Dr Paul Clayton 2008


Apples and fruits are generally considered to be healthy; but these complex chemical factories contain many hundreds of different compounds, and not all of them are good for you. Take furan, for example; tiny amounts of this suspected carcinogen are produced in apple cider (and probably apple juice) if the beverage is left exposed to sunlight or UV (Fan & Geveke ’07). Furan is also produced when cut pieces of fruit are left lying around; although apple slices are relatively unaffected, while grape and pineapple produce rather larger amounts (Fan & Sokorai ’08). Apples and plant foods in general also contain traces of fungal toxins, some of which, such as the aflatoxins, are known carcinogens.

But let’s keep this in perspective. There is a huge amount of evidence that eating fruit and vegetables is associated with a reduced risk of many diseases, including cancer; and so it seems very likely that these types of foods must contain chemo-protective compounds. Which brings us back to apples …

There are at least two compounds in apples which have very persuasive and well-documented modes of anti-cancer action; flavonoids such as quercitin, and the fibre, specifically pectin.

Quercitin and related flavonoids are extremely good at killing colon and other cancer cells in vitro (Kern et al ’07, Psahoulia et al ’07, Dihal et al ’08). Dietary pectin acts as a prebiotic in the gut, in that it stimulates the growth of ‘friendly bacteria’ such as lactobacilli and bifids. These bacteria utilise pectin as a substrate, breaking it down to short chain fatty acids such as butyric acid; and butyric acid has potent chemo-protective properties. You would expect, therefore, that apple consumption would change the flora and chemistry of the large bowel in a healthy and cancer-protective direction, and that is exactly what a small human study in 2008 demonstrated (Waldecker et al ’08).

If this is meaningful, epidemiological studies should show that apple consumption is associated with reduced cancer incidence; and there are indeed trials that show just this. One epidemiological study, carried out by scientists at the well-known Mario Negri Institute in Milan found that apple consumption was consistently linked to a reduced risk of a wide range of cancers (Gallus et al ’05).

Another study carried out at Edinburgh University (my own dear alma mater) came to a broadly similar conclusion; higher intakes of flavonoids such as quercitin, which in Scotland is largely derived from apples and onions, were linked to a dose-dependent reduction in the risk of colorectal cancer (Theodoratou et al ’07). Indeed, in the highest intake group, the incidence of colorectal cancer was two thirds lower than in the lowest intake group ? which appeared to make the flavonoids very protective indeed. I must point out that a larger American study had previously found no such connection (Lin et al ’06). According to the authors, ‘These data provide little support for the hypothesis of an association between flavonoid intake and colorectal cancer risk, at least within the ranges of intakes consumed in the populations studied.’ (I’ll come back to this important point of levels of intake later).

The next level of proof consists of studies in which apples and apple products are fed to animal models, to see if they reduce the risk of colon and other cancers. In one very interesting experiment, whole apple extracts fed to rats were shown to confer considerable protection against mammary cancer (Liu et al ’05). Most convincingly, from a science point of view, the degree of protection was directly related to the amount of apples consumed. Rats eating the equivalent of 6 apples a day were better protected than those eating 3 apples a day. One-a-day rats had even less protection, but still did better than their apple-free siblings.

A second rodent experiment, carried out at the German Federal Research Institute for Nutrition and Food at Karlsruhe, made significant progress towards identifying the key cancer-protective ingredients (Barth et al ’07). The scientists showed that cloudy apple juice, containing both flavonoids and pectin, was more effective in protecting against colon cancer than either the flavonoids or the pectin on its own. In other words, the combination of the ingredients in whole fruit gave better results than a purified extract containing only flavonoids, such as those sold in a variety of less sophisticated supplements.

Moving from mouse to man, at least one clinical intervention study has examined the therapeutic effects of quercitin administered to human patients with familial adenomatous polyposis, a genetic condition associated with a high risk of colon cancer. In this small trial (Cruz-Correa et al ’06), high doses of quercitin and curcumin (a similar flavonoid derived from the spice turmeric) reduced the number and size of polyps in the colon by a very significant 60%.

