Curcumin: Potential Health Benefits, Molecular Mechanism of Action

Chapter 7

Curcumin: Potential Health Benefits, Molecular Mechanism of Action, and Its Anticancer Properties In Vitro and In Vivo

Downloaded by UNIV OF GUELPH LIBRARY on July 6, 2012 | http://pubs.acs.org Publication Date: January 12, 2006 | doi: 10.1021/bk-2006-0925.ch007

Resmi A n n Matchanickal and Mohamed M . Rafi Department of Food Science, The New Jersey Agricultural Experiment Station, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901

In recent years the food industry has seen an exponential rise in the interest of companies and consumers alike towards the development of foods that are not only nutritious and pleasing to the senses, but also provide the body with important health benefits. In 1989 after much debate, Dr Stephen DeFelice defined nutraceuticals as any substance classified as a food or part of a food with medical or health benefits that range from the prevention to the treatment and/or cure of a disease. Soon after a new discipline was born: nutragenomics, dedicated to the study of how natural molecules present in foods alter the molecular expression of genes in each individual. The nutraceutical curcumin is a polyphenolic yellow pigment found in turmeric, the ground form of the Curcuma longa species. The interest that the medical world has shown towards this molecule stems from the fact that several studies have shown promising results in the use of this nutraceutical as a potential agent to prevent and fight cancer. Researchers are not yet clear on the exact mechanism of action, but they believe that curcumin's anticancer potential has to do with its ability to suppress the proliferation of cells. Curcumin has been shown to down-regulate the activity of two major transcriptor factors NF-κΒ and AP-1, scavenge reactive oxygen species (ROS), suppress mitogen-activated protein kinases (MAPKs) generated by

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© 2006 American Chemical Society

In Herbs: Challenges in Chemistry and Biology; Wang, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2006.

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inflammatory stimuli, suppress the expression of pro-inflammatory enzymes cyclooxygenases (COX-2) and lipoxygenases (LOX), induce apoptosis in the cancer cells by up regulating p53 protein and induce Phase II detoxification enzymes. In addition to its anticancer potential, curcumin has also been found to be a good antioxidant, anti-inflammatory and anti-mutagenic agent as a result of the different moieties in its chemical structure. So far turmeric has been found to be safe at doses up to 2200 mg daily that is equivalent to 180 mg of curcumin. However, its low bioavailability due to extensive intestinal metabolism has put into question its efficacy in the body.

Cancer Chemprevention and Diet Cancer continues to be one of the most difficult and complicated diseases to tackle despite the major advances in medical technology for its diagnosis and treatment. As a result, the medical community is looking to find new ways to decrease the burden of the disease. Nowadays, the focus has shifted from treatment to prevention, in light of some promising research that has shown that of all the environmental factors, dietary components appear to play a major role in the initiation/progression of the disease. One of the countries that has inspired researchers to approach the cancer problem through a dietary perspective is India, a rapidly developing country characterized for having one of the most diverse populations and diets in the world. Spices have been used for many years to add exotic flavors, aromas and colors to foods. In Asian cultures (eg. India and China), spices also play a special role as "healing tools" for a variety of diseases (7). It was not until recently that researchers discovered that spices contain as many beneficial phytochemicals as fruits and vegetables. Thus, there has been a recent interest by the scientific world to study and understand how these phytochemicals transform themselves into "natural healers" when they are ingested in adequate quantities. Scientists have discovered that common herbs/spices such as parsley, ginger, turmeric, fenugreek, clove, cardamon, cinnamon, mint, garlic, mustard and chili peppers have various hidden therapeutical properties such as: production of enzymes that detoxify carcinogens, inhibition of cholesterol synthesis, estrogen blockers, lowering of blood pressure etc. In many cultures, spices are viewed as capable of boosting energy, relieving stress, protecting the nervous system, aiding in digestion and relieving symptoms of the common cold (1). Turmeric is one of the spices that has caught most of the attention because its main component, curcumin, has shown significant potential as an anti-cancer agent,



