Reporting Source: "Researchers Find that Chocolate Compound Stops Cancer Cell Cycle in Lab Experiments." Science Daily, April 18, 2005.
Primary Source : "Pentameric Procyanidin from Theobroma cacao Selectively Inhibits Growth of Human Breast Cancer Cells." Molecular Cancer Therapeutics, April 2005; 4:537-546.
Expert Comments by M. William Audeh, MD
Asst. Clinical Professor of Medicine, UCLA
Medical Oncologist, Cedars-Sinai Comprehensive Cancer Institute, Los Angeles, CA
By Mary Batten
Finding a natural substance in food that could help prevent breast cancer has been the subject of much wishful thinking and many dietary studies. Researchers have investigated low-fat diets, high-fiber diets, soy, flaxseed, Omega-3 oils, fruits and vegetables, and eating less red meat. Results have been mixed or inconclusive. The most definitive study on diet and breast cancer to date was announced at the 2005 annual meeting of the American Society of Clinical Oncology (ASCO). The study found that eating a low-fat diet could reduce risk of cancer recurrence by 42 percent among breast cancer survivors with estrogen receptor (ER) negative tumors. This study did not address breast cancer prevention but it does add another reason to follow a low-fat eating plan.
Dietary factors are extremely difficult to study because of lack of control of the amounts of foods eaten, incomplete recall by study participants, the effect of eating foods during adolescence, and the interaction between an individual's genetic make-up and diet. The current study avoided those pitfalls because it was performed on breast cancer cell cultures in a laboratory. Thus the researchers, led by Robert Dickson, PhD, professor of oncology at the Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, were able to quantify and control precisely their test procedures. This research was basic science that may or may not lead to some practical application down the road. The finding that a compound in chocolate seems to stop cancer cell division is intriguing and warrants further study. However, there is no evidence at this time that eating chocolate will reduce one's cancer risk or treat a current case of cancer (Ref. 1).
"I would want to stop at the point of saying it should influence anybody's dietary habits," Dr. Dickson told Breastlink. "What we're studying are very interesting and possibly exciting clues from common dietary substances but on highly experimental model systems."
Current breast cancer treatments involve surgery, followed by radiation and hormonal and/or chemotherapy. Some of these treatments have toxic side effects. The drugs used in chemotherapy affect normal cells as well as cancer cells. Researchers are trying to develop targeted drugs that only attack cancer cells and do not harm normal cells. One approach is to look for compounds that can block genes involved in transforming a normal cell into a cancer cell. "There are all kinds of chemicals in the food we eat that potentially have effects on cancer cells, and a natural compound in chocolate may be one," Dr. Dickson said.
Chocolate is made from the beans of cacao trees. Like some other plants, it is rich in natural antioxidants known as flavonoids. Studies have shown that antioxidants may protect cells from the damage caused by unstable molecules known as free radicals, which are thought to contribute to both heart disease and cancer. The primary family of flavonoids contributing to the antioxidant benefit in chocolate is the procyanidins. The strongest of these procyanidins is pentamer. "There's a long history in the literature of these compounds that we were studying in chocolate being involved in human health," Dr. Dickson said. Several in vitro studies have shown that pentamer inhibits growth of breast cancer cells (Ref. 2).
What Was Being Studied?
The effect of pentamer, a naturally occurring chemical in chocolate, on breast cancer cell cultures.
How Was Information Gathered?
This was a laboratory study in which the researchers conducted experiments to see what happened in vitro when they used a purified preparation of pentamer on a variety of human breast cancer cell lines, compared to treatment on normal breast cells. The cell lines chosen were those involved in most types of breast cancer: some had estrogen receptors and others did not have them. The researchers also chose cell lines with and without p53 mutation, which is known to be involved in breast and many other kinds of cancer.
Using different tests, the researchers identified four proteins in breast cancer cells that regulate cell division, or proliferation, which is also known as the cell cycle. These proteins have specific groups of phosphates attached to them, Dr. Dickson said. Removing the phosphates changes the proteins' function. "Pentamer seems to cause the cell to release several very specific phosphate groups from proteins that result in stopping the cell cycle."
Using proteomics techniques, the researchers found that pentamer selectively targets the proteins involved in the control of cellular growth, proliferation, survival, and apoptosis. When treated with pentamer, all four proteins were deactivated and the breast cancer cells stopped dividing. The investigators conclude that further research will be important to determine whether pentamer can be "an effective chemopreventive and chemotherapeutic agent against human breast cancer" (Ref. 1).
The research in Dr. Dickson's laboratory will continue to address cell cycle regulation. "I believe the most interesting question here is to try to understand the mechanism whereby this pentamer compound in chocolate causes the removal of those regulatory phosphate groups on the protein," he says. He hopes that other researchers will investigate the effect of pentamer on human breast cancer cells grown in experimental animals. If those kinds of experiments yield positive results, safety testing could begin, perhaps leading to clinical trials. "It's possible that chocolate could have compounds such as this pentamer that could relate to either cancer prevention or cancer therapy, but it's too soon to tell," he says.
Who Funded This Study?
This study was funded by a grant from Masterfoods USA, a division of MARS, Inc., a major producer of chocolate products. One of the researchers, Leo J. Romanczyk, was associated with Masterfoods. However, this investigation was well conducted and represents good basic science. Masterfoods supports research into biologically active compounds in chocolate at various institutions.
