Cancer is the second most common cause of death in the US and accounts for nearly 1 of every 4 deaths there. The World Health Organization estimates that, worldwide, there were 14 million new cancer cases and 8.2 million cancer-related deaths in 2012. It is expected that annual worldwide cancer cases will rise from 14 million in 2012 to 22 million by 2030. This is despite the fact that there is a clear link between lifestyle and cancer prevention.
An estimated one third of the most common cancers can be prevented through consumption of a primarily plant-based diet, minimizing chronic inflammation, stress-management strategies, maintaining a healthy weight (BMI), and regular physical exercise.
Cancer is today described as occurring in three stages: initiation, promotion, and progression. Initiation is thought to often involve a primary mutation in the DNA leading to a cell with increased potential for growth but still dependent on additional genotypic and epigenetic changes to achieve complete transformation to malignancy. Often, if these co-required epigenetic changes do not occur, the mutation will not manifest into cancer. Frequently, initiation is generated by genotoxic carcinogens that directly damage DNA, while promotion involves the activation and clonal proliferation of initiated cells possibly also by an epigenetic mechanism. Progression is the development of that early cancerous clone of cells into a fully malignant phenotype via both further genetic and epigenetic mechanisms. Malignant cells have minimal requirements for growth factors and are relatively resistant to normal growth regulation and apoptosis, resulting in uncontrolled growth that is the sine qua non of cancer.
Two thousand years ago, the Charaka and Sushruta samhitas, two well-known Ayurvedic compendiums, described two related categories of swellings, one inflammatory (arbuda) and the other non-inflammatory (granthi), though this division is somewhat indefinite. Arbuda is considered to be the more malignant form of the two, corresponding to our modern word “cancer”. There are suggestions in the ancient Ayurvedic medical texts that arbuda is a secondary outcome of a chronic inflammatory pathology. For example, arbuda and granthi come under the category of diseases called “śopha”. Śopha can be loosely translated as an “inflammatory swelling”. Sushruta was very lucid in his description of arbuda: “The disturbed doshas established in any part of the body afflict the mamsa dhatu and produce a swelling which is fixed, hardened, only slightly painful, circular, broad-based, slowly growing and does not suppurate.” This is perhaps an indication that śopha, especially when it persists in chronic form, predisposes the individual to develop arbuda. In Charaka’s narrative on the treatment of vātarakta (gouty arthritis), a chronic inflammatory disease affecting the joints of the body, arbuda is described as sometimes occurring as a complication.
Inflammation can be acute or chronic. Acute inflammation is defined as a rapid local response to cellular injury that is marked by capillary dilatation, polymorphonuclear (PMN) neutrophilic infiltration, redness, heat, pain, swelling, and often loss of function and that serves as a healthy mechanism initiating the elimination of noxious agents and of damaged tissue. Chronic inflammation may sometimes begin with a relatively rapid onset or, most commonly, in a slow, insidious, and even unobserved manner, and that continues for several weeks, months, or years and has an ambiguous and indistinct cessation, even becoming perpetual.
Chronic inflammation occurs when the injurious agent (or substances resulting from its presence) persists in the lesion, and the affected tissues reparative response is not sufficient to completely overcome and eliminate the continuing effects of the injuring agent. Histopathologically, chronic inflammation is characterized by infiltrates of lymphocytes, plasma cells, and macrophages; PMN’s are less abundant; fibrosis, which indicates the body’s efforts to heal, is also present. Today, we know that chronic inflammation may be a causative factor in a variety of cancers. In general, the longer the inflammation persists, the higher the risk of cancer. Hence, acute inflammation, such as occurs in response to a transient trauma or infection, is not a risk factor for the development of neoplasia, though many of the same molecular mediators are generated in both acute and chronic inflammation. In general, inflammatory leukocytes such as neutrophils, lymphocytes, monocytes, macrophages, and eosinophils provide the substances that are thought to mediate the development of inflammation-associated cancer, although other cells also contribute, including the altered pre-cancerous cells themselves.
Inflammatory mediators include among others: tumor necrosis factor, nitric oxide, adhesion molecules, derivatives of arachidonic acid (prostaglandins, leukotrienes), cytokines, chemokines, and free radicals. Chronic exposure to these mediators leads to increased cell proliferation, mutagenesis, epigenetic modifications, oncogene activation, and angiogenesis. The ultimate result is the proliferation of cells that have escaped normal growth control. Recently there has been evidence from animal models (i.e. mice, zebrafish) that chronic inflammation can promote cancer and possible insights into the mechanisms involved.
