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Conventional medicine offers little hope in the fight against deadly malignant melanoma, but there are multiple foods, botanicals, and vitamins with proven anti-melanoma activity within nature’s pharmacopeia
Cutaneous malignant melanoma, one of the most aggressive types of tumors, accounts for 75% of death due to cancer, and its incidence is on the rise worldwide (1, 2). In North America, it has become the most prevalent form of cancer for the demographic aged 25 to 29 (3). When detected early, surgical excision of the primary site is the standard of care. However, metastatic melanoma, wherein the tumor cells detach from the primary growth and disseminate to distant organs, is notoriously resistant to conventional radiation, immunotherapy, and chemotherapy (3).
Even after surgical removal, recurrence is a distinct possibility, and therapies employed by the biomedical paradigm have limited success (4). Commonly employed treatments include the DNA alkylating chemotherapeutic agent, dacarbazine, which have response rates of 10 to 26%, most of which are partial, and are accompanied by side effects including anemia, nausea, neutropenia, and thrombocytopenia (5). More selective therapies such as BRAF inhibitors, targeted for the small percentage of advanced melanoma patients with a genetic BRAF V600 mutation, are associated with widespread resistance and the development of other cancers, including keratoacanthoma and squamous cell carcinoma, as side effects (6).
For metastatic melanoma, the five-year survival rate is dismal at less than 25% (6). However, there are evidence-based natural substances supported by the scientific literature for their anti-melanoma effects, which may be used as an adjunctive approached alongside other multi-pronged strategies.
Although regarded in modernity as a pesky garden weed, dandelion, or Taraxacum officinale, has long been a staple of traditional Chinese, Middle Eastern, and Native American folk medicine (3, 7, 8). It has been used by traditional medical systems for digestive, kidney, liver, and spleen disorders, as well as tumors of the lung, breast, and uterus (7). Dandelion is renowned in holistic medicine as a detoxifying agent, but is also anti-inflammatory, anti-oxidant, anti-angiogenic (prevents growth of blood vessels that supply tumors with nutrients), anti-nociceptive (attenuates sensation of pain), and anti-cancer (3).
Studies have demonstrated that dandelion transforms mouse melanoma cells from a proliferative phenotype, which epitomizes the profligate cell division of cancer growth, to a differentiated phenotype representative of restoration of a normal cell cycle (9, Salem et al., 2004). Lupeol-a, the triterpene compound in dandelion found to elicit this effect, is cytostatic, meaning that it inhibits cell growth and multiplication (9).
Taraxacum japonicum, a species of dandelion native to Japan, has also been shown to suppress two stages of carcinogenesis, namely, tumor initiation and promotion (10). It was concluded that a triterpenoid compound called taxasterol within dandelion is a chemopreventative, meaning an agent that slows or prevents the development of cancer (10). In an in vitro study, researchers propose that dandelion root extract represents a novel chemotherapeutic agent, as it selectively induced apoptosis, or programmed cell death, in human melanoma cells, while preserving noncancerous cells (3). Not only do healthy cells remain unaffected, but “melanoma cells retain the signals to commit suicide long after DRE [dandelion root extract] has been removed from the system” (3).
According to researchers, various compounds in dandelion root, including triterpenes, sesquiterpenes, coumarins, and phenolic compounds likely work synergistically to invoke anti-cancer effects (3). They conclude, “We believe that this nontoxic extract can undergo precipitous translation from bench top to bedside, with dandelion products that are already commercially available in the form of tea and supplements…as a chemotherapeutic against aggressive chemoresistant cancers” (3). For those with ragweed allergies, however, caution may be warranted because dandelion can be cross-reactive since they both reside in the Asteraceae (Compositae) family.
UV-induced sunburn lesions, which represent a potent risk factor for melanoma, are inhibited by caffeine, which elicits a sunscreen-like effect in rodent studies (1). Not only does caffeine suppress growth of melanoma cells in vitro and in vivo, but it also up-regulates cell suicide, also known as apoptosis, induced by UV exposure (1). This effectively enhances clearance of defective precancerous cells (1).
One epidemiological study compiled data from 74,666 women in the Nurses' Health Study, 89,220 women in the Nurses' Health Study II, and 39,424 men in the Health Professionals Follow-up Study, comprising over 4 million person-years of follow-up (1). After adjusting for confounding variables, it was found that a high caffeine intake (≥ 393 mg/day) was associated with a lower risk of cutaneous malignant melanoma than a low intake (< 60 mg/day) (1). This correlation was particularly prominent in women, where high caffeine intake decreased risk by 22% relative to low intake (1).
