2011-04-27 Rober E. Carroll MD The Role of Curcumin in Colon Cancer Prevention
An Interview with Robert E. Carroll, MD
April 27, 2011, By Kirkham R. Hamilton, PA-C
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KIRK HAMILTON: Hi, my name is Kirk Hamilton, your host of Staying Healthy Today. Our message is simple: To provide you credible usable health information from interviews and our educational resources to help you Be and Stay Well in the busy modern world. Please take a few moments before or after listening to this interview to browse through the Prescription2000.com website, the home of Staying Healthy Today Radio, for our free educational services.Today's show topic is "The Role of Curcumin in Colon Cancer Prevention." Our guest today is Dr. Robert E. Carroll, M.D., associate professor of medicine and staff physician at the University of Illinois Medical Center and a staff physician at the Jesse Brown VA Medical Center. Dr. Carroll co-authored a paper entitled "Phase 2A Clinical Trial of Curcumin for the Prevention of Colorectal Neoplasia," in Cancer Prevention Research in March 2011.
Welcome Dr. Carroll. Thanks so much for being on the show today.
DR. ROBERT CARROLL: Oh thanks for inviting me.
KIRK HAMILTON: So tell me a little about your - you know what you're doing right now and
your educational background that led you to your position.
DR. ROBERT CARROLL: Okay. I'm a gastroenterologist. I treat patients with GI diseases. But I had an interest in colon cancer and did some research while I was doing my training in an animal colon cancer model and became interested with some of the early changes in the colonic mucosa as cancers formed called aberrant crypt foci (ACF). But I have followed that up in - working in a colon cancer screening clinic. We've performed a few studies on patient with what are now called cancer reductive agents or chemopreventive agents. I see patients with colon cancer and I see patients who come in for colon cancer screening and that's been the bulk of my academic career - has been working in that area. I'm an associate professor of medicine at the University of Illinois and I've been here off-and-on for about 20 years.
KIRK HAMILTON: Tell me, colon cancer. You know, what's the prevalence of it. It is increasing, decreasing? I always think of Katie Couric when I think of colon cancer. So it is on the rise or are we getting a handle on it?
DR. ROBERT CARROLL: After 1992, I think where - colon cancer screening began to become a bit more extensive, more people were undergoing colon cancer screenings. I think since - I'd have to check the statistics exactly, but I think since 1999 they see maybe a little bit of a reduction primarily in white people, Caucasians, because they've been a little bit more compliant with screening. But the rates are still a little bit higher in African-Americans, a little bit lower in Hispanic populations. Those are probably, some dietary and lifestyle related. We don't understand all of the reasons for the differences. But it's still the third most prevalent cancer, second or third most prevalent cancer common in both men and women. But breast in women is probably first, prostate in men is probably first, and then if you combine those two, colon cancer comes in third because it affects sort of men and women about equally.
KIRK HAMILTON: Is the main way to screen colonoscopy?
DR. ROBERT CARROLL: Right now there are other techniques. There are radiology techniques called CT colonography that are effective, but not very prevalent, not paid for by a lot of insurance companies. There are some new stool testings that will look for genetic signatures of colon cancer, but I would say no, right now our most effective weapon for early detection and diagnosis is screening colonoscopy.
KIRK HAMILTON: What are Western diet and lifestyle factors that you think increase the colon cancer risk especially in the West?
DR. ROBERT CARROLL: Certainly tobacco use is one of them. There's some - several studies now showing there's an increased association with colon polyps or colon adenomas as well as colon cancers, particularly rectal cancers. There seems to be a strong link between obesity and just - not necessarily any individual dietary factor but probably too much caloric intake. There seems to be some relationship between type 2 diabetes and obesity and colon cancer risk. So as we've gotten fatter probably - as the nation's gotten fatter over the last 20 years, probably our risks have increased. Red meat in the diet. There's lower rates of colon cancer among vegetarians and vegans. I guess those are probably the major ones.
KIRK HAMILTON: What got you interested in studying this spice herb curcumin?
