The healing spice

Turmeric raises hope for the treatment of Alzheimer's, cancer and other diseases 

The history of the search for new medicines is littered with stories of rummaging through ancient lists of folk remedies and gathering plants while wandering in the woods. Many accepted medicinal compounds have been discovered in trees, shrubs, molluscs and even soil. The origin of aspirin in the bark of the willow tree, cholesterol-lowering statins from mold, and artemisinin against malaria was discovered in a bush whose use is accepted in traditional Chinese medicine. However, the "Shaman Pharmaceutical Compounds" company, which raised 90 million dollars to search for folk knowledge for new medicinal sources, and was widely publicized, had to lower its intentions until it finally sold its products as nothing more than food supplements before closing its doors.

Now the trend may reverse again. Some natural compounds - such as resveratrol extracted from red wine and omega-3 fatty acids from fish oil - have recently gained attention after initial research suggested that they could be used to cure or prevent diseases, inexpensively and without many side effects. Turmeric, a yellow-orange powder extracted from the Asian turmeric plant curcuma longa, has now joined the list of these compounds. If so, turmeric is no longer just another ingredient of curry or tandoori, used since ancient times to season food and prevent spoilage.

A chapter from a book about to be published, for example, describes the biologically active ingredients found in the spice. According to the book, the substance curcumin and similar compounds called curcuminoids act as antioxidants, anti-inflammatories, antivirals, bactericides and fungi and have the potential to act against cancer, diabetes, rheumatism, Alzheimer's disease and other chronic diseases. In 2005, curcumin was mentioned in about 300 scientific and technical articles appearing in the US National Library of Medicine database, PubMed, compared to about 100 mentions just five years earlier.

Scientists, who sometimes jokingly call themselves curcuminologists, are drawn to this compound for its multiple beneficial effects on the body and its apparently low toxicity. They are now wondering how the spice and its derivatives can be used not only for healing but also as a cheap preventive medicine against the most dreaded diseases. The spice also has some enticing therapeutic properties. Since it disrupts so many biological pathways, it may be useful in anti-cancer therapy: malignant cells will have difficulty developing resistance and will have to undergo many mutations to avoid its multifold attack.

However, is the compound ready for widespread use? Some studies suggest caution. Among the 1,700 references to curcumin in PubMed are several studies showing that a compound that affects so many biological pathways can sometimes hit the wrong switch and actually encourage disease.

Long medical history

Turmeric, called "Haldi" in Hindi, "Jiang Huang" in Chinese, "Manjal" in Tamil (and simply "Iksa" when splashed on a white sports shirt at a picnic and creates a yellow stain) has a medical history that stretches back 5,000 years. So it was used as a main remedy for scabbing wounds, for blood purification and for the treatment of stomach ailments in the Indian Ayurvedic system of medicine.

The first report in PubMed on the biological activity of curcumin is from 1970, when a group of Indian researchers reported the effects of the compound on cholesterol levels in rats. The pace of research increased in the 90s. One of the leading researchers was Bharat Agrawal, a scientist who previously worked at Genentech and then turned to turmeric. He took a different approach in his search for cancer treatments. His work led him indirectly to curcumin.

In the 80s, Agrawal and his team were the first to isolate two important molecules of the immune system that cause the death of tumors and were identified as having the potential to fight cancer: TNFα and TNFβ. These two molecules are able to destroy cancer cells if they are applied to targeted tissues, but when they are carried in the bloodstream they acquire other properties and actually encourage the growth of tumors. Both TNF compounds activate an important protein, the nuclear factor kappa B (NF kappa B), which in turn activates a whole army of genes involved in inflammatory processes and cell division.

This connection between inflammatory processes and the uncontrolled division of cancer cells prompted Agrawal to return to his roots. In 1989, he moved to the MD Anderson Cancer Center at the University of Texas and began searching for compounds that could reduce inflammation and have an anti-cancer effect. He remembered from his youth in India that turmeric is considered an anti-inflammatory in Ayurvedic medicine, so he decided to try the spice. "We took some turmeric from the kitchen and threw it on some cells," he recalled. "We couldn't believe it. The substance completely blocked the action of TNF and NF kappa B.