The inverse relationship between caffeine intake and melanoma risk was likewise more apparent for melanomas occurring on anatomic sites such as the head, neck, and extremities, which receive greater sun exposure, compared to sites on the trunk normally insulated from the sun (1).
A staple in traditional Ayurvedic and Unani medical systems, ashwagandha or Withania somnifera is an adaptogenic herb that increases non-specific resistance to chemical, biological, and physical insults, enhances survival during stress, and counteracts pathology (11). It has historically been used to augment energy and to treat musculoskeletal conditions such as arthritis and rheumatism (12). In addition to its anti-stress effects, ashwagandha is classified as an antioxidant, anti-parkinsonism, anti-ageing, antiulcerogenic, and anti-tumor agent (Halder et al., 2015). In fact, it exhibits anti-tumor effects in human breast, prostate, renal, pancreatic, fibrosarcoma, leukemia, and mouse lung adenoma cells (13).
Notably, a crude water extract of ashwagandha reduced viability of human malignant melanoma cells in a dose- and time-dependent manner (13). Morphological changes in ashwagandha-treated cells appeared, such as formation of apoptotic bodies, nuclear blebbing, and DNA fragmentation, indicating that ashwagandha induced programmed cell death in melanoma cell lines (13). The authors conclude that the ashwagandha extract exhibited a potent chemotherapeutic effect, or cytotoxic effect, on human malignant melanoma cells (13).
Not just limited to holiday romance, the festive plant mistletoe, a hemiparasitic evergreen shrub, is routinely used in complementary cancer therapy in Central Europe (14). Since ancient times, it has been perceived as a mystical plant and was used for ailments of the spleen and kidney in the middle ages (15). Mistletoe likewise demonstrates anti-hypertensive, anti-rheumatic, anti-diabetic, and antioxidant effects, but since the early twentieth century, it has been used as a cancer therapy (15).
Although human trials are conflicting, in vivo and in vitro studies have highlighted anti-tumor effects of mistletoe against acute lymphoblastic leukemia, various carcinomas, and melanoma cells (15, 16, 17). In addition, mistletoe has prolonged survival in patients with pancreatic cancer as well as breast and gynecological cancers in human studies (18). One systematic review analyzed 23 controlled clinical trials of mistletoe in cancer, including cancers of the bladder, breast, colon, genital, head and neck, kidney, lung, and stomach, as well as gliomas and melanoma (19). Although results were mixed and heterogeneity of studies was identified, statistically significant increases in survival and quality of life were reported in eight and three trials, respectively (19).
In another review, 22 of 26 randomized controlled trials (RCTs) and all 10 of 10 non-RCTs analyzed reported that mistletoe improved quality of life in patients with malignant disease (20). Mistletoe likewise reduces the side effects of conventional cytoreductive treatments (20). When used in concert with conventional treatments, mistletoe consistently improved “coping, fatigue, sleep, exhaustion, energy, nausea, vomiting, appetite, depression, anxiety, ability to work, and emotional and functional well-being in general” (20, p.142).
Especially relevant to cancer is the immunomodulatory effect of mistletoe extract, as mistletoe can enhance both humoral (antibody-mediated) and cellular immune responses when injected into cancer patients (21), potentially increasing the ability of the immune system to eliminate cancer. In fact, in a mouse melanoma model, mistletoe exerted its anti-cancer effects by promoting secretion of a signaling molecule called interleukin-12 (IL-12), which causes immune cells in the spleen to proliferate (22), up-regulating immune defenses against cancer. Also, researchers state that, “Polysaccharides present in the herb and in berries increased phagocytic activity of granulocytes and macrophages in in vitro experiments,” which increases the ability of immune cells to eat and dispose of defective or neoplastic cells (15, p. 378)
It is hypothesized that water soluble mistletoe lectins are the active anti-cancer constituents in the plant, along with polysaccharides, phenolic compounds, and viscotoxins (14, 23). Lectins in particular induce programmed cell death, or apoptosis, in cancer cell lines, and exhibit direct cytotoxic (cancer cell killing) activity (15). Commercial methods of aqueous mistletoe purification are not able to extract water insoluble triterpenoids, which have anti-melanoma effects (24).