DR. ROBERT CARROLL: It was actually a colleague of mine at the University of Michigan who's been interested in chemoprevention or the cancer reductive field. Dr. Dean Brenner approached me about designing a trial to test this drug in people who were at some increased risk for colon cancer. And we sort of picked a smoker's group because there was a lot of them in our population. Curcumin as I understand - as I have read and talking with Dean about this, is a component of the spice tumeric. It's apparently used in sort of Indian curries typically, our typical exposure to it is eating Indian food. But this would be sort of - this is a purified compound made from the tumeric root. It grows like a ginger root, sort of underground. It's a rhizome that is pulled up and then grated. It gives the yellow color to curry. But - so curcumin is an active compound that's been extracted from tumeric. These in animals studies is shown to have a number of positive effects on cancer cell lines. And in animal models of colon cancer it's been shown to reduce the rates of colon cancer. It had been tried - it'd been tested in several phase I trials and found to be fairly well tolerated and a safe drug to use. With colon cancer prevention, you're giving - you know you're talking about using an agent in a lot of people for maybe longer periods of time so you want to - we wanted something that was safe. So this drug was interesting. It had also been used effectively in some patients with inflammatory bowel disease and seems to reduce the inflammation in inflammatory bowel disease.
KIRK HAMILTON: Is the effect of curcumin then, is the proposed biochemistry because it's an anti-inflammatory agent, because it modulates fatty acids?
DR. ROBERT CARROLL: It seems to be an anti-inflammatory agent and it also has antioxidant activity. It inhibits a number of growth receptors and inflammatory and oxidation pathways. So it modulates inflammation, it modulates oxidant damage. Both of those things are known - are thought to be important in the sort of early phases of carcinogenesis.
KIRK HAMILTON: Is the main thing that you look for when you see if something is effecting the GI tract, these aberrant crypt foci, is that - tell me about those.
DR. ROBERT CARROLL: Okay. Well the aberrant crypt foci is an interesting lesion. It was - we'd known about them in animals for probably 20 years. They were first reported in the animal models. But once better endoscopic technology was developed in I guess the mid the 90s where you could start to magnify the lining of the human colon, there was a group of Japanese investigators who identified these lesions and said - in Japan they have a strong association with the presence of adenomas and colon cancer. They are found predominantly in the left side of the colon and you need to dye the lining of the colon with a sort of dilute methylene blue or indigo carmine dye and then you can magnify the colonic mucosa and visualize them. Whether or not they are precursors or the first step in cancer is controversial. It's - many of these lesions may go on to form other types of polyps that don't have a cancer risk. The question that's intrigued me is, are they are marker of genetic damage and sort of a colon at risk for developing adenomas. The literature on that is still a bit unclear in the human studies, and there's been couple of American trials that hadn't thought that they've had such a strong association with adenomas. But there are a couple of reported trials now, ours with curcumin and there's another published trial that show that the agent metformin seemed to be able to reduce the presence of aberrant crypt foci in the human colon.
KIRK HAMILTON: Where did you come up with the dosages you got of 2 to 4 grams a day of curcumin?
DR. ROBERT CARROLL: That's a good question. Actually it was in a conference call with the FDA. We had a very purified formulation of the compound and in phase I studies it had been used safely up to 12 grams. We picked a lower dose and then 100% dose escalation based on the absence of toxicity and they had fairly strict guidelines for what we would call toxicity and whether or not it would cause liver function abnormalities, some blood tests. So we picked a modest dose, but people have taken up to 12 grams a day, but we picked a low dose that had been effective in it - that the equivalent dose in animals had been effective and then we asked for a 100% dose escalation.
KIRK HAMILTON: Did you take it with meals or away from meals, or how did you take it?
DR. ROBERT CARROLL: I think they took it in the morning and they were asked to take it with juice or some people even recommended taking it with some tomato paste. They thought that might increase absorption. But they took it as capsules and we didn't have too much in the way of restrictions on how they took it.
KIRK HAMILTON: So they took it once a day basically?
DR. ROBERT CARROLL: Yes.
KIRK HAMILTON: Okay. And so tell us a little about the study and what you found.
DR. ROBERT CARROLL: So they took it for 30 days and we had them get a baseline endoscopic exam. We have reported that smokers had increased prevalence of these lesions. And we had predicted that if the curcumin was going to have an effect on aberrant crypt foci that it would lower prostaglandin levels and leukotriene levels which are inflammatory markers that were - that we could measure in the colon by sort of sensitive high performance liquid chromography assays. So the 2 gram dose had no effect on the ACF number at all and it didn't reduce either the prostaglandin E2 or
lipo-oxygenase levels. But at the 4 gram dose we did see a marked, a little bit over 40% reduction but it was not associated with any changes in the prostaglandin levels, so this effect seems to be independent of the prostaglandin-leukotriene pathway.
KIRK HAMILTON: Well it's interesting, you know, because I work in an integrative medicine practice and curcumin is used for all kinds of inflammatory disorders so I'm just trying to get a feel for the - were the leukotrienes reduced?