94 anti-inflammatory, anti-mutagenic agent in both in vitro and in vivo studies (2-3). However, the efficacy and bioavailability of curcumin in the human body is under investigation, due to its extensive intestinal metabolism (4). One of thee major hurdles in the earlier stages of the nutraceutical movement was establishing a complete and descriptive definition for the term nutraceutical. Finally in 1989, Dr Stephen DeFelice put to rest the feud by defining nutraceuticals as "any substance considered a food, or part of a food, with medical or health benefits, including the prevention, treatment or cure of disease"(5). There are over 35 plant based nutraceuticals each with a distinctive bioactive molecule. For example: garlic contains diallyl sulfide, soy contains genestein, grapes contain resveratrol and turmeric contains curcumin (6). The completion of the Human Genome Project in 2003 (7) was an important milestone for researchers around the world because it confirmed the existence of genetic differences amongst individuals in response to external factors such as diet. Thus, the science of nutragenomics was born to study how nutraceuticals such as curcumin affect the molecular expression of genetic information in each individual. It is a discipline that combines nutrition, molecular biology and genomics (8). The key difference between nutrition and nutrigenomics is that the former treats individuals as genetically identical while the latter takes into consideration genetic differences also known as single nucleotide polymorphisms or SNP's (8). Curcumin is a natural yellow, orange dye derived from the rhizome of Curcuma longa. It is not water soluble, but it does solubilize in ethanol and other organic solvents (9). There is one study that reports having increased the water solubility of curcumin by a factor of 10 as well as improving its photochemical stability by complexing curcumin with a cyclodextrin (10). Curcumin's melting point is 183° C and its molecular weight is 368.37. There are three main molecules present in curcumin, which are collectively known as curcuminoids (Figure 1). Curcumin has a brilliant yellow hue at pH ranges of 2.5-7.0 and becomes reddish at pH >7 (2). 4

Figure 1. Structures of curcuminoids)

Chemoprevention encourages the use of special diets and chemicals of natural or synthetic origin to reverse, suppress or prevent cancer from progressing and becoming invasive (77). Chemopreventative agents can be



95 divided into two subgroups: blocking agents that interfere with initiation and tumor suppressor agents that affect promotion/progression stage of carcinogenesis. Most nutraceuticals (including curcumin) are considered to be tumor suppressor agents because they cannot prevent initiation from taking place but they can reverse the promotion and progression stages. A disease as complicated as cancer needs a good chemotherapeutic agent that has a variety of mechanistically distinct but complementary properties that will aid in regulating cell growth, differentiation and survival (//). Chemoprevention of cancer through the consumption of edible phytochemicals is the cheapest, most readily applicable and accessible approach to cancer control known so far. With healthcare costs being so high, chemoprevention is a cost effective approach to promote the awareness and encourage the consumption of food containing phytochemicals as a cancer preventative strategy for the general public (11). Phytochemicals are defined as non-nutritive components in plants that have significant anti-carcinogenic and anti-mutagenic properties (6). Plants not only provide us with essential vitamins and minerals, but they are also responsible for 80,000-100,000 of the secondary metabolites on the planet. Unfortunately for us, some of the best phytochemicals (eg. curcumin) are unique to certain plant species (turmeric), which are often either absent or present at very low levels in the typical American diet (12). Thus, due to poor dietary choices the average consumer is ignoring many of these beneficial phytochemicals. Although it helps to classify phytochemicals as blocking or suppressing agents, we have to acknowledge that the ability of a single phytochemical to prevent tumor development is a combination of several sets of intracellular effects rather than a single biological response. The key is to first figure out how nutraceuticals function in plants in order to further understand their possible mechanism within the human body. Ironically, we use spices as food additives to provide added flavor, while some plants produce these phytochemicals as a self defense mechanism in order to discourage consumption by their predators (13).

Mechanisms of Action of Curumin In Vitro

Suppression of NF-κΒ and AP-1 NF-κΒ and AP-1 are ubiquitous eukaryotic transcription factors that act as mediators between external and internal stimuli in the cellular signaling cascades and are therefore prime targets of a diverse class of chemopreventative phytochemicals (6). NF-κΒ is a transcription factor that is inducible and ubiquitously expressed in genes involved in cell survival, cell adhesion, inflammation, differentiation and growth (14). It also plays a fundamental role in