Agrawal went on to publish his research showing that blocking the NF kappa B pathway using curcumin inhibits the replication and proliferation of various types of cancer cells. This study served as a springboard for early clinical trials at the M. D. Anderson Center in which curcumin was used as an adjunctive drug in the treatment of pancreatic cancer and multiple myeloma. Additional trials are starting now and trials are already taking place in various places to prevent, among other things, colon cancer and Alzheimer's disease. Preliminary studies in cells or animals have shown that curcumin may be active against a variety of inflammatory diseases, including pancreatitis, rheumatism, intestinal and stomach inflammations, allergy and fever. Also, the experiments with curcumin show promising results in the field of diabetes, autoimmune diseases and cardiovascular diseases.

Until now, the large clinical trials necessary to prove the effectiveness against cancer and other diseases have not been conducted. However, Agrawal became the aggressive knight of the spice that Vasco da Gama brought to Europe from his travels in the East. Agrawal wrote a chapter in a new textbook, which he also co-edited, called "Curcumin: The Pure Indian Gold."

The M.D. Anderson Institute, which is a world-renowned cancer research institute, has begun to encourage the use of turmeric more than one would expect from a therapeutic approach that has not gone through the full rigors of clinical trials. The questions and answers section on the institute's website recommends buying turmeric from a particular wholesale supplier, who paid Agrawal a speaking fee. This company even issued a press release stating that its product is the "chosen ingredient" of the M. D. Anderson Institute.

The question and answer section also suggests that cancer patients gradually increase the daily dose of the spice up to 8 grams, 40 times the amount consumed in the average Indian menu. The accepted dosage of most pharmaceutical substances is, however, in the range of milligrams. In one of the paragraphs, the site even claimed that "after eight weeks you can expect a real benefit." When Agrawal was asked if he was not concerned about side effects due to the dose of eight grams per day, he replied that in small clinical trials at other institutes the dose reached up to 12 grams and that the patients would inform him of any disturbing effect that the dose recommended by M. D. Anderson had . The researcher, who himself swallows one curcumin pill daily, rejects the typical caution taken by researchers before conducting large-scale, well-controlled clinical trials. "People take a lot of other supplements and I don't think you need anything else if you're taking turmeric," Agrawal says.

Does curcumin promote cancer?

M. D. Anderson's question section and a stream of press releases from various institutes about the wonders of turmeric ignore a small collection of professional articles that point to a dark side: the possibility that the spice may actually sometimes encourage the survival of cancer cells. In 2004, Yosef Shaul from the department of molecular genetics at the Weizmann Institute of Science in Rehovot studied the enzyme 1NQO which regulates the amount of the known protein p53. When p53 levels rise in cells, the protein engages in a defensive maneuver that causes damaged or cancerous cells to stop dividing or even commit suicide.

Shaul and his colleagues found that an anticoagulant, dicoumarol, and similar compounds blocked the 1NQO enzyme that prevented p53 from doing its job. The researchers wondered what would happen if they exposed p53 in normal cells and myeloid leukemia cancer cells to antioxidants like curcumin and resveratrol. To their surprise, they found that curcumin, which inhibited this enzyme, prevented p53 from sending the abnormal cells to the gallows. This finding was published in 2005 in the prestigious scientific journal "Records of the National Academy of Sciences of the USA". Agrawal responded to these studies by pointing to work showing the opposite, that curcumin actually activates p53.

Clinical researchers will now have to determine whether Saul's work in cell cultures is related to what happens when a person eats the compound. The concentrations of curcumin in the cell cultures of the researchers at the Weizmann Institute were between 10 and 60 micromolar, and are approximately equal to the levels reached in some of the test-tube experiments conducted at M. D. Anderson. However, Shaul says that since curcumin hardly passes from the intestine into the bloodstream and it also breaks down quickly in the body, the concentration in the blood plasma of a patient who consumes eight grams will not ultimately exceed 2.0 micromolar. Although the concentration can be higher in the stomach, intestines and liver. High levels are also possible if researchers develop means to increase the concentration of curcumin in the bloodstream.

