensis

Berberis aquifolia

B. vulgaris

Curcuma longa

Echinacea spp. 

Stimulants of IgG & IgM Production

Panax ginseng 

Anti-inflammatory

Ananas comosus

Curcuma longa 

Fibrinolytic

Allium sativum

Ananas comosus 

Macrophage Activation

Allium sativum

Aloe vera

Berberine derivatives:

Hydrastis canadensis

Berberis aquafolia

B. vulgaris

Coumarine derivatives:

Angelica sinensis-dong quai

Meliotus officinalis-sweet clover

Trifolium pratense- red clover

Echinacea spp. 

Anti-metastatic

Ananas comosus

Larix spp.

modified citrus pectin (MCP) 

Cytotoxic (IV administration)

Catharanthus roseus- periwinkle

vinblastin,vincristine,

vindesin,vinorelbine

Podophyllum peltatum-mayapple-podophyllotoxin

Taxus batacca- English yew- docetaxel

Taxotere®

Taxus brevifolia- Pacific yew- paclitaxel

Taxol®

Viscum album-mistletoe- Iscador®] 

Materia Medica 

Allium sativum (Liliaceae) - Garlic

As a food and a medicine, garlic comes closest to being a true panacea. Research has proved garlic's immune-potentiating ability, including activation of NK and T-cells. ^(1,2,3,4.)  Garlic is fibrinolytic, decreases platelet aggragation ^(5,6,7)  and has been shown to have direct anti-tumor effects. 8,9,10.  It is also a potent broad-spectrum antimicrobial, effective against alpha- and beta- Strep., E. coli., Klebsiella pneumonia, Mycobacterium, Salmonella, Staph. aureus, and Proteus spp. ^{(17, 18, 19)} 

Aloe vera (Liliaceae) - Aloes

Acemannan, a water-soluable polysaccharide in Aloe vera, is a known immuno-stimulant ^(27,28) and anti-viral. ⁽²⁹⁾   It's mechanism of action is thought to be via stimulation of macrophage secretion of Tumor Necrosis Factor (TNF), interleukon, and interferon. 

Ananas comosus (Bromeliaceae) - Pineapple (bromelain)

Bromelain is a sulfur-containing proteolytic enzyme from the stem of the pineapple plant. Other constituents include a non-proteolytic plasminogen activator, a peroxidase, and several protease inhibitors. ^(22,23)

Bromelain possesses significant anti-inflammatory activity by selective inhibition of pro-inflammatory prostaglandins. ^{(16, 20)}  It also possesses fibrinolytic activity secondary to plasminogen activator ⁽²¹⁾ which may account for the antimetastatic properties seen in vivo. ^{(24, 25, 26)} 

Astragalus membranaceus (Leguminosae) - Astragalus, Milk Vetch, Huang QI

Astragalus increases NK and T cell activity ^(11,12) in both normal and immunocompromised hosts.⁽¹³⁾   It increases interferon production and is antibiotic against Shigella, Strep., Staph. and Diplococcus.⁽¹⁵⁾ 

Berberine derivatives:

Hydrastis Canadensis - (Ranunculaceae) - Goldenseal   

Berberis aquafolia - (Berberidaceae) - Oregon Grape

Berberis vulgaris - (Berberidaceae) - Barberry 

Berberine, an alkaloid derivative from various plants, has demonstrated significant antitumor effects with kill rates of 81% in vivo and 91% in vitro. This compares favorably to BCNU, a chemotherapeutic agent with a kill rate of 43% in vitro. ⁽³⁰⁾ 

Berberine sulfate also shows macrophage activation and cytostatic activity against tumor cells in vitro. ⁽³¹⁾  Berberine is well known for its broad spectrum antimicrobial activity ^(32,33,34)  which is most effective in a neutral to alkaline medium. ⁽³⁵⁾ 

Courmarin derivatives:

