Epigenetics, Diet and Cancer

From Healthwire.
By Colin Champ, MD

Radiation Oncologist
Nutritional Expert

http://www.myhealthwire.com/news/breakthroughs/1068

 

Posted by Dr. Colin Champ – Friday, June 5th, 2015
Several weeks ago we discussed the potential cancer-fighting benefits of eating broccoli and Brussels sprouts.

These benefits were not from the vitamins or nutrients present in the vegetables…

They were not from all the so-called antioxidant benefits either…

They were through chemoprevention by upregulating the body’s innate mechanisms to fight free radicals, oxidative damage, and the potential for resulting cancer.

What this benefit illustrates is the important link between food and the fight against cancer. Cancer, once thought of as a metabolic disease, then purely a genetic disease, and now a combination of the two, appears to be more closely linked with our diet than ever before.

Because, whether you believe that cancer is purely metabolic, purely genetic, or a combination, both our genetics and metabolism appear to be largely affected by what we eat…

Epigenetics: A Stronger Link between Diet and Cancer?

Very simply put, epigenetics is the study of cellular interactions with our DNA that do not change our genes, but rather alter how they are expressed. The most common of these epigenetic processes is DNA methylation, where DNA is silenced by the addition of a methyl group to one of its base pairs. The other is histone acetylation. Histones package and organize our DNA, and they can be regulated by the addition of an acetyl group or removal via histone deacetylase (HDAC). Histones also protect our DNA from damage and stand guard like a bouncer refusing or allowing access.

The exact mechanisms are quite nuanced, and the field as a whole remains exciting, yet controversial…

Genes like p21 stop malignant cells from progressing through their cell cycle and bax activates apoptosis, which is a programmed cell death. This helps to stop cancer cells from progressing or to outright kill them. These genes can be silenced by HDACs (by acetylation). HDAC inhibitors can stop the silencing of these genes, allowing them to stop cancer in its tracks.1 Some data even suggests that HDAC inhibitors may selectively lead to apoptosis in cancer cells while sparing normal cells.2

Malfunctioning HDACs

Recent research has shown that abnormal acetylation occurs in cancer cells. In fact, some researchers have even referred to loss of acetylation as one of the “hallmarks of human cancer.”3 Many different types of cancer appear to overexpress HDACs, including lung, liver, prostate, colorectal, and gastric cancer.4 Furthermore, overexpression is correlated with decreased survival in these patients. Part of this is due to suppression of genes that actually block cancer growth, known as tumor suppressor genes. HDACs may also shut off DNA damage repair genes, like the infamous BRCA gene associated with breast cancer.5 This would allow mutations to occur that could eventually lead to cancer.

On the other hand, HDACs are not that straightforward as elevated expression in other cancer types has not shown such a detriment. Yet, the significant results of these studies has led to the recent attempt to use HDAC inhibitors to treat cancer.4 Two recent drugs, vorinostat and romidepsin, have been approved for usage with a malignancy called cutaneous T-cell lymphoma.

When Food Becomes Medicine… Again

Amidst all the excitement regarding HDAC inhibitors as potential cancer treatment, the importance of food in the fight against cancer once again surfaces. Through epigenetics and the study of HDAC inhibitors, the scientific world began to realize that food can modify our genes. While in the past, many have doubted any effect of food on cancer avoidance and treatment, data continues to accumulate revealing the vital link between diet and cancer.

As discussed previously, “toxic” elements of vegetables such as sulforaphane actually work to upregulate our innate damage repair systems. Sulforaphane from broccoli and other cruciferous vegetables apparently has other significant cancer-fighting properties as it inhibits HDAC, just like the approved drugs mentioned above.1 Studies in humans reveal that after the consumption of one cup of broccoli sprouts, blood draws reveal HDAC inhibition in as little as three hours.1 The authors of this study stated that HDAC inhibition and histone hyperacetylation was as effective as or even greater than the approved agent vorinostat. I even participated in a clinical trial using vorinostat to sensitize radiation therapy.6

Perhaps we could have used broccoli instead…

Vegetables are not the only HDAC inhibitors. Butter has many health benefits, like cancer-fighting CLA. Not only is butter delicious, but it contains butyric acid, an HDAC inhibitor. Data as far back as the 1970s revealed the effect of butyrate on HDAC.7 Other dietary sources of HDAC inhibitors are garlic, onions, selenium-rich foods like Brazil nuts, resveratrol found in grapes and wine, green tea, and circumin.8

