Introduction
Curcumin, commonly called diferuloyl methane, is a hydrophobic polyphenol derived from rhizome (Turmeric) of the herb Curcuma longa.
Turmeric is a member of the Curcuma botanical group, which is part of the ginger family of herbs, the Zingiberaceae. The root and rhizome stem of the Curcuma longa plant is crushed and powdered into ground Tumeric. Ground Tumeric is used worldwide as principal curry powder's ingredient and contains approximately 2% of Curcumin, that is one of the most powerful phytochemicals whit biological effects including antioxidant, anti-inflammatory, inhibition of angiogenesis and anti-tumor activity.
Curcumin molecular formula is C 21 H 20 O 6
Plants provide health benefits
Certain plants manufacture chemicals that repel predators, parasites and diseases. Like most of these pharmacologically-active metabolites, Curcumin is involved in self-defense. Plants with higher levels of organic compounds that deter attackers become more successful, because of their advanced protection. In nature’s never-ending interaction between predator and prey, insects evolve the ability to digest plant toxins, while plants evolve stronger chemicals to deter their enemies. This is a very important field of ecological research, scientists have discovered that these phytochemicals are useful not only for plant’s protection against insects, but also provide human health benefits. Curcumin’s structure is very similar to other natural polyphenolics produced by plants in response to infectious attack.
Effects against cancer
Extensive research over the last half century has revealed important functions of Curcumin. In vitro and in vivo research has shown various activities, such as anti-inflammatory, cytokines release, antioxidant, immunomodulatory, enhancing of the apoptotic process, and anti-angiogenic properties. Curcumin has also been shown to be a mediator of chemo-resistance and radio-resistance. The anti-cancer effect has been seen in a few clinical trials, mainly as a native chemoprevention agent in colon and pancreatic cancer, cervical neoplasia and Barrets metaplasia. Curcumin's potent anti-proliferative activity interacting with several intracellular signal transduction pathways may potentiate the anti-tumor effect of gemcitabine, a nucleoside analog used as chemotherapy. The anticancer potential of curcumin stems from its ability to suppress proliferation of a wide variety of tumor cells.
Curcumin down-regulates transcription factors NF-kappa B and AP-1 and regulates trascription of Egr-1; down-regulate the expression of COX2, Lox (lipooxygenase), NOS, MMP-9, TNF, chemokines, cell surface adhesion molecules and cyclin D1.
It also down-regulate growth factor receptors such as EGF, HER2, FGF, VEGF, PDGF and insulin growth factor (IGF)-1, it results in suppression of tumor growth.
Curcumin also inhibit the activity of c-Jun N-terminal kinase, protein tyrosine kinases and protein serine/threonine kinases, signal transducers for cellular proliferation.
Curcumin also causes DNA damage and endoplasmic reticulum (ER) stress and mitochondrial-dependent-induced apoptosis through the activation of caspase-3, a cysteine protease that plays essential roles in apoptosis, necrosis, and inflammation.
Studies showed that curcumin works on cell surface receptors, in particular it inhibites the expression of Bcl-2, Bcl-xL, survivin, and XIAP, and induces the expressions Bax, Bak, PUMA, Bim, and Noxa and death receptors with induction of apoptosis.
It has been also reported that curcumin-induced apoptosis is mediated through the impairment of ubiquitin proteasome system (UPS), the direct inhibition of proteasome activity also causes an increase in half-life of IκBα that ultimately leads to the down-regulation of NF-κB activation, thus activating the apoptotic pathway.
Finally it induces tumor suppressors, such as p53/p21 pathway. The transcription factor p53 has been reported to play a very important role in apoptosis. As a tumor suppressor, p53 is responsible for protecting cells from tumorigenic alterations. The studies showed that curcumin selectively increases p53 expression at G2 phase of carcinoma cells and releases cytochrome c from mitochondria, which is an essential requirement for apoptosis.
Scientists have identified more than 40 biomolecules that are involved in cell death induced by curcumin. Curcumin and Cancer Cells: How Many Ways Can Curry Kill Tumor Cells Selectively? 2010
In this picture targets up-regulated by curcumin are in a blue box, those down-regulated are in a yellow box, and those unaffected are in a white box.
NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls the transcription of DNA. It plays a key role in regulating the immune response to infection. Incorrect regulation of NF-kappaB has been linked to cancer, in fact active NF-kappaB turns on the expression of genes that keep the cell proliferating and protect the cell from conditions that would otherwise cause it to die via apoptosis.
In this picture you can see how Curcumin works aganist NF-kappa B with consequent inhibition of inflammation and proliferation.
AP-1 (the activator protein 1) is a transcription factor, that regulates gene expression in response to a variety of stimuli, including cytokines, growth factors, stress, and bacterial and viral infections. AP-1 in turn controls a number of cellular processes including differentiation, proliferation, and apoptosis. An excess of AP-1 activity is typical in cell’s proliferation.