DR. ROBERT CARROLL: No. They - 5 HETE was the leukotriene marker in the leukotriene B4 pathway which is an inflammatory marker, didn't seem to go down at all. We had predicted that maybe - the data in smokers suggested if you looked in like bladder mucosa or the lung mucosa the prostaglandins and leukotriene concentrations were elevated. But actually if you look at our baseline levels of prostaglandins, they're really not that much different than reported on some of the normal controls and the FAP studies. So the prostaglandin level in smokers, in the colon of smokers, there isn't probably a strong inflammatory reaction to the swallowed carcinogens in cigarette smoke.
KIRK HAMILTON: So in the 30 days you did this were there any side effects?
DR. ROBERT CARROLL: Yeah, there's some - a little bit of GI upset in a few patients, mild headache, no laboratory abnormalities. Sort of mild - sort of mild GI upset, some peopled reported diarrhea. Interestingly people who had a baseline history of constipation felt that it was actually sort of improved their bowel movements and they were happy with the effect. And actually four people quit smoking - or three people quit smoking during the study - at the end of the study. And they thought that it - the drug had some mild antidepressant effects and they thought that it actually helped them quit smoking.
KIRK HAMILTON: Huh. And they weren't trying.
DR. ROBERT CARROLL: They hadn't planned to try before they started taking it. That was something we found sort of the end of the study.
KIRK HAMILTON: Well that's a good thing because that's something simple to do. So there weren't a lot of side effects.
DR. ROBERT CARROLL: It was a very safe - very safe. And the side effects were minimal. They didn't - they lasted, sort of lessened in two or three days and it didn't require them to discontinue the drug. So they weren't disabling.
KIRK HAMILTON: So where do you go with this? Are you going to try to do another study for a longer period of time?
DR. ROBERT CARROLL: We'd like to try and understand the mechanism of how the drug is working a little bit better. So we're thinking about perhaps a 4 gram trial in a more expansive population. Perhaps some patients who have colonic adenomas and see what the effect in a 30-day trial would be. So we're looking at maybe designed phase II trials that would sort of follow-up on what we found at the 4 gram dose. We kind of know - we kind of saw an effect with 4 grams but we don't quite understand how it's working. We're cautious and we think before we go into sort of a big cancer prevention trial like an adenoma reduction trial where you're involving multiple centers that we should try and learn a little bit more about the antioxidant effects of this drug and perhaps its effects on some of the early cells in the colon crypt.
KIRK HAMILTON: Can a colon polyp grow significantly in 30 days? I'm really ignorant.
DR. ROBERT CARROLL: No. Not significantly. But it - most drugs that have biological effects, the thinking is that you'll see those effects on the colonic mucosa within 30 days. Now I think if you were going to be - if you were talking about using this as a chemoprevention agent, you'd be taking it for a longer period of time like six months or a year.
KIRK HAMILTON: Okay. Do you have any other comments you want to make on your study on the curcumin?
DR. ROBERT CARROLL: I've been intrigued that it has such a long history in, they call it Ayurvedic Medicine. But Indian physicians have been using this drug for years to treat inflammation, to treat digestive disorders, and it's interesting that it's now sort of coming into its own both in the GI field and in inflammatory bowel disease and in the cancer prevention field. There's a group at MD Anderson that are interested in trying to improve this drug's absorption and that thought that it might be effective in other cancers outside of the GI tract, pancreas. But's it funny that it has such a long history in medicine sort of outside of the United States. And we're only starting to I think become aware of its potential benefits.
KIRK HAMILTON: So in review, just in general for those who listen to, in your opinion reduce the risk of colon cancer, you would have people lose weight, obviously.
DR. ROBERT CARROLL: Yeah. Lose weight, eat less red meat, stop smoking if they're smokers, and exercise more. It seems like the things your mother told you to do when you were in your
20s are still applicable. And there's been a lot of focus on folate and specific dietary supplements. There's probably no magic dietary supplement that's gonna prevent you from getting colon cancer. What's gonna prevent, reduce your risk for cancer is a healthy lifestyle. And that involves sorts of all phases of things, diet, weight, you know modest uses of alcohol and not smoking, and getting exercise. It's clear for prostate and breast, the cancers that affect most of our lives, sort of the bulk of the population. For the most part can be prevented by adopting a healthy lifestyle. That's very hard to do.
KIRK HAMILTON: Well Dr. Carroll thanks for taking time out of your busy day for coming on and talking about this topic. And I want to thank you and hopefully we'll talk to you again.
DR. ROBERT CARROLL: Okay.
KIRK HAMILTON: And I want to thank you, the audience, for listening to this edition of Staying Health Today Radio. And until next time, Stay and Be Well.
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