The mediterranean Diet, Cancer Prevention and Malignancy Reversal via Cellular Redifferentiation
The scientific literature contains thousands of peer-reviewed studies that show the benefits of the Mediterranean Diet (MD) for just about all diseases, including inflammatory illnesses like cancer, Alzheimer and cardio-vascular events. Even though there are many variants of MDs among Europeans, North Africans and Middle Easterns, there is a core that permeates all MDs, the composition of which are tomatoes, garlic, onions, vegetables, legumes, flavanoid-rich fruits, whole grains, roots, lignans spices, olives and olive oil, nuts, cheese (1) other fermented foods like sauerkraut and yogurt, fish, wine (2) and lots of sunlight. (3) Hundreds of cancer-related studies looked into this core and-or elements thereof.
EVIDENCE FROM META-ANALYSES THAT MDs ARE ANTI-CANCER FOODS
The first one we look at is the meta-analysis published in BMJ in 2008. This report showed that strictly following the Mediterranean diet reduced the risk of dying from cancer and cardiovascular disease as well as the risk of developing Parkinson’s and Alzheimer’s disease, the results of which were reported to bet 9%, 9%, and 6% reduction in overall, cardiovascular, and cancer mortality respectively. Additionally a 13% reduction in incidence of Parkinson’s and Alzheimer’s diseases is to be expected provided strict adherence to the diet is observed. (4)
Another meta-analysis published by the The American Journal of Clinical Nutrition two years later in 2010 found that the Mediterranean diet conferred a significant benefit with regard to the risk of chronic diseases, such as cardiovascular disease and cancer. (5)
In 2011, still another meta-analysis published in the Journal of the American College of Cardiology analyzed the results of 50 studies (35 clinical trials, 2 prospective and 13 cross-sectional) covering about 535,000 people to examine the effect of a Mediterranean diet on metabolic syndrome.The researchers reported that a Mediterranean diet is associated with lower blood pressure, blood sugar, and triglycerides, parameters which are also relevant for cancer. (6)
Another couple years later, in 2013, the American Journal of Clinical Nutrition published in 2013 a study that compared Mediterranean, vegan, vegetarian, low-glycemic index, low-carbohydrate, high-fiber, and high-protein diets with control diets. The research concluded that Mediterranean, low-carbohydrate, low-glycemic index, and high-protein diets are effective in improving markers of risk for cardiovascular disease and diabetes. And again, when these markers are good, they usually are also beneficial to cancer regression. (7)
In 2014, two meta-analyses found that adherence to a Mediterranean diet was associated with a decreased risk of type 2 diabetes. (8) while during this same year, a systematic meta-analytical review found that adherence to the Mediterranean diet was associated with a decreased risk of over-all cancer mortality. (9) (10)
Lastly in 2015, the highest adherence score to a MD was significantly associated with a lower risk of all-cause cancer mortality (Cf EXHIBIT A).
ONE OF THE MOST POWERFUL ANTI-CANCER MOLECULE, APIGENIN, HAS BEEN SHOWN TO BE ABUNDANT IN MEDITERRANEAN DIETS
In this perspective, a 2013 study orchestrated by the Ohio State University’s Comprehensive Cancer Center’s geneticist and health science experts (11) found Apigenin was prevalent in the Mediterranean Diet, in particular in plant-based foods, vegetables, fruits, celery, parley and chamomile tea in particular. This is a significant finding because Apigenin can reeducate a cancer cell to redifferentiate back into a healthy cell.
“By altering a very specific step in gene regulation, (12) this compound essentially re-educates cancer cells into normal cells that die as scheduled ” (13) (Source)
The researchers also showed in this work that apigenin binds with an estimated 160 proteins in the human body, suggesting that other nutrients linked to health benefits (eg, “nutraceuticals”), might have similar far-reaching effects.
OTHER SIGNIFICANT ANTI-PATHWAYS ARE ACTIVATED THANKS TO THE MEDITERRANEAN DIET’S CORE MOLECULES
Another beneficial effect that comes from the MD’s Core, in particular from oleuropein aglycone (OLE), the main polyphenol found in the extra virgin olive oil, is it’s cellular autophagy activation, that which has a beneficial impact on cancer control and reversal. (14) (EXHIBIT B). Mediterranean nuts have also shown to help lots with vascular health, glucose stability, ketones and the immune system, thanks to which cancer incidence is lowered, especially for those who do not strictly adhered to the MD’s core. (EXHIBIT C).