By M. William Audeh, MD
Asst. Clinical Professor of Medicine, UCLA
Medical Oncologist, Cedars-Sinai Comprehensive Cancer Institute
8700 Beverly Blvd., Los Angeles, CA 90048
This was a laboratory study done on cell lines. It wasn't a study done on real people or testing any sort of therapy on human beings with breast cancer. As a laboratory test, it was a very well done study and there's really no issue regarding the science behind it.
With respect to pentamer, the compound they tested, there are many substances derived from nature that will do that sort of thing in the test tube when you expose cancer cells to them. But it's quite a leap to go from the test tube to a human being because you have to deal with things like toxicity of high doses of one of these compounds to other parts of the body; you have to find a good way to get it into the body, whether it can be given orally or whether it needs to be given through some other route; and then, it remains to be seen whether real cancer in people will behave the same as cancer cells in a test-tube environment. Given all those "ifs," I would say, yes, so far, so good on this particular substance.
Pentamer is one of the procyanidins, which is a huge family of compounds that come from a wide variety of natural sources, mainly fruits. The issue as to whether this particular type -- the pentamer -- is the best of the lot, is not answered by this study. . A literature search reveals that this same sort of effect has been observed with other members of this family of molecules. They are found in many dietary sources, not just the cocoa bean. In fact, this whole family of substances -- the flavonoids -- is actually found in pretty high amounts in most American diets. They come from other sources, such as apples, berries, a variety of nuts, and some of the beans and legumes. So people get these things in various forms from a lot of different foods. The real question is whether it's going to be more helpful to take it in its natural form or to purify this particular form, the pentamer, in large doses and use it as a real medicinal.
There's quite a bit of literature about how diets that are rich in these types of compounds promote health. The procyanidins act as antioxidants primarily and reduce the oxidant damage produced by free radicals. They will reduce heart disease, for example. But what was interesting and, I think, unique about this study was the demonstration of another effect of this compound (pentamer) against breast cancer cells specifically. This was the modification of some growth-regulating proteins to shut them down in the pathways that may be overactive in cancer cells. This effect was more pronounced in cancer cells than in the normal cells.
So there's no question that pentamer has more than just an antioxidant effect because antioxidants by themselves wouldn't be expected to slow or stop the growth of cancer cells. Antioxidants would be expected to diminish the chance that a cancer would ultimately develop by protecting the DNA from damage. But as far as a cancer that's already up and running, there isn't a lot of information to suggest that an antioxidant would stop the growth of the cancer.
When thinking about natural compounds, it's always important to (ask what they're doing in the plant in the first place. They weren't put there for us to find them as medicinals. They have evolved in the history of these plants to perform a function, and it's interesting where they're found. They're found in the peels and in the colored outside peels of lots of fruits and they're also found at high levels in the covering of seeds. As antioxidants, they are very important to protect the fruit and the seed inside from oxidant damage; but the other thing that they do is act as antibacterials. There's also quite a bit of data showing that these are antimicrobial compounds. The way they inhibit or kill bacteria is probably related to what we're seeing with this cancer cell effect. It's more than just an antioxidant; it's also a growth-inhibiting effect which is there to protect the plants from being invaded by microbes. In this case, we're appropriating that natural function and using it not only as an antioxidant but also as a weapon against a different kind of invader.
Every time you find a plant or natural substance that has an unexpected effect on a cancer cell, it is almost always because there's something about the cancer cell that is similar to what the plant was using that substance for, whether it's as a pesticide or a growth-preventive compound or something to protect it from the damaging effects of sunlight, which is essentially an oxidizing process.
There's another interesting fact about this family of compounds: if you look at the levels of these procyanidins in various foods, the absolute highest concentration that I saw described in the literature is in cinnamon. Again, not surprising, because these are the molecules that provide some flavor to a lot of the things that we have in our diet. So although it would be nice to say that chocolate is the only one that's got it, the truth is, I suspect, that you'll find pentamer in lots of food substances that we consider healthful.
No one should go away from this study thinking that they can prevent breast cancer by eating chocolate. This was strictly a laboratory study. The pentamer the researchers used was actually a purified substance from cocoa, which is not the same as the chocolate that we eat. The chocolate that we eat is mainly fat; essentially it's butter with cocoa flavoring. So the way that we ingest chocolate would not really get you a lot of this substance, but it would certainly get you a lot of fat. It certainly doesn't mean that a little chocolate wouldn't possibly help but lots of other sources, primarily fruits and nuts, will have this as well.
1. Ramljak D, Romanczyk LJ, Metheny-Barlow L, Thompson N, et al. "Pentameric Procyanidin from Theobroma cacao Selectively Inhibits Growth of Human Breast Cancer Cells." Molecular Cancer Therapeutics, April 2005; 4:537-546.
2. Kozikowski AP, Tuckmantel W, Bottcher G, Romanczyk LJ Jr. "Studies in Polyphenol Chemistry and Bioactivity. 4.(1) Synthesis of Trimeric, Tetrameric, Pentameric, and Higher Oligomeric Epicatechin-Derived Procyanidins Having all-4,8-Interflavan Connectivity and Their Inhibition of Cancer Cell Growth through Cell Cycle Arrest." Journal of Organic Chemistry 2003; 68:1641-58.
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