However, one mouse study using a novel method to produce triterpenoid-enriched mistletoe extracts found that this variety amplified the anti-tumor effects of mistletoe (14). Compared to the control group, which had a dense network of blood vessels surrounding the tumor, the mistletoe extract and solubilized triterpenoids elicited anti-angiogenic effects, causing blood vessels around the tumor to collapse, preventing delivery of nutrients to the tumor (14). In this model, mistletoe extracts led to the significant suppression of tumor growth, which was further enhanced by combined treatment with triterpenoids (14).
Sulforaphane is an isothiocyanate compound found in all cruciferous vegetables, such as arugula, broccoli, Brussel sprouts, cabbage, cauliflower, chard, collard greens, radish, rutabaga, turnip, wasabi, and watercress. However, it is particularly concentrated in broccoli sprouts, which contain 10 to 100 times the glucoraphanin content of the mature plants, which is a glucosinolate of sulforaphane (25). In vitro and in vivo models demonstrate that sulforaphane induces apoptosis, or cell suicide, in melanoma cells, as indicated by predictable morphological changes that occur with cell death, such as condensation and fragmentation of genetic material and a step in cellular disassembly called membrane blebbing (26).
In an animal model, when sulforaphane was administered simultaneously with melanoma development, “There was 95.5% inhibition of lung tumour nodule formation and 94.06% increase in the life span of metastatic tumour bearing animals” (27). At a mechanistic level, sulforaphane prevented invasion of melanoma cells to secondary sites by inhibiting the activation of matrix metalloproteinases (MMPs), enzymes which hydrolyze, or degrade extracellular proteins such as collagens and elastin and allow for tumors to migrate (27).
The researchers conclude, “These results raise the possibility that SFN [sulforaphane] may be a promising candidate for molecular-targeting chemotherapy against melanoma” (26, p. 332).
Gonzalez and colleagues (2012) proposed the revolutionary bioenergetic theory of carcinogenesis, which posits that cancer originates when cells revert to a more primitive phenotype favoring uncontrolled proliferation and cell immortalization (28). This occurs as an adaptive response to ensure survival in the harsh cellular milieu and toxic external environment that so drastically departs from the one in which we evolved (28).
Cancer cells resort to inefficient energy production via cytosol-based glycolysis instead of the mitochondrial-based, oxygen-dependent oxidative phosphorylation, which is the primary generator of energy currency in the body (29). One reason malignant cells switch to fermentation, or anaerobic (oxygen-independent) processes for energy production, is due to defective mitochondrial membrane potential, which can be corrected by vitamin C (29).
In this respect, ascorbate, the water-soluble vitamin C, may be helpful by increasing electron flux through the mitochondria, restoring energy production such that apoptosis of cancer cells, which is an energy-intensive process, can occur (29). Vitamin C also optimizes cellular differentiation and intercellular communication, both of which are compromised in a cancerous state and perpetuate tumor growth (29).
Further, vitamin C up-regulates the proliferation and activity of lymphocytes, or white blood cells, and prevents oxidative damage that would engender further mitochondrial dysfunction (30, 31). In addition, vitamin C increases the anti-malignancy effects of lysosomes, the ‘garbage disposal’ organelles that reside within white blood cells, which control cell death and survival and render cancer cells vulnerable to death pathways (32, 33).
Likewise, vitamin C promotes collagen formation, which can sequester tumors, inhibit their growth, and prevent tumor metastasis (30). Along the same lines, vitamin C interferes with the action of hyaluronidase, an enzyme which degrades connective tissue and allows tumors to spread, in order to wall off the tumor with ground substance (30).
Remarkably, high concentrations of vitamin C are selectively toxic to tumors but not to normal tissues (6). In particular, it elicits anti-cancer effects by facilitating the formation of hydrogen peroxide (a reactive oxygen species) in the extracellular space, which can produce other free radicals such as aldehydes and hydroxyl radicals that in turn jeopardize cell viability (34). Hydrogen peroxide not only generates double-stranded DNA breaks, which induces death of cancer cells, but it also recruits immune cells to the site of the tumor to eliminate cancer cells (35, 36). Whereas normal cells have adequate levels of catalase, an enzyme to detoxify hydrogen peroxide and prevent cellular damage, malignant cells are deficient in this antioxidant enzyme, harboring 10 to 100 fold less catalase content than healthy cells (37).