The evidence clearly shows that the Mediterranean diet is so rich in flavanoids and other super-nutrients that it can impact both the incidence and treatment results of cancer as well as many other chronic diseases (Cf EXHBIT D). It’s apigenin-based ability to convert cancer cells back into normal cells is also extraordinary. Contrarily to most pharmaceutical drugs which target a single molecule and produce many side or toxic effects, the Mediterranean diet targets many useful pathways while enhancing vitality and even longevity (via the telomere length “pathway”). (15)
Founder and director of the French Pyrénean Holistic Medicine Retreat Center and the American Advanced Cancer Research Institute, Pr Joubert is a former professor of public int’l law, litigator, a holistic oncologist and longevity expert.
PRECISION AND REFERENCE NOTES
(1). For mountainous Mediterranean areas in countries like South France and South Italy and even Northern Spain, the cheese is often pesticide free or organic, raw and from the sheep or goat more than from the cow.
(2). Several studies have demonstrated that polyphenols form olive oil, lycopene from tomatoes, resveratrol from red wine and capsaicin from red pepper have multiple anticancer properties affecting several metabolic pathways involved in cancerogenesis, apoptosis, and metastasis.
(3). A recently emerging alternative or complementary hypothesis to the Mediterranean diet is that differential exposure to solar ultraviolet radiation accounts for the disparity in cardiovascular health and cancer between residents of Mediterranean and more northerly countries. The proposed mechanism is solar UVB-induced synthesis of Vitamin D in the oils of the skin, which has been observed to reduce the incidence of coronary heart disease, and which rapidly diminishes with increasing latitude. Wong A (2008). “Incident solar radiation and coronary heart disease mortality rates in Europe”. Eur J Epidemiol. 23 (9): 609–14 Furthermore, the incidence of melanomas in the Mediterranean countries is lower than in Northern Europe and significantly lower than in other hot countries such as Australia, just like with most other countries, as show all cancer maps.
(4). Sofi F, Cesari F, Abbate R, Gensini GF, Casini A (2008). “Adherence to Mediterranean diet and health status: meta-analysis”. BMJ (Clinical research ed.) 337 (sep11 2): a1344.
(5). Sofi, F; Abbate, R; Gensini, GF; Casini, A (November 2010). “Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis.”. The American journal of clinical nutrition 92 (5): 1189–96.
(6). Kastorini C-M, Milionis H, Esposito K, Giugliano D, Goudevenos J, Panagiotakos D. (2011). “The Effect of Mediterranean Diet on Metabolic Syndrome and its Components”. Journal of the American College of Cardiology 57 (11): 1299–1313.
(7). Ajala O., English P., Pinkney J. (2013). “Systematic review and meta-analysis of different dietary approaches to the management of type 2 diabetes”. The American Journal of Clinical Nutrition 97 (3): 505–516.
(8). Koloverou, E; Esposito, K; Giugliano, D; Panagiotakos, D (July 2014). “The effect of Mediterranean diet on the development of type 2 diabetes mellitus: a meta-analysis of 10 prospective studies and 136,846 participants.”. Metabolism: clinical and experimental 63 (7): 903–11
(9). Schwingshackl, L; Hoffmann, G (15 October 2014). “Adherence to Mediterranean diet and risk of cancer: a systematic review and meta-analysis of observational studies.”. International Journal of Cancer. Journal International Du Cancer 135 (8): 1884–97
(10). Which is not surprising since we know that cancer regression also benefits when insulin and IGF-1 (ie, an insulin growth factor hormone) are decreased.
(11). Doseff oversaw this work with co-lead author Erich Grotewold, professor of molecular genetics and director of Ohio State’s Center for Applied Plant Sciences (CAPS). The two collaborate on studying the genomics of apigenin and other flavonoids, a family of plant compounds that are believed to prevent disease. The research appeared in the online early edition of the journal Proceedings of the National Academy of Sciences. See http://researchnews.osu.edu/archive/apigenin.htm
(12). Through additional experimentation, the team established that apigenin had relationships with proteins that have three specific functions. Among the most important was a protein called hnRNPA2. This protein influences the activity of messenger RNA, or mRNA, which contains the instructions needed to produce a specific protein. The production of mRNA results from the splicing, or modification, of RNA that occurs as part of gene activation. The nature of the splice ultimately influences which protein instructions the mRNA contains. Doseff noted that abnormal splicing is the culprit in an estimated 80 percent of all cancers. In cancer cells, two types of splicing occur when only one would take place in a normal cell – a trick on the cancer cells’ part to keep them alive and reproducing.In this study, the researchers observed that apigenin’s connection to the hnRNPA2 protein restored this single-splice characteristic to breast cancer cells, suggesting that when splicing is normal, cells die in a programmed way, or become more sensitive to chemotherapeutic drugs.“So by applying this nutrient, we can activate that killing machinery. The nutrient eliminated the splicing form that inhibited cell death,” said Doseff, one of the main scientists in the Ohio State’s team.