Those mechanisms involve activation of inflammatory signal pathways such as the NF-κB signal pathway, signal transducer and activator of transcription 3 (STAT-3), and hypoxia-inducible factor 1alpha (HIF-1 alpha). These substances cause the release of inflammatory mediators such as the proinflammatory cytokines (e.g. TNF and IL-1β) and proinflammatory enzymes that mediate production of prostaglandins (e.g. COX-2) and leukotrienes (e.g. lipooxygenase), together with expression of adhesion molecules and matrix metalloproteinases (MMPs). This cascade of events can lead to chronic inflammatory diseases such as arthritis, atherosclerosis, inflammatory bowel disease, chronic sinusitis, or even cancer.
In particular, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a type of transcription factor central to the production of chronic inflammation. Transcription factors bind to regions of DNA just adjacent to the genes that they regulate. Depending on the transcription factor, the transcription of the adjacent gene is either up- or down-regulated. NF-κB is a protein complex that controls the transcription of DNA to messenger RNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. Incorrect regulation of NF-κB has been linked to cancer, inflammatory, and autoimmune diseases, septic shock, viral infection, and improper immune development.
NF-κB, which in essence is a gene regulator (i.e. transcription factor), is itself regulated by its own genes. NF-κB is a protein composed of two protein subunits, p50 and p52; the creation of these subunits is regulated by two specific genes NFKB1 and NFKB2, respectively. Both p50 and p52 subunits are required to make a NF-κB protein. Whereas the production of p50 is an ongoing (“constitutive”) process, p52 production is a tightly controlled process regulated by its gene, NFKB2. In theory, any epigenetic factor which could inhibit or diminish the activity of either the NFKB1 or NFKB2 genes, could effective block production of NF-κB, resulting in an anti-inflammatory phenotype (effect).
Guggulu, the gum resin from Commiphora mukul, a small tree, is traditionally used to treat inflammation, internal tumors, obesity, liver disorders, and malignant sores and ulcers in Ayurvedic medicine. The first documented evidence of the anti-inflammatory activity of guggul was reported in 1960;confirmatory reports followed in the 1970's, but it was not until 2004 that guggulsterone was demonstrated for the first time to suppress activation of the proinflammatory transcription factor NF-κB and the genes regulated by NF-κB. Guggulsterone has been identified as one of the major active components of this gum resin. Guggulsterone mediates gene expression through regulation of various transcription factors, including NF-κB which in turn leads to inhibition of inflammation and cell proliferation, induction of apoptosis, and suppression of angiogenesis.
Exactly how guggulu modifies gene expression at the molecular level is still a complete mystery, which we would like to investigate. Epigenetic phenomena, including DNA methylation and covalent histone modifications, have already been shown to be critical in the regulation of inflammatory genes. Our guess is that guggulu works by correcting epigenetic alterations affecting NFKB1 and NFKB2 genes which have occurred due to environmental factors and age-related epigenetic drift. In addition, there is also preliminary evidence to show guggulsterone inhibition of STAT-3. It is intriguing that certain anti-inflammatory drugs (such as nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors) have shown antineoplastic effects in both pre-clinical tumor models and clinical trials. These anti-inflammatory drugs interfere with eicosanoid signaling and metabolism, suppress the neoplastic process, and can decrease oxidative stress and angiogenesis. Medzhitov R, Horng Transcriptional control of the inflammatory response. Nat Rev Immunol. 2009 Oct; 9(10):692-703.
Interestingly, the potent antitumor effects of phytochemicals, such as curcumin, from turmeric, the green tea polyphenol epigallocatechin gallate (EGCG), and resveratrol from grapes, are in large part attributed to their anti-inflammatory activities . Like guggulsterone, all three of these plant-derived chemicals (curcumin, EGCG, and resveratrol) inhibit inflammation at least in part by suppressing the transcriptional activity of NF-κB. In addition, as already mentioned, guggulsterone may also inhibit the transcriptional activity of STAT-3.
An epigenetic factor is something that affects genes without changing the nucleotide sequence and which can be inherited through cell division. Epigenetic mechanisms (or “marks”) involve the addition or removal of small chemical groups (e.g. commonly methyl or acetyl groups) to or from DNA bases or chromatin.