In the 1970s, Nobel Prize winner Linus Pauling conducted experiments demonstrating that high dose vitamin C therapy elongated survival of cancer patients by four times compared to controls (38). In another study, “all melanoma cell lines were susceptible to ascorbate-mediated cytotoxicity,” and “pharmacologic ascorbate was superior or equivalent to dacarbazine as an anti tumor agent” (6, p. 193). In mouse melanoma cells, ascorbic acid induced apoptosis by acting as a pro-oxidant and increasing intracellular levels of reactive oxygen species, which disrupted membrane potential and lead to cell death (39).
Researchers state, “While AA [ascorbic acid] alone may not be enough of an intervention in the treatment of most active cancers, it appears to improve quality of life and extend survival and it should be considered as part of the treatment protocol for all patients with cancer” (29, p. 31). Intravenous vitamin C is optimal, as oral supplementation is unlikely to generate plasma concentrations required to kill tumor cells (37). The combination of vitamin C with other mitochondrial support such as B vitamins, magnesium, coenzyme Q10 (CoQ10), acetyl L-carnitine, alpha lipoic acid, pyrroloquinoline quinone (PQQ), D-ribose, creatine, and phospholipids, would be ideal for reversing the metabolic derangements observed in cancer (38, 40).
Polyphenols, which represent secondary metabolites of plants that evolved as defense mechanisms against pests and ultraviolet radiation, confer protection from cardiovascular disease, diabetes, osteoporosis, neurodegenerative disorders, and cancers (41). Catechin, a polyphenol in green tea, has been elucidated to render collagen resistant to degradation by the mammalian enzyme collagenase (42). Therefore, researchers tested various polyphenols to see if they could inhibit the basement membrane degradation that is essential to melanoma metastasis to the lungs (43).
For metastasis to take place, tumor cells must be liberated from the primary tumor into circulation, adhere to the extracellular matrix, and invade a secondary site via the proteolytic cleavage of the basement membrane, or the fibrous layer of connective tissue that divides epithelial cells from the underlying lamina propria (43). Finally, the malignant cells attach to the secondary site and tumor growth resumes (43). However, metastasis could be arrested if any one of the steps in this sequential process were prevented (43).
In this experiment, curcumin, from the spice turmeric, and ellagic acid, which is abundant in red grapes, were directly toxic towards melanoma cells even at low concentrations, indicating their anticarcinogen potential (43). Further, many of the polyphenols significantly reduced melanoma metastasis to the lungs, with curcumin, catechin, rutin (from figs, apples, and tea), epicatechin (from dark chocolate), and naringin and naringenin (from grapefruit) reducing lung tumor colonies by 89.28%, 82.2%, 71.2%, 61%, 27.2%, and 26.1%, respectively (43). In order of appearance, these polyphenols increased lifespan of animals by 142.85%, 80.81%, 63.59%, 55.29%, 26.6%, and 27.18% (43).
The best strategy would be to obtain polyphenolic compounds from whole foods sources in order to obtain the synergistic effects of other active constituents. As a general rule, the deeper pigmented the fruit or vegetable, the higher the polyphenolic content. Polyphenols inhibit cancer through pleiotropic mechanisms, including “estrogenic/antiestrogenic activity, antiproliferation, induction of cell cycle arrest or apoptosis, prevention of oxidation, induction of detoxification enzymes, regulation of the host immune system, anti-inflammatory activity and changes in cellular signaling” (41).
For those with a family history of melanoma interested in prevention, sun exposure is a contentious topic. According to researchers, “It has been documented that the role of sunlight in melanoma differs according to anatomic site, which is supportive of the hypothesis that melanomas may arise through divergent etiologic pathways” (1).
Although frequency of ultraviolet (UV) radiation-induced sunburns represents one of the primary risk factors for (44), the relationship between sun exposure and melanoma risk is convoluted. A longitudinal study tracking 38,000 women for 15 years, in fact, found that chronic sun exposure was protective against malignant melanoma, whereas intermittent sun exposure elevated melanoma risk (45). Contrary to popular belief, sun exposure was found to be protective, as it was also correlated with significantly reductions in cardiovascular and all-cause mortality (45). Therefore, habitual insulation from the sun is clearly deleterious, but safe sunning practices should still be observed to avoid burning and potential detriment.
Although human trials are deficient, people with cancer now cannot wait for research to be translated into clinical practice and adopted as standard of care. Given the nontoxic nature of the aforementioned interventions, they can easily be incorporated into the arsenal of modalities used to reverse cancer as elements of a multi-faceted approach that addresses diet, exercise, sleep, stress, social support, latent infections, hormonal balance, detoxification, and mitochondrial dysfunction.
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