Subtitle: Why Petri dish studies don't always translate into benefit for patients
While I am an enthusiastic supporter of naturally-derived compounds as the source of drugs, I am extremely disappointed and dismayed at how non-prescription natural products are promoted indirectly for disease treatment. Patients with cancer or HIV/AIDS are those most often preyed upon by manufacturers of the "next great cure" - hence, the convergence of cancer and natural products leads me to today's post, the first in a multi-part series of general comments on the marketing of herbal or dietary supplements.
Case in point for this series is the spice, turmeric, and the pure compound derived from it, curcumin. I could pick any natural compound, including some on which I work in my own laboratory, but curcumin is special because of the amount of press and scientific attention it has received. The literature abounds with over 1700 reports, mostly from studies of cancer cells grown in Petri dishes, on how curcumin can kill cancer cells, act as an antinflammatory agent, among other activities.
There is no doubt that the results in these reports are true for cells growing in a dish, but extrapolating those results to a whole person taking a curcumin supplement is a very long stretch that requires far more evidence. Most importantly, and the subject of this and the next post is the following question:
Do concentrations of curcumin (or any compound) with anticancer effects in cell culture actually occur in the bloodstream of patients who take dietary supplements containing the compound?
To understand the translation of cell culture studies to the whole person, we must first consider all of the systems operating in the human body that are not present when human cells are grown in plastic Petri dishes.
In my first week of pharmacology lectures to pharmacy and medical students, or in my two-hour "Mini-Med School" lecture to the general public, we talk about the barriers to drug action in discussing the concepts of drug absorption, distribution, metabolism, and excretion, often called ADME to refer collectively to these four important physiological factors that influence drug action.
These concepts apply to any chemical taken into the body (we sometimes use the "xenobiotic" to refer broadly to anything we take in). These concepts apply regardless of whether the substance ingested is a chemical found naturally in plants and herbs or a chemical that is synthesized at the lab bench by a chemical or pharmaceutical company.
When we ingest a drug orally, there are many determinants to how much of that drug gets into the bloodstream and, ultimately, to the site of its desired action. None of these processes are in operation in Petri dish studies, except in highly specialized experiments.
So let's consider what additional hurdles a drug, herbal ingredient, or vitamin must overcome to be of any use to the human body.
The first barrier to drugs taken by mouth is the highly acidic environment of the stomach. Next, are the epithelial cells lining the stomach and, more importantly, the twenty-some-odd feet of the small intestine. Some drugs are poorly absorbed from the intestine into the bloodstream and some portion, or all of it, simply passes through the intestines unabsorbed and out with the feces. For drugs that have characteristics that allow them to be absorbed, blood from the intestines then must pass through the liver (via the hepatic portal vein) before being distributed to the rest of the body.
The liver is a glorious organ. The liver has a tremendous capacity for metabolizing drugs and chemicals to inactive substances, as one might expect for an organ that has evolved over millions of years being exposed to chemicals (and toxins) normally encountered in our omnivorous diet. I often refer to the liver as "the catalytic converter of the body." In fact, many drugs and toxic substances are so effectively inactivated by liver metabolism that we call this inactivation the "first-pass effect" - to indicate the percentage of drug metabolized during its first past through the liver after being absorbed in the intestine. The enzymes of the liver even have the capacity to metabolize chemicals that have not yet even been invented! (I should also note to the more technical audience that the intestinal epithelium itself contains some of the same drug metabolizing enzymes found in the liver, such that metabolism can start even earlier).
For a drug to have its desired effect, it must also be distributed to its site of action, rapidly and in high enough concentrations to have an effect. All this occurs while our blood is being very rapidly filtered by our kidneys. Our kidneys are amazing filtration systems, clearing our blood of water-soluble metabolites with a capacity of 180 to 400 liters per day - compared with the 4 or so liters of liquid in our 5.5 liters of blood, that means that the kidneys filter our blood completely almost 100 times a day.
Some drugs that do make it into the blood in high concentrations may not get to certain sites, or compartments. For example, the brain is well-protected from many types of drugs by cell junctions in brain blood vessels that create what is known as "the blood-brain barrier." Drugs that work best in the brain are usually more fat-soluble than most: drugs like anesthetics, opioid pain killers, antidepressants, and drugs for Parkinson's disease - since they can bypass these cellular junctions and get across the cells. Here's a fun fact: the non-sedating antihistamines like Claritin don't cross the blood-brain-barrier as well as sedating antihistamines like Benadryl. If you could somehow put Claritin directly into the brain, it would be just as sedating as Benadryl.