Egr-1 is a protein that in humans is encoded by the EGR1 gene. It is a nuclear protein and functions as a transcriptional regulator. The products of target genes it activates are required for differentiation and mitogenesis. Studies suggest this is a tumor suppressor gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.
COX2 is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane, important during inflammation. It is demonstrated the expression of COX2 is higher in many neoplastic diseases. In fact one of its products, prostaglandin H2, is converted by enzyme PTGES2 into prostaglandin E2, that may trigger progression of cancer.
MMP-9 (matrix metallopeptidase 9) is an enzyme involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling. In disease processes it can be very dangerous because allows migration of neoplastic cells.
TNF (tumor necrosis factor) is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction. It is produced chiefly by activated macrophages , although it can be produced by many other cell types as CD4+ lymphocytes, NK cells and neurons. The primary role of TNF is in the regulation of immune cells. TNF, being an endogenous pyrogen, is able to induce fever, apoptotic cell death, sepsis, cachexia, inflammation and to inhibit tumorigenesis and viral replication. Dysregulation of TNF production has been implicated in a variety of human diseases, in particular excessive production of TNF is associated with cancer.
A simple immage that summarizes Curcumin effects.
Bioavailability of Curcumin
Curcumin can be taken at high doses, but unfortunately exhibits poor bioavailability, with difficults caused by poor absorption, rapid metabolism, and rapid systemic elimination. To improve the bioavailability of curcumin, numerous approaches have been undertaken:
- use of adjuvant like piperine that interferes with hepatic glucuronidation, a way to eliminate drugs;
- use of liposomal curcumin;
- use of curcumin nanoparticles;
- use of curcumin phospholipid complex;
- use of structural analogues of curcumin, that has been reported to have a rapid absorption with a peak plasma half-life.
Bioavailability of Curcumin: Problems and Promises. 2007
Some clinical trials
Human studies of curcumin in cancer prevention and treatment are in the very early stages.
In scientific studies, curcumin does not absorb well from the intestine, so that big doses must be taken for even small amounts to get into the blood circulation. Large doses of curcumin would need to be taken in order to study any effects it might have in the body.
One study of 15 patients with colorectal cancer was done to find out how much curcumin they could safely take, and whether they could take a dose large enough to even be detected in the blood. The patients were able to take 3.6 grams of curcumin without noting ill effects. At this high dose, some curcumin and its products were found in the blood. Lower doses may be enough to directly affect the stomach and intestine. Even though it does not absorb well into the bloodstream, curcumin absorbs into the colon lining and into cancerous tissues in the colon. Small studies have found most people in study groups were able to take up to 10 grams of curcumin per day for a period of a few weeks without noticing problems other than the large volume of pills. There are also studies going on now that try different ways to formulate curcumin so that it absorbs well enough to be tested in humans.
A 2008 study showed effects of Curcumin in Patients with Advanced Pancreatic Cancer. These patients received 8 g curcumin by mouth daily until disease progression, with restaging every 2 months. Twenty-five patients were enrolled, with 21 evaluable for response. Circulating curcumin was detectable as drug in glucuronide and sulfate conjugate forms, albeit at low steady-state levels, suggesting poor oral bioavailability. Two patients showed clinical biological activity. One had ongoing stable disease for 18 months; interestingly, one additional patient had a brief, but marked, tumor regression accompanied by significant increases in serum cytokine levels. Scientists found that Curcumin down-regulates expression of trascriptional factors that increase cellular proliferation. This brought to conclusions that oral curcumin is well tolerated and has biological activity in some patients with pancreatic cancer. Phase II Trial of Curcumin in Patients with Advanced Pancreatic Cancer. 2008
On Wednesday 28 October 2009 was published an article in the British Journal of Cancer in which is said that molecules found in curry ingredients have been shown to kill oesophageal cancer cells in the laboratory. Scientists based at the Cork Cancer Research Centre treated oesophageal cancer cells with curcumin. They found that curcumin started to kill cancer cells within 24 hours. The cells also began to digest themselves.
The results additionally showed that curcumin kills cells by triggering lethal cell death signals.
Dr Sharon McKenna, lead study author, based at the Cork Cancer Research Centre, University College Cork, said:
“These exciting results suggest scientists could develop curcumin as a potential anti-cancer drug to treat oesophageal cancer. Scientists have known for a long time that natural compounds have the potential to treat faulty cells that have become cancerous and we suspected that curcumin might have therapeutic value. Dr Geraldine O’Sullivan-Coyne, a medical researcher in our lab had been looking for new ways of killing resistant oesophageal cancer cells. She tested curcumin on resistant cells and found that they started to die using an unexpected system of cell messages.”