96 the immune system where it controls the expression of cytokines and the major histocompatibility complex genes (2). In resting cells, NF-κΒ can be found in the cytoplasm bound to the inhibitory IkB proteins, which prevent it from relocating to the nucleus. NF-κΒ is activated by various carcinogens and tumor promoters such as benzopyrene, U V radiation and phorbol esters. Once activated, the NF-κΒ is released into the nucleus as a result of the phosphorylation, ubiquitination and degradation of IkB. Activation of NF-κΒ is tightly regulated by IkB which complexes and sequesters NF-κΒ in the cytoplasm. There are many kinases involved in the phosphorylation of IkB, which are all linked to cytokine specific receptors and proteins and eventually converge on NF-κΒ inducing kinase (NIK). Once this kinase gets activated, it then phosphorylates and activates the IkB kinase complex (IKK). The activation of the I K K complex leads to IkB phosphorylation and degradation followed by the release of NF-κΒ. A study using intestinal epithelial cells (IEC), found that curcumin blocked NF-κΒ activation by blocking the signal leading to I K K activity (75). The activation of NF-κΒ promotes cell survival, due to the expression of several genes such as bcl-2, bcl-xl, cyclin D l , COX-2 and others, which are regulated by NF-κΒ and are involved in the survival of cancerous cells. Curcumin suppresses many inflammatory genes that are regulated by NF-κΒ such as TNF, COX-2 and N O S (2). Activating protein-1 (AP-1) activity is induced by a wide range of stimuli and environmental insults such as growth factors, cytokines, neurotransmitters, polypeptide hormones, bacterial and viral infections and other physical and chemical stresses. The ability for this transcription factor to control an eclectic collection of biological processes is based on its structural and regulatory complexity (76). AP-1 is a complex between dimers of Jun proto-oncogene family with the Fos proto-oncogene family. The Fos proteins form stable heterodimers with Jun proteins thereby enhancing the D N A binding capacity. We have yet to find a clear explanation on how curcumin inhibits AP-1, but there are three potential mechanisms which are: 1 ) Alteration of the redox status of cells, 2) Inhibition of Jun-N-terminal kinase (JNK) which is needed for AP-1 activation 3) Inhibition of the fos-jun-DNA complex. Thus down-regulation of AP-1 by curcumin may explain its ability to suppress chemical carcinogenesis (2).


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ρ53, ΒΑΧ, B C L - 2 , P21, Apotosis, Cell Cycle Typically cells die either by necrosis or by programmed cell death, also known as apoptosis. The difference between both is that necrosis is characterized by the loss of plasma membrane integrity without damage to the nucleus, while apoptosis is an organized degradation of the cellular components (77). Curcumin induces apoptosis in cancer cells taken from the colon, liver, and breast.(/#). One of the major properties of curcumin is the inhibition of apoptosis, which takes place through either a mitochondria-dependent or mitochondriaindependent pathway depending on the cell type involved. Curcumin activates caspase 8, which leads to cleavage of B I D , loss of mitochondrial potential, opening of transition pores, release of cytochrome C, activation of caspase 9 and 3, activation and cleavage of P A R P and finally D N A fragmentation and apoptosis. Curcumin also exerts apoptosis by down-regulating anti-apoptotic proteins such as bcl-2 and bcl-xL. A study found that curcumin induced Bax through p53, which caused the release of cytochrome c from the mitochondria, thus leading to apoptosis (79). The tumor suppressor gene p53 is mutated, deleted or rearranged in more than 50% of all human tumors. This gene is also known as "the guardian of the genome" because it triggers apoptosis or cell cycle arrest in response to D N A damage. In normal cells p53 is in charge of preventing the replication of damaged D N A , reducing genetic instability and allowing the cells to perform critical repair functions before going through the cell cycle (79). Bax is a pro-apoptotic protein (member of the Bcl-2 family) that is up-regulated in a number of cells during p53-mediated apoptosis. It has been well established that the fate of cells depends upon the balance between proteins that mediate cell death, such as Bax (pro-apoptotic) and Bcl-2/Bcl-xl (antiapoptotic). The ratio of proapoptotic vs. antiapoptotic proteins is critical in defining the cell's threshold for undergoing apoptosis. Curcumin is known to suppress the proliferation of a wide variety of tumor cells from breast, colon, renal and prostate induced by growth factors such as IL2, PDGF and PHA. This attribute is due in part to curcumin's effect on the cell cycle (2). Treatment of cells with curcumin arrests the cell cycle at the G - M stage in several cell types, which consequently causes a reduction in the expression of genes such as p53, p21, Bcl-xl and up-regulation of Bax (20). The possible molecular targets and mechanism of action of curcumin is shown in Figure 2. 2


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Curcumin: Potential Health Benefits, Molecular Mechanism of Action

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