Once drugs are in the bloodstream, they are cleared from the blood at a certain rate, some quickly, some slowly, depending on the collective contribution of all the processes we have described. Some drugs get tagged, or conjugated, with a sugar-molecule, and that permits the kidney to actively secrete it into the urine, leading to its elimination. But when those sugar-conjugated drugs (called "glucuronide conjugates") find their way back into the intestine (via secretion in the bile), enzymes in the intestine can clip off the sugar molecule, releasing free and active drug that has a chance to get reabsorbed and do its thing again. Some drugs are broken down by enzymes in the blood. On the other hand, a little known fact is that some drugs may even be made more active by virtue of chemical metabolism, a process observed with the pain-killer and cough suppressant, codeine, whose action is due mostly to its conversion to the active metabolite, morphine.
All of these competing effects go into the decision of how much of a drug dose is given and how often that dose must be taken each day.
So, without trying to be too confusing, the message here is that there is a lot more to consider when reading a report on "scientific research" about an herb or supplement, and then deciding whether it is useful for treating cancer.
In the next installment of this series, we will look closely at specific studies of curcumin and the studies published by a well-known curcumin manufacturer to help make some sense out of claims made for the anticancer activity of this natural product.
I remember a similar issue with chondroitin supplementation (which I still see on the shelves at the supermarket). You could take the stuff in huge doses but it didn't actually create a blood-level because you simply digest the stuff without it ever entering the bloodstream.
Good post though, it's good to give people the background on this, as most people seem to think whatever they swallow goes right into their bodies and "they are what they eat." But isn't the deeper problem not just an absence of education about pharmacokinetics but this idea that "natural" is somehow better than "unnatural" and that wishful thinking is more important to alties than actual data? My view of the crap in the supplement aisle is just that it's the stuff that either has failed to show benefit in every clinical trial so by law they can't actually attribute any real benefit on the bottle, or that they're just too lazy or cheap to adequately test these substances, so why would I want to take any of it? If they did any good they'd be legally able to write the indications on the bottle rather than write BS like "promotes well-being."
mostly from studies of cancer cells grown in Petri dishes, on how curcumin can kill cancer cells
I bet soy sauce and ketchup could kill cancer cells in petri dishes, too.
This is analogous to the thimerosal-causes-autism lobby's claim that because thimerosal kills neurons in vitro, it must cause autism in vivo. It would be great if you could write about that sometime.
Their claim is maybe a little more credible because there's no digestive process involved, and they make much of an infant's undeveloped blood-brain barrier, but I have a feeling it is just as much hokum as the rest of their junk science.
Not soy sauce or ketchup. It's French's Mustard you want. It contains turmeric, which gives this condiment its bright yellow color. Just open your mouth and pour it in! You'll be fighting cancer and/or HIV/AIDS in no time.
I think one appeal of curcumin is the bright yellow color of the substance. Something so strongly colored has to be good for one disease or another (I'm trying to think like a health-conscience altie, though I'm probably doing a poor imitation of one).
One shortcoming of Abel's perspective is that it fails to acknowledge the scientific foundation of why curcumin has potential as an anti-cancer agent. Evidence of this potential has been widely published in the peer reviewed literature. Of course additional research is required to better understand, confirm, and realize that potential. Abel's commentary would be better applied toward describing where the knowledge gaps exist and the pathway for future research.
I had no sense that Abel was denying the potential but that rather that he was addressing those who see the research and misuse it for supplement marketting purposes, preying on vulnerable patients suggesting that if they eat tumeric or take a supplement, it will help their disease. In other words, marketing it before it is figured out if its potential can be harnessed in a utile way.
As a cancer patient, I have seen numerous supplement companies and patients advocating curcumin supplements, or ridiculous things like advising patients to sprinkle tumeric on their breakfasts, claiming that it will help their disease. I think Abel's post was directed at patients who read these kinds of inappropriate claims.
I hope you will consider sharing these basic principles in print form and providing it to the media.
It seems that many in the supplement industry have been promoting supplements to laypersons unchallenged - based on this kind of preliminary scientific evidence.
Here's a few commercials copied from LEF.org, a group that sells vitamins and specialize in what might be called pseudoscience as a sales technique. Note that they do not mention the kind of study in any of the citations:
"Resveratrol sensitizes chemotherapy-resistant lymphoma cells to treatment with paclitaxel-based chemotherapy (Jazirehi AR et al 2004)."