Curcumin induces apoptosis-independent death in oesophageal cancer cells
A 2011 study took advantage of the fact that curcumin stays in the intestine rather than absorbing into the blood. Researchers tested it to find out if it could reduce the number of cancer precursors in the colon and rectum. They measured compounds that help promote cancer in rats, did colonoscopies to count abnormal crypt foci (a very early sign that colon cancer may be developing) in biopsy samples, then gave 2 to 4 grams of curcumin a day to 44 smokers. After a month on the curcumin, the researchers did second colonoscopies and biopsies to see if there was a lower concentration of pro-carcinogenic substances in the colon and rectum. The compounds were at the same level as they were before the study. But the smokers who took 4 grams of curcumin a day had fewer abnormal crypt foci after the study, while the smokers who took 2 grams a day had the same number as before. Researchers are still looking at whether curcumin might actually reduce the number of colon and rectum cancers.
Tumeric
On September 2012 a clinica trial showed that Curcumin-cyclodextrin complexes potentiate gemcitabine effects in an orthotopic mouse model of lung cancer. Curcumin has low solubility, so scientists have used cyclodextrins (CD) as an excipient allowing a considerable increase of aqueous solubility and bioavailability of curcumin. The effects of solubilised curcumin have been evaluated in cell cultures as well as in an in vivo orthotopic lung tumour mouse model.
They used in particular a combination of Curcumin and Gemcitabine, a nucleoside analog used as chemotherapy. They demonstrated that Curcumin, when given orally in a CD-solubilised form, reduces lung tumour size in vivo. In vitro experiments show impaired tumour cell proliferation and increased cell apoptosis. Moreover, their data underlined a potential additive effect of curcumin with gemcitabine thus providing an efficient therapeutic option for antilung cancer therapy. Curcumin-cyclodextrin complexes potentiate gemcitabine effects in an orthotopic mouse model of lung cancer. 2012
Further clinical trials are going on to find out what role, if any, turmeric and curcumin may play in the prevention or treatment of cancer.
Nutrition and Curiosities
Curcuma longa is one of the key ingredients in many Asian dishes. Indian traditional medicine, called Ayurveda, has recommended turmeric in food for its potential medicinal value, an active research topic. Its use as a coloring agent is not of primary value in South Asian cuisine.
Curcuma longa is typically used in its dried, powdered form, that is one of ingredients for Curry powder, a mixture of spices of widely varying composition based on South Asian cuisine, that in north India is called garam masala. It is used in particular with meat and rice, but sometimes is also used as ingredient for drinks, yogurt and bisquits. Its health benefits have been described for thousands of years in traditional Indian and Chinese medicine largely because of its proven efficacy in treating conditions with inflammation. Marco Polo, writing of his travels in China, described Tumeric in the 13th century, explaining its affinity with saffron and its large use in that land. In fact Curcuma is also called “indian saffron”.
Symbolic is Fauja Singh’s case. At the grand old age of 102, Fauja Singh is the world's oldest marathon runner. He is a world record holder in his age bracket. His current personal best time for the London Marathon (2003) is 6 hours 2 minutes, and his marathon record, for age 90-plus, is 5 hours 40 minutes, at the age of 92, at the 2003 Toronto Waterfront Marathon. The key, according to Singh, to conquering his daily 10-mile training regimen is drinking copious amounts of tea and in particular eating plenty of ginger curry, a simple sour, spicy and sweet curry.
Here is the 102 years old Fauja Singh. May curry be the cause of his excellent health?
Conclusion
Evidence has also been presented to suggest that Curcumin can suppress tumor initiation, promotion and metastasis. Pharmacologically, Curcumin has been found to be safe, is considered GRAS (General Recognition And Safety) by the american FDA (Food and Drug Administration). All of these studies suggest that Curcumin has enormous potential in the prevention and therapy of cancer, it's important a continue science research about Curcumin's benefits, that may become very helpful in the future medicine. First of all we can improve the use of a spice such as curry powder for our meals.
Bibliography
Anticancer potential of curcumin: preclinical and clinical studies. 2003.
Curcumin: from food spice to cancer prevention. 2009
Curcumin as an anti-cancer agent: review of the gap between basic and clinical applications. 2010.
Phase II Trial of Curcumin in Patients with Advanced Pancreatic Cancer. 2008
Curry compounds kill oesophageal cancer cells in lab. 2009
Curcumin-cyclodextrin complexes potentiate gemcitabine effects in an orthotopic mouse model of lung cancer. 2012
Curcumin and Cancer Cells: How Many Ways Can Curry Kill Tumor Cells Selectively? 2010
Bioavailability of Curcumin: Problems and Promises. 2007
Curcumin induces apoptosis-independent death in oesophageal cancer cells