(13). http://researchnews.osu.edu/archive/apigenin.htm See also AACR (2015) The dietary flavonoid apigenin sensitizes malignant tumor cells to tumor necrosis factor–related apoptosis-inducing ligand Mano Horinaka1, Tatsushi Yoshida1, Takumi Shiraishi12, Susumu Nakata1, Miki Wakada1 and Toshiyuki Sakai1
(14). Oncotarget. 2015 Oct 14. doi: 10.18632/oncotarget.6119
(15). Cf Age (Dordr). 2015 Apr;37(2):24. doi: 10.1007/s11357-015-9758-0. Mediterranean diet and leukocyte telomere length in a multi-ethnic elderly population.
Cancer Med. 2015 Oct 16.
Adherence to Mediterranean diet and risk of cancer: an updated systematic review and meta-analysis of observational studies.
Schwingshackl L1, Hoffmann G1.
The aim of the present systematic review and meta-analysis of observational studies was to gain further insight into the effects of adherence to Mediterranean Diet (MD) on overall cancer mortality, incidence of different types of cancer, and cancer mortality risk in cancer survivors. Literature search was performed using the electronic databases PubMed, and EMBASE until 2 July 2015. We included either cohort (for specific tumors only incidence cases were used) or case-control studies. Study specific risk ratios, hazard ratios, and odds ratios (RR/HR/OR) were pooled using a random effect model. The updated review process showed 23 observational studies that were not included in the previous meta-analysis (total number of studies evaluated: 56 observational studies). An overall population of 1,784,404 subjects was included in the present update. The highest adherence score to an MD was significantly associated with a lower risk of all-cause cancer mortality (RR: 0.87, 95% CI 0.81-0.93, I2 = 84%), colorectal cancer (RR: 0.83, 95% CI 0.76-0.89, I2 = 56%), breast cancer (RR: 0.93, 95% CI 0.87-0.99, I2 =15%), gastric cancer (RR: 0.73, 95% CI 0.55-0.97, I2 = 66%), prostate cancer (RR: 0.96, 95% CI 0.92-1.00, I2 = 0%), liver cancer (RR: 0.58, 95% CI 0.46-0.73, I2 = 0%), head and neck cancer (RR: 0.40, 95% CI 0.24-0.66, I2 = 90%), pancreatic cancer (RR: 0.48, 95% CI 0.35-0.66), and respiratory cancer (RR: 0.10, 95% CI 0.01-0.70).
No significant association could be observed for esophageal/ovarian/endometrial/and bladder cancer, respectively. Among cancer survivors, the association between the adherence to the highest MD category and risk of cancer mortality, and cancer recurrence was not statistically significant. The updated meta-analyses confirm a prominent and consistent inverse association provided by adherence to an MD in relation to cancer mortality and risk of several cancer types.
© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
Oncotarget. 2015 Oct 14.
Oleuropein aglycone induces autophagy via the AMPK/mTOR signalling pathway: a mechanistic insight.
Rigacci S1, Miceli C1, Nediani C1, Berti A1, Cascella R1, Pantano D2, Nardiello P2, Luccarini I2, Casamenti F2, Stefani M1.
The healthy effects of plant polyphenols, some of which characterize the so-called Mediterranean diet, have been shown to arise from epigenetic and biological modifications resulting, among others, in autophagy stimulation. Our previous work highlighted the beneficial effects of oleuropein aglycone (OLE), the main polyphenol found in the extra virgin olive oil, against neurodegeneration both in cultured cells and in model organisms, focusing, in particular, autophagy activation. In this study we investigated more in depth the molecular and cellular mechanisms of autophagy induction by OLE using cultured neuroblastoma cells and an OLE-fed mouse model of amylod beta (Aβ) deposition. We found that OLE triggers autophagy in cultured cells through the Ca2+-CAMKKβ-AMPK axis. In particular, in these cells OLE induces a rapid release of Ca2+ from the SR stores which, in turn, activates CAMKKβ, with subsequent phosphorylation and activation of AMPK. The link between AMPK activation and mTOR inhibition was shown in the OLE-fed animal model in which we found that decreased phospho-mTOR immunoreactivity and phosphorylated mTOR substrate p70 S6K levels match enhanced phospho-AMPK levels, supporting the idea that autophagy activation by OLE proceeds through mTOR inhibition. Our results agree with those reported for other plant polyphenols, suggesting a shared molecular mechanism underlying the healthy effects of these substances against ageing, neurodegeneration, cancer, diabetes and other diseases implying autophagy dysfunction.