M. D. Anderson's question section can give the impression of certainty by recommending a dose of eight grams. But the low concentration of curcumin in the blood and the resulting need to increase the amount of curcumin consumed so that the substance actually fights diseases pose a challenge that will continue to haunt curcumin researchers. Researchers cite animal studies that suggest the multifaceted benefits of curcumin. In all these studies, the amount of curcumin consumed in animals is equivalent to the amount less than eight grams in humans and the concentration in the blood is usually in the nanomolar range. "We don't know how to explain how such low concentrations of curcumin benefited the experimental animals," says Shaul.

The most important thing when taking a new drug is the dosage. Any medicinal substance, including aspirin, is toxic in high concentration. The optimal dose to achieve desired levels of a new pharmaceutical substance in the blood plasma is determined after repeated cycles of preclinical experiments in tissue cultures and mice. So far the pharmaceutical companies are not fighting each other to be the first to conduct such trials with curcumin. They prefer targeted treatments: damage to a certain receptor, for example, may cure a disease and reduce the side effects, while a drug with a wide range of activities may, in theory, increase the chance of an unwanted side effect. Another reason is the vexing issue of property rights to folk remedies.

Turmeric is the cover model of one of the most famous legal disputes of "biological robbery". In this battle, a research organization supported by the Indian government is fighting against a patent registered by the University of Mississippi in 1995 for the use of the spice in wound healing. The US Patent Office revoked the patent rights after the Indian Council of Scientific and Industrial Research questioned whether one of the criteria for patenting - that the invention be new - had been met. The council justified its opposition with the help of an article in an Indian journal from 1953 that dealt with the spice and with the help of a quote from an ancient Sanskrit text that dealt with the medicinal properties of turmeric.

Following this, the ministry registered patents for certain uses of curcumin after it was isolated from the spice. Following the cancellation of the patent, the pharmaceutical companies will never be able to get approval for a patent for a product with a wide range of activity, which would protect them from competitors who produce medicines based on the spice itself. Some small companies are still trying to exploit the promise inherent in the substance by changing its chemical structure to create a new, more active compound that will allow them intellectual property.

San Diego-based AndroScience is preparing to enter the first phase of clinical trials in 2007 to test a possible anti-acne drug based on curcumin-derived compounds discovered in a joint study with the University of North Carolina at Chapel Hill. The "Cary Preservative Materials" company from the Triangle Research Park in North Carolina is trying in a similar way to raise capital that will allow it to start clinical trials with curcumin derivatives developed at Emory University. But in this era of targeted drugs, venture capitalists, fearing side effects, are hesitant to support new drugs that work in a wide variety of pathways. Agrawal was a co-founder of Carey Pharmaceuticals and holds patents in the field. And yet he believes that chemists will find it difficult to improve nature. Changing the curcumin may only produce unwanted side effects for patients, he says.

If the multiple obstacles in the way of development are overcome and it is possible to ensure the safety of use, curcumin will be able to provide a cheap alternative to conventional drugs. Greg Cole from the University of California at Los Angeles (UCLA) and the US Army Veterans Administration is building on positive results in rodents and is organizing a clinical trial in humans to test if curcumin can prevent the accumulation of amyloid deposits that burden the brains of those affected by Alzheimer's disease. If the experiment is successful, Cole and his research partner (who is also his wife), Sally Protacchi, plan to offer products that can be added to cooking oil (to encourage bioavailability) and eaten as part of a meal to inhibit the accumulation of platelets - a recipe that rich and poor alike will be able to afford. for themselves in the aging world.
And more on the subject

Inhibition of NAD(P)H:Quinone Oxidoreductase 1 Activity and Induction of p53 Degradation by the Natural Phenolic Compound Curcumin. Peter Tsvetkov et al. in Proceedings of the National Academy of Sciences USA, Vol. 102, pages 5535-5540; April 12, 2005.
Multiple Biological Activities of Curcumin: A Short Review. Radha K. Maheshwari et al. in Life Sciences, Vol. 78, pages 2081–2087; 2006.
The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease. Edited by Bharat B. Aggarwal, Young Joon Surh and Shishir Shishodia. Springer (in press).