Epigenetic marks are, in effect, additional ways of storing information and regulating gene expression. We still have no idea how these epigenetic modifications are passed on in cell division over many generations. We do know that although these modifications appear to be very stable, they can be effected by many factors including diet, chemicals, environment, pathological conditions, and even mental state. We know that inflammation in some way contributes to the initiation and development of cancer but the molecular mechanistic aspects of this phenomenon are not clearly understood. One model that links inflammation to the oncogenic transformation based on a positive feedback loop mechanism involving NF-κB, RNA-binding protein Lin-28, let-7 microRNA, and IL-6 cytokine. It is likely that epigenetic factors play a major role in any such mechanism.
We know that both the normal aging process as well as dietary factors (including herbal medicines) can affect DNA methylation at promotor sites of genes involved in aging and disease. The majority of changes in the genome involve loss of methylation affecting CpG sites (cytosine-phosphate-guanine) which were previously methylated. The presence of these methyl groups usually creates a DNA conformation which blocks access to certain genes and renders them “silent”. Since thousands of genes are normally epigenetically silenced in every differentiated cell type, the unintended activation of these genes due to de-methylation often increases unwanted gene expression. It should be noted, though, that the hyper-methylation of other genes is the cause of unwanted effects. A number of studies suggest that DNA methylation and other persisting epigenetic changes to both DNA and chromatin induce differentiated direct cells back into a “stem-cell like” state predisposing to cancer, partly explaining a higher risk of carcinogenesis in older people or those chronically exposed to toxic agents.
Dietary constituents, by affecting the DNA methylation status, no doubt positively or negatively affect disease risk and progression and probably also the aging process. There are dietary enzyme co-factors such as folate and vitamins B12 and B6, as well as methyl group donors such as methionine (nuts, beef, lamb, cheese, fish, oats, soy, eggs, and legumes), choline (eggs, dairy, nuts, legumes cauliflower, broccoli, cabbage bok choy), betaine (wheat, shellfish, spinach, and sugar beets) and serine (soy, eggs, lentils, nuts, seeds) that increase methylation, and selenium (brazil nuts, oysters, fish, whole wheat, chia seeds, sesame seeds, flaxseeds, barley, rye, oats, beef) green tea polyphenols and bioflavonoids (e.g. epigallocatechin-3-gallate, genistein, ellagic acid, quercetin and hesperidin) that reduce methylation.
However, while some reports indicate that hypomethylation-promoting dietary constituents are profitable, others show that in fact methylation-promoting nutrients are beneficial . Also, it is likely that some whole foods and whole plant products may be discovered to have amphoteric effects—promoting methylation and demethylation where required in different parts of the epigenome. Our FHMR lab is interested in exploring this possibility for specific Ayurvedic plant medicines including guggulu, ashwagandha, shallaki, and others.
It should come as no surprise that the current available data, being extremely reductionist in nature, does not support the recommendation of either a hypo- or hyper-methylating diet that would specifically slow down or even reverse disease- or aging-related methylation changes. All we are left with is confusion.
In my view, until further knowledge clarifies this, a balanced approach is obviously what is called for which should consist of both de-methylation and methylation-promoting whole nutrients; such an approach will allow your endogenous mechanisms to work optimally. Trying to eat in an unnatural way by increasing this or that individual nutrient or vitamin or imposing some artificial “structure” on one’s diet will inevitably lead to problems. So what is that balanced approach?
Ayurveda gives us a very straightforward and intuitive approach to healthy eating which emphasizes freshness, moderation, variation and including the six tastes. Unless medically indicated, no effort should be made to identify any particular nutrient or metabolic need. Whole foods and plants contain multiple bioactive components (the majority of them still unidentified or investigated) and their naturally-occurring synthesis in naturally-occurring proportions and geometrical relations might be more beneficial than artificial formulations of selected “active” nutrients. As it has been previously shown for individual human supplementation with A, C, beta-carotene, and E vitamins, this can often lead to disastrous results.
Rather, Ayurveda places emphasis on fresh, locally grown when possible, organic foods and herbs. The diet can be adjusted to address doshic or seasonal requirements but even that should be undertaken with utmost care and guidance. Proper cooking methods will help “pre-digest” most foods; about 20% of foods should be raw. Lovingly prepared, slowly eaten foods enjoyed in a relaxed setting will no doubt lead to better epigenetic health. I will write more about epigenetic diets, herbal epigenetic effects, and epigenetic drift in future blogs.