Questions remain, however, as to how effective quercitin and related flavonoids might be in protecting against cancer at other systemic sites such as the breast or prostate. Because the compound is so insoluble in water, it has long been assumed that not enough of it could be absorbed to achieve therapeutic levels in the tissues. And this is where a recent Chinese study provides a tantalising clue which might resolve many of the above contradictions.

In this fascinating animal experiment (Yuan et al ’06), quercitin was wrapped in liposomes – tiny lipid particles which, when ingested, improve the bioavailability of the flavonoid. When given in this way to animals with pre-existing tumours, quite reasonable doses of quercitin exerted significant cancer-suppressing activity. When I say ‘quite reasonable’, I am referring to a dose of apple flavonoids that might be consumed in around two pounds of apples, depending on variety (Nybom et al ’06). And to create liposome-like quercitin, with good bio-availability, the apples should be consumed together with a fatty food such as cheese – ie as part of a hearty meal.

But who can eat that much? Our problem is that we are so inactive that many of us get by on 2,200 calories a day, which is not very much more than Basal Metabolic Rate, ie the amount of energy required to sustain life. This makes it impossible for us to eat healthy amounts of food, as the mid-Victorians did, without putting on prodigious amounts of weight. And so the amounts of fruit and vegetables that would confer significant chemo-protection, as they did during the last half of the 19th century, are almost impossible for us to eat. The resulting epidemic of cancer is all around us.

Unfortunately, the current government recommendations are, unsurprisingly, so pathetic as to be actively misleading. Their 5-a-day campaign may help to reduce the problems of heart disease, but this level of dietary intake confers little if any protection against cancer. The American Cancer Association recommends 9 portions of fruit and veg / day, and this, by coincidence, is more or less the level of intake that gave our mid-Victorian ancestors a cancer rate about 10 percent of today’s excessive levels (Charlton & Murphy ’04).

The mid-Victorians were protected by quercitin in other ways too. When meat is cooked it produces carcinogenic compounds such as the heterocyclic amines, which explains why a high meat diet is so strongly linked to an increased risk of colorectal cancer. The mid-Victorians very often cooked meat by boiling it together with onions (Clayton & Rowbotham ’08) – and flavonoids in onions or in apples are very effective in reducing the formation of heterocyclic amines (Cheng et al ’07).

I have focused here on apples and onions, but other fruits and vegetables are equally important – and these are not the only studies to find benefits of fruits in cancer prevention and treatment. A recent study in California found low doses of freeze-dried grape powder could inhibit the development of colorectal cancer in human patients (Holcombe et al ’07). As with the apple studies above, it transpired that a flavonoid (in this case resveratrol) was involved – but not on its own. There were synergistic effects between resveratrol and other grape compounds. The take-home message remains, therefore, take more exercise, and eat a lot more fruits and vegetables, if you really want to avoid cancer.


References

Barth SW, Faehndrich C, Bub A, Watzl B, Will F, Dietrich H, Rechkemmer G, Briviba K. Cloudy apple juice is more effective than apple polyphenols and an apple juice derived cloud fraction in a rat model of colon carcinogenesis. J Agric Food Chem. 2007 Feb 21 55(4):1181-7.

Charlton J and Murphy, M (eds). The Health of Adult Britain 1841-1994. 2 vols. London: National Statistics, 2004.

Cheng KW, Wu Q, Zheng ZP, Peng X, Simon JE, Chen F, Wang M. Inhibitory effect of fruit extracts on the formation of heterocyclic amines. J Agric Food Chem. 2007 Dec 12-55(25):10359-65.

Clayton P, Rowbotham J. An Unsuitable and Degraded Diet. Journal of the Royal Society of Medicine, 2008, in press.