"Green tea, which contains epigallocatechin gallate (EGCG), triggers lymphoma cell death (Bertolini F et al 2000; Katsuno Y et al 2001)."
"Genistein, found in soy extracts, induces cell death in lymphoma cells (Baxa DM et al 2003; Buckley AR et al 1993). It increases the effectiveness of chemotherapy for lymphoma by making cells more susceptible to agents that cause lymphoma cell death (Mohammad RM et al 2003)."
It should also be noted that cancer cells, like fish out of water, are changed when removed from the host environment - that is, they no longer behave as fish.
Finally, I ask that people making comments on this subject avoid refering to lay persons who are persuaded by info-ads like this as "alties." There are many intelligent people who are understandably seduced by these ads, because they do not yet have the background provided here. It's particularly easy to be seduced by easy solutions when diagnosed with an often fatal disease.
Karl Schwartz raises enough good questions for me to write this blog for the rest of the year, and then some. But let me seize upon his last point while we are in the middle of this discussion:
"Finally, I ask that people making comments on this subject avoid refering to lay persons who are persuaded by info-ads like this as "alties." There are many intelligent people who are understandably seduced by these ads, because they do not yet have the background provided here. It's particularly easy to be seduced by easy solutions when diagnosed with an often fatal disease."
Indeed, most cherry-picking, misrepresentation, and otherwise stretching of the peer-reviewed scientific literature by supplement manufacturers and advocates seems intended specifically to target the educated cancer patient and their family by throwing around terms like, NF-kappaB, apoptosis, synergy, and histone deacetylases.
By appearing on the surface to be based in science, I fear that some of these marketing materials can be quite persuasive to even a highly-educated and critical patient reaching for any hope they can.
Hence, I would echo Karl's call for focus on the information we are discussing here, and not the uncritical zealotry. I doubt that anything we provide here will change the mind of the most fervent and uncritical supporters of alternative medicine.
Instead, the goal of this series is to provide complete and unbiased factual information to the educated and critical patients and family members who are looking for answers in their journey through cancer.
Hi Abel-- this question was asked on a lymphoma support board-- perhaps you might address it in a comment or in the next thread. Anjou
I will post your questioni on Abel's blog-- perhaps he will answer it
> I have read that bioperine is essential for the human update and delivery to teh blood stream for curcumin. Science or not?
> Also, I have read that mixing curcumin with a fatty food like cottage cheese, it will bind with the fats which are uptaken into your lymph system directly and not through the liver like when take in capsule form with bioperine. Science or not?
> I do both the cottage cheese in the morning and the bioperine in the morning, this along with lots of other stuff including healthy, whole foods, exercise and plenty of sleep.
> Curious if my info is correct?
Here are some thoughts on the subject That I and another poster has in another forum.
One thought I have had about cucurmin.... It changes the color of the stool when you take several caps a day. I wonder if some of its healing effects is not directly from the bloodstream but is held within its ability to stay in the stool and have direct physical contact with the lining of the intestines and colon. I also wonder if it modifies in some way the components of stool making it less inflammatory to the lining of the colon. Just some thoughts...
I was also thinking about the study they have done on cucurmin regarding how long it remains in the bloodstream, indicating that some cucurmin products that test out to last longer in the bloodstream might be more effective...
Perhaps it does not need to be in the bloodstream long. Perhaps its action, once in the bloodstream and in contact with the cell matrix only needs to be a short time. Perhaps it delivers what it needs in a short time and does not need continual contact with the cell to have an effect. This paradigm within conventional medicine of need for constant emersement in a strong dose of medicine could be wrong. God knows its wrong with homeopathy. I've also found it wrong for a number of herbs that effect a change with small dosage in short time spans.
Perhaps it does not need to be in the bloodstream at all. Perhaps it only needs to get into the lymphatic system. The intestinal tract is loaded with contact with the lymphatic system. This would just be a reflection of the long long neglect and misunderstanding by the scientific medical community at large of the lymphatic system and its role in immunity and detoxification of the body.
Perhaps the more of it that goes into the bloodstream and the longer it stays there the less effective it is?
Good thought, and remember, Dr Steve Martin at Grouppe Kurosawa recommends dissolving the curcumin in coconut oil so that it will be transported via lauric acid in the lymphatic system, not the blood system. I use the coconut oil method and I can vouch for it's dramatic lessening of joint and muscle pain.