Angelica sinensis - (Umbelliferaceae) - Dong quai

Metolium officinalis - Sweet clover

Trifolium pretense - (Leguminosae) - Red clover

Coumarin (1,2-benzopyrone) is a component of several medicinal plants that have been used historically in the treatment of cancer. Recent research has shown an immunomodulatory effect through activation of macrophages and monocytes. ⁽³⁹⁾ 

Curcuma longa - (Zingiberaceae) - Turmeric

Curcumin, a major component in turmeric, is a potent antioxidant and hepatoprotectant. It has been shown to inhibit cancer in all stages of development (initiation, promotion, and progression), ⁽³⁶⁾ and provide symptom relief when used topically on external cancers. ⁽³⁷⁾ 

Anti-inflammatory effects are believed due to its ability stabilize lysosomal membranes and uncouple oxidative phosphorylation. At higher doses, curcumin stimulates endogenous corticoid release. ⁽³⁸⁾ 

Echinacea purpura, E. angustifolia (Compositae) - Purple coneflower

Echinacea is one of the most widely studied medicinal herbs, and its immune-potentiating effects are not in question. 

Arabinogalactin, a purified polysaccharide from E. purpura, has been shown to activate macrophage cytotoxicity to tumor cells, increase interferon production, stimulate T-lymphocyte production and activity, enhance NK cell activity and increase levels of circulating neutrophils. ^{(40, 41, 42,43)} 

Echinacea stimulates non-specific defense mechanisms including alternate complement pathway. ⁽⁴⁴⁾  It is anti-tumerogenic in animal models. ⁽⁴⁵⁾ 

Eleutherococcus senticosis - (Araliaceae) - Siberian ginseng

Eleutherococcus has been shown to both elevate numbers and activate helper / inducer lymphocytes and NK cells. ⁽⁴⁶⁾ 

It has been revered in Russia as an adaptogen, and studies confirm that it normalizes numerous physical functions regardless of the direction of imbalance. ⁽⁴⁷⁾ 

Larix occidentalis, L. dahurica - (Pinaceae) - Larch

Larch is a deciduous conifer that contains an arabinogalactan similar to that in other "immune enhancing" herbs including Echinacea spp., Baptisia tinctora, and Curcuma longa. 

Larch arabinogalactans have been shown to reduce the number of liver metastasis in multiple studies ^{(48,49,50,51)}, perhaps by acting as a "reverse lectin" and blocking tumor binding sites. ⁽⁵²⁾  A similar effect has been noted for Modified Citrus Pectin (MCP). (See below) 

Panax ginseng - (Araliaceae) - Chinese or Korean ginseng

Ginsenosides, an active constituent in P. ginseng, have been shown to increase both the number and the activity of lymphocytes in healthy subjects. ⁽⁵³⁾ 

Large doses in lab animals (human equivalent of 500 -125,000 mg) for five days increased IgG and IgM formation by 50 and 100% respectively, and enhanced NK cell activity and interferon production. ⁽⁵⁴⁾ 

Ginseng has long been considered an adaptogenic herb, and recent research verifies that it increases resistance to physical and chemical stress. ^(55,56) 

Modified Citrus Pectin (MCP)

Pectin, a high molecular-weight polysaccharide present in the cell wall of all plants, can be pH degraded to produce a modified (smaller) polysaccharide with anti-metastatic capabilities. ⁽⁵⁷⁾  MCP appears to bind with galectins on cancer cell surfaces, inhibiting aggregation and adherence to normal cells ⁽⁵⁸⁾ and offering anti-metastatic protection in animal models. ^(59,60,61) 

In Summary

Much more is known about the management of cancer, including how to evoke durable remissions and even cure, than is generally used or discussed in conventional medicine. Perhaps this is because some of the most powerful and proven therapies do not require drugs or invasive intervention. 

"Those who battle nature as their enemy will lose; those who use nature to battle their enemy will win." ---Mark Ziemann, R.N.
 

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