Cruz-Correa M, Shoskes DA, Sanchez P, Zhao R, Hylind LM, Wexner SD, Giardiello FM. Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. Clin Gastroenterol Hepatol. 2006 Aug4(8):1035-8.

Dihal AA, van der Woude H, Hendriksen PJ, Charif H, Dekker LJ, Ijsselstijn L, de Boer VC, Alink GM, Burgers PC, Rietjens IM, Woutersen RA, Stierum RH. Transcriptome and proteome profiling of colon mucosa from quercetin fed F344 rats point to tumor preventive mechanisms, increased mitochondrial fatty acid degradation and decreased glycolysis. Proteomics. 2008 Jan 8(1):45-61.

Fan X, Sokorai KJ. Effect of ionizing radiation on furan formation in fresh-cut fruits and vegetables. J Food Sci. 2008 Mar 73(2):C79-83.

Fan X, Geveke DJ. Furan formation in sugar solution and apple cider upon ultraviolet treatment. J Agric Food Chem. 2007 Sep 19 55(19):7816-21.

Gallus S, Talamini R, Giacosa A, Montella M, Ramazzotti V, Franceschi S, Negri E, La Vecchia C. Does an apple a day keep the oncologist away? Ann Oncol. 2005 Nov 16(11):1841-4.

Holcombe RF, Stamos M, Hope C, Planutis K, Nguyen AV, Crase A, Sakowsky S. Freeze dried grape powder inhibits a panel of Wnt pathway target genes in normal colonic mucosa: Results of a pilot trial in patients with colon cancer. Society for Integrative Oncology’s Fourth International Conference, Clinical Botanical Research: Session IV, November 16, 2007.

Kern M, Pahlke G, Balavenkatraman KK, B+APY-hmer FD, Marko D. Apple polyphenols affect protein kinase C activity and the onset of apoptosis in human colon carcinoma cells. J Agric Food Chem. 2007 Jun 27 55(13):4999-5006.

Lin J, Zhang SM, Wu K, Willett WC, Fuchs CS, Giovannucci E. Flavonoid intake and colorectal cancer risk in men and women. Am J Epidemiol. 2006 Oct 1 164(7):644-51.

Liu RH, Liu J, Chen B. Apples prevent mammary tumors in rats. J Agric Food Chem. 2005 Mar 23 53(6):2341-3.

Nybom H, Rumpunen K, Hovmalm HP,. Marttila S, Rur M, Garkava-Gustavsson L, Olsson ME. TOWARDS A HEALTHIER APPLE – CHEMICAL CHARACTERIZATION OF AN APPLE GENE BANK. ISHS Acta Horticulturae 765: XXVII International Horticultural Congress – IHC2006: International Symposium on Plants as Food and Medicine: The Utilization and Development of Horticultural Plants for Human Health

Psahoulia FH, Drosopoulos KG, Doubravska L, Andera L, Pintzas A. Quercetin enhances TRAIL-mediated apoptosis in colon cancer cells by inducing the accumulation of death receptors in lipid rafts. Mol Cancer Ther. 2007 Sep 6(9):2591-9.

Theodoratou E, Kyle J, Cetnarskyj R, Farrington SM, Tenesa A, Barnetson R, Porteous M, Dunlop M, Campbell H. Dietary flavonoids and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2007 Apr 16(4):684-93.

Waldecker M, Kautenburger T, Daumann H, Veeriah S, Will F, Dietrich H, Pool-Zobel L, Schrenk D. Histone-deacetylase inhibition and butyrate formation: Fecal slurry incubations with apple pectin and apple juice extracts. Nutrition April 2008, 366-374

Yuan ZP, Chen LJ, Fan LY, Tang MH, Yang GL, Yang HS, Du XB, Wang GQ, Yao WX, Zhao QM, Ye B, Wang R, Diao P, Zhang W, Wu HB, Zhao X, Wei YQ. Liposomal quercetin efficiently suppresses growth of solid tumors in murine models. Clin Cancer Res. 2006 May 15 12(10):3193-9.