Arrowind, most of the points you raise run counter to what is known so far about curcumin. No curcumin preparation published to date reaches the lymphatics or the bloodstream at concentrations necessary for anticancer effects. There may be benefit in the colon, however, simply because the compound makes it to the large intestine for the very reason that it is poorly absorbed, even with use of bioperine/piperine.
The idea by the person at Grouppe Kurosawa is not based in fact. Coconut oil may increase blood absorption of curcumin slightly but there is no data to support it helps absorption into the lymphatics. Unless lauric acid is chemically conjugated to curcumin, lauric acid will go primarily into the lymphatics and a small amount of curcumin will go into the bloodstream with the rest remaining in the intestines. If the coconut oil method is really working for you personally, it is not likely due to absorption into the lymphatics.
Arrowind, Regarding homeopathy, a systematic review of homeopathy-based trials that might be of interest:
"RESULTS: A total of 326 articles were identified, 91 of which were retrieved for detailed evaluation.
Sixteen trials that assessed 9 different conditions were included in the study.
With the exception of attention-deficit/hyperactivity disorder and acute childhood diarrhea (each tested in 3 trials), no condition was assessed in more than 2 double-blind randomized clinical trials.
The evidence for attention-deficit/hyperactivity disorder and acute childhood diarrhea is mixed, showing both positive* and negative results for their respective main outcome measures.
For adenoid vegetation, asthma, and upper respiratory tract infection each, 2 trials are available that suggest no difference compared with placebo. For 4 conditions, only single trials are available.
CONCLUSION: The evidence from rigorous clinical trials of any type of therapeutic or preventive intervention testing homeopathy for childhood and adolescence ailments is not convincing enough for recommendations in any condition."
Homeopathy for childhood and adolescence ailments: systematic review of randomized clinical trials.Altunc U, Pittler MH, Ernst E. **Complementary Medicine, Peninsula Medical School, University of Exeter, Exeter, United Kingdom.
* Positive findings in any single study can be the result of chance. Similarly, the pattern of shotgun pellets on a wall will cluster in spots, but it does not mean that characteristics of the wall caused the pellets to combine in those areas. So, placebo/homeopathy (no treatment) sometimes can appear to have a treatment affect. In olden times, perhaps, no treatment and time (homepathy) was often better for the patient than pseudomedicine (potions etc), which had only toxicities and no treatment effects.
** The conclusions of the reviewing group should relieve suspicion because they come from of a group involved in Complementary medicine.
Karl, thanks for adding this review of homeopathy to the comment thread. I neglected to address that point in Arrow's diatribe.
Indeed, Ernst is chair of a well-regarded complementary and alternative medicine program in England and he and Pittler are widely-regarded as being very even-handed in assessing the veracity of the wide spectrum of alternative approaches.
Just an addendum to my comment about lauric acid as brought to my attention by scorpiotiger quoting Skepzilla, a PhD biochemist who provides consultation to the healthiertalk.com forums. Because lauric acid is a C-12 fatty acid, it does not behave completely like longer chain fatty acids. Work from the fifties published in JBC suggests that 15-55% of lauric acid is absorbed into the lymphatics with the remainder absorbed into the hepatic portal circulation. So, while lauric acid may enhance curcumin absorption somewhat, the compound would still have to get through the liver before going to the systemic circulation. The phenolic hydroxyls on curcumin are great substrates for UDP-glucuronyltransferase (and sulfotransferase), with about 50% existing in the blood as the inactive glucuronide at 1 hour after ingestion of 3.6 grams (trial here: parent, 11 nM; sulfate, 9 nM; glucuronide 16 nM), so this is why so little curcumin makes it into the bloodstream. It is instead conjugated to glucuronic acid, then secreted into the bile and off to the fecal and urinary excretion routes.
i am not a rocket sicentist. very poor and with stage 2 breast cancer 9 years ago. no money for chemo. after surgery, drank curcumin extract 3 times a day. i am still taking it. if it did not help my cancer i dopn't know what did. my last tests showed no sign of the disease.
"The phenolic hydroxyls on curcumin are great substrates
for UDP-glucuronyltransferase (and sulfotransferase),
with about 50% existing in the blood as the inactive
glucuronide at 1 hour after ingestion of 3.6 grams"
........... inactive WHERE, would be the question.