Some studies have even stated that “dietary HDAC inhibitors have been shown to have a similar regulatory effect as pharmacological HDAC inhibitors without the possible side-effects.”8

Fasting and Ketosis — More Potential Benefits

The benefits of ketosis and fasting in regards to weight loss, repair of metabolic derangement, a potential preventative mechanism for Alzheimer’s,9 while synergizing with cancer treatment10–13 have led to well-deserved interest in both of these activities. Recent data have shown further potential for a ketogenic diet or even periodic ketosis as ketone bodies (β-hydroxybutyrate) have been found to be an endogenous HDAC inhibitor.14

In Conclusion

Studies are underway testing new and innovative cancer therapeutic agents with epigenetic effects including HDAC inhibitors. Yet, food, fasting, and ketosis appear to affect similar pathways. Not surprisingly, these natural activities that humans have engaged in for millions of years may potentially provide cancer-fighting benefits. Once again, we should appreciate the power of lifestyle and food with regards to cancer prevention and treatment.

“Let food be thy medicine and medicine be thy food.”

To Your Health,

Dr. Colin Champ

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Dr. Colin Champ is a practicing radiation oncologist and nutritional expert. He is the author of Misguided Medicine: The truth behind ill-advised medical recommendations and how to take health back into your hands” You can hear more from him as the host of the incredibly popular Caveman Doctor podcast.

References:

1. Dashwood RH, Ho E. Dietary histone deacetylase inhibitors: from cells to mice to man. Semin Cancer Biol. 2007;17(5):363-369. doi:10.1016/j.semcancer.2007.04.001.

2. Dai Y, Chen S, Kmieciak M, et al. The novel Chk1 inhibitor MK-8776 sensitizes human leukemia cells to HDAC inhibitors by targeting the intra-S checkpoint and DNA replication and repair. Mol Cancer Ther. 2013;12(6):878-889. doi:10.1158/1535-7163.MCT-12-0902.

3. Fraga MF, Ballestar E, Villar-Garea A, et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet. 2005;37(4):391-400. doi:10.1038/ng1531.

4. West AC, Johnstone RW. New and emerging HDAC inhibitors for cancer treatment. J Clin Invest. 2014;124(1):30-39. doi:10.1172/JCI69738.

5. Di L-J, Fernandez AG, De Siervi A, Longo DL, Gardner K. Transcriptional regulation of BRCA1 expression by a metabolic switch. Nat Struct Mol Biol. 2010;17(12):1406-1413. doi:10.1038/nsmb.1941.

6. Shi W, Lawrence YR, Choy H, et al. Vorinostat as a radiosensitizer for brain metastasis: a phase I clinical trial. J Neurooncol. 2014;118(2):313-319. doi:10.1007/s11060-014-1433-2.

7. Riggs MG, Whittaker RG, Neumann JR, Ingram VM. n-Butyrate causes histone modification in HeLa and Friend erythroleukaemia cells. Nature. 1977;268(5619):462-464. http://www.ncbi.nlm.nih.gov/pubmed/268489. Accessed May 30, 2015.

8. Bassett SA, Barnett MPG. The role of dietary histone deacetylases (HDACs) inhibitors in health and disease. Nutrients. 2014;6(10):4273-4301. doi:10.3390/nu6104273.

9. Gasior M, Rogawski MA, Hartman AL. Neuroprotective and disease-modifying effects of the ketogenic diet. Behav Pharmacol. 2006;17(5-6):431-439. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2367001&tool=pmcentrez&rendertype=abstract. Accessed February 26, 2015.

10. Veech RL. The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukot Essent Fat Acids. 2004;70(3):309-319. doi:10.1016/j.plefa.2003.09.007.

11. Abdelwahab MG, Fenton KE, Preul MC, et al. The Ketogenic Diet Is an Effective Adjuvant to Radiation Therapy for the Treatment of Malignant Glioma. PLoS One. 2012;7(5):e36197. doi:10.1371/journal.pone.0036197.

12. Klement RJ, Champ CE. Calories, carbohydrates, and cancer therapy with radiation: exploiting the five R’s through dietary manipulation. Cancer Metastasis Rev. 2014:1-13. doi:10.1007/s10555-014-9495-3.

13. Champ CE, Palmer JD, Volek JS, et al. Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme. J Neurooncol. 2014;117(1):125-131. doi:10.1007/s11060-014-1362-0.

14. Shimazu T, Hirschey MD, Newman J, et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science. 2013;339(6116):211-214. doi:10.1126/science.1227166.

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