Br J Nutr. 2015 Sep 14;114(5):804-11.
Nut consumption is inversely associated with both cancer and total mortality in a Mediterranean population: prospective results from the Moli-sani study.
Bonaccio M1, Di Castelnuovo A1, De Curtis A1, Costanzo S1, Bracone F1, Persichillo M1, Donati MB1, de Gaetano G1, Iacoviello L1; Moli-sani Project investigators.
Nut intake has been associated with reduced inflammatory status and lower risk of CVD and mortality. The aim of this study was to examine the relationship between nut consumption and mortality and the role of inflammation. We conducted a population-based prospective investigation on 19 386 subjects enrolled in the Moli-sani study. Food intake was recorded by the Italian version of the European Project Investigation into Cancer and Nutrition FFQ. C-reactive protein, leucocyte and platelet counts and the neutrophil:lymphocyte ratio were used as biomarkers of low-grade inflammation. Hazard ratios (HR) were calculated using multivariable Cox proportional hazard models. During a median follow-up of 4·3 years, 334 all-cause deaths occurred. As compared with subjects who never ate nuts, rare intake (≤2 times/month) was inversely associated with mortality (multivariable HR=0·68; 95 % CI 0·54, 0·87). At intake ≥8 times/month, a greater protection was observed (HR=0·53; 0·32, 0·90). Nut intake (v. no intake) conveyed a higher protection to individuals poorly adhering to the Mediterranean diet (MD). A significant reduction in cancer deaths (HR=0·64; 95 % CI 0·44, 0·94) was also observed, whereas the impact on CVD deaths was limited to an inverse, but not significant, trend. Biomarkers of low-grade inflammation were reduced in nut consumers but did not account for the association with mortality. In conclusion, nut intake was associated with reduced cancer and total mortality. The protection was stronger in individuals with lower adherence to MD, whereas it was similar in high-risk groups (diabetics, obese, smokers or those with the metabolic syndrome), as compared with low-risk subjects. Inflammation did not explain the observed relationship.
J Agric Food Chem. 2001 Jun;49(6):3106-12.
Flavonoid (myricetin, quercetin, kaempferol, luteolin, and apigenin) content of edible tropical plants.
Miean KH1, Mohamed S.
Studies were conducted on the flavonoids (myricetin, quercetin, kaempferol, luteolin, and apigenin) contents of 62 edible tropical plants. The highest total flavonoids content was in onion leaves (1497.5 mg/kg quercetin, 391.0 mg/kg luteolin, and 832.0 mg/kg kaempferol), followed by Semambu leaves (2041.0 mg/kg), bird chili (1663.0 mg/kg), black tea (1491.0 mg/kg), papaya shoots (1264.0 mg/kg), and guava (1128.5 mg/kg). The major flavonoid in these plant extracts is quercetin, followed by myricetin and kaempferol. Luteolin could be detected only in broccoli (74.5 mg/kg dry weight), green chili (33.0 mg/kg), bird chili (1035.0 mg/kg), onion leaves (391.0 mg/kg), belimbi fruit (202.0 mg/kg), belimbi leaves (464.5 mg/kg), French bean (11.0 mg/kg), carrot (37.5 mg/kg), white radish (9.0 mg/kg), local celery (80.5 mg/kg), limau purut leaves (30.5 mg/kg), and dried asam gelugur (107.5 mg/kg). Apigenin was found only in Chinese cabbage (187.0 mg/kg), bell pepper (272.0 mg/kg), garlic (217.0 mg/kg), belimbi fruit (458.0 mg/kg), French peas (176.0 mg/kg), snake gourd (42.4 mg/kg), guava (579.0 mg/kg), wolfberry leaves (547.0 mg/kg), local celery (338.5 mg/kg), daun turi (39.5 mg/kg), and kadok (34.5 mg/kg). In vegetables, quercetin glycosides predominate, but glycosides of kaempferol, luteolin, and apigenin are also present. Fruits contain almost exclusively quercetin glycosides, whereas kaempferol and myricetin glycosides are found only in trace quantities.
Copyright (c) 2015: Advanced Cancer Research Institute and agents.