Many tumors (including possibly that of suz, post #15,
breast cancer?) are rich in glucuronidases, and indeed
glucuronide conjugates with tumor-toxic aglycones have
been the subject of much investigation (and for all I know,
by now, are actually used in therapy). Curcuminoid
glycoconjugates, formed endogenously, might be (MIGHT
be) really nifty anti-tumor prodrugs -- manufactured,
strangely enough, in one's own body. (And the issue of
increasing the levels of "inactive" curcuminoids, or of
bypassing the conjugation mechanisms, might be a red
herring in these instances.)
Notes added in proof:
Curr Med Chem Anticancer Agents. 2003 Mar;3(2):139-50.
Glucuronides in anti-cancer therapy.
Chen X, Wu B, Wang PG.
Department of Chemistry, Wayne State University, Detroit, MI 48202, USA.
Glucuronide prodrugs have shown promising efficacy in anti-cancer therapy due to their increased specificity and reduced systemic toxicity. The prodrugs can be used in prodrug monotherapy (PMT), which is based on elevated tumor beta-glucuronidase activity. beta-Glucuronidase activates the low-toxic prodrugs into highly cytotoxic agents specifically in the tumor site. The specificity of the prodrugs can be further improved by combined use with monoclonal antibodies against tumor-specific antigens, namely antibody-directed enzyme prodrug therapy (ADEPT); and the potency of the prodrugs can be greatly enhanced with the incorporation of an appropriate radionuclide in the combined chemo- and radio-therapy of cancer (CCRTC) strategy. The prodrugs can also be utilized to modify liposomes for efficient delivery of anti-cancer drugs.
Cancer Metastasis Rev. 1985;4(1):81-101.
Glycosidases in cancer and invasion.
Bernacki RJ, Niedbala MJ, Korytnyk W.
Glycosidases have been demonstrated to be elevated in the interstitial fluid of tumors, sera of animals and patients with tumors, and in some tumor tissue as compared to normal adjacent tissue. Elevations of serum beta-N-acetylglucosaminidase and beta-glucuronidase most commonly have been found to occur and these enzymes have been shown to be secreted into the extracellular medium by many different tumor cell types in vitro. The mechanism of cellular release of these hydrolytic enzymes probably involves tumor lysosomal exocytosis. Increased tumor glycosidase levels may promote increased tumor cell shedding from primary tumors, local invasion and perhaps be responsible directly, or indirectly for structural changes in tumor cell surface glycoconjugates. These cell surface changes could facilitate tumor cell thrombus formation, secondary site implantation and attachment in the microcirculation to endothelial cells and/or subendothelial basement membrane components. Other studies have demonstrated a correlation between metastatic cell potential and increased endoglycosidase and polysaccharide lyase activity. Generally, metastatic tumor cell variants have been found to be more invasive and capable of degrading proteoglycan basement membrane components, in part due to these increased levels of degradative enzymes. Hence, it is of considerable interest to develop inhibitors against these enzymes. Initial studies with glucuronidase inhibitors in the therapy of bladder tumors have been promising and with the advent of better agents and the use of appropriate in vitro metastatic models it may be possible to design and develop agents which interfere in various metastatic events and limit tumor progression.
And, even more interesting: elevated glucuronidase
may be a general phenomenon in inflammations and
other tissue damage situations, apart from cancer.
Wow! Could endogenously-produced curcuminoid
glycoconjugates be as though tailor-made for these
conditions, targetting the precise points of cell
damage (perhaps even in proportion to the degree
Ann Univ Mariae Curie Sklodowska Med. 2003;58(2):386-9.
Beta-glucuronidase in physiology and disease.
BasiÅska A, FloriaÅczyk B.
Department of Biochemistry and Molecular Biology, Medical University of Lublin.
beta-glucoronidase (EC 18.104.22.168) is a lysosomal enzyme catylysing the decomposition of beta-D-glucoronides--compounds arising as a result of the combination of beta-D-glucoronic acid and a number of compounds both exo- and endogenous, containing hydroxylic, carboxylic, amine, imine or thiol groups. The most common test evaluating the activity of the enzyme is that using phenolphtalein glucoronide as a biosynthetic substrate. The freed aglycons are colorimetrically assayed. The activity of beta-glucoronidase increases in many pathological conditions: liver infammations, cirrhosis of the liver, inflammations of other organs, cholestatic jaundice, tuberculosis, sarcoidosis and also in neoplasms. Many authors point to beta-glucoronidase as a sensitive indicator signalling cell damage.