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Curcuminoids from Curcuma longa in the fight against cancer and age related disorders.

Acute vs. chronic inflammation

The inflammatory cycle is often treated with a 'band-aid' type approach to quell immediate pain. However it is inflammation as a lingering rather than an acute process that is increasingly attracting attention. It is considered as the root cause of many diseases that remain poorly understood or treated. Cardiovascular disease, a leading cause of mortality in the world, is no longer considered a disorder of lipid accumulation but rather a disease process characterised by low grade inflammation of the vascular lining (endothelial cells) and an inappropriate 'wound healing response' of the blood vessels (Rikder 2000). Cancer is another chronic degenerative disease that is initiated and promoted by lingering inflammation often triggered by environmental or nutritional factors, i.e. carcinogen (Ohshima 2005). Similarly the devastating neurodegenerative disorder, Alzheimer's disease (AD) is hypothesised as being caused by dysfunction of the immune system reacting to chronic inflammation of the central nervous system (Fiala 2007a).

A number of epidemiological and laboratory studies have demonstrated that individuals with the above cited diseases may have elevated serum levels of cytokines such as nuclear factor kappa beta (NFkB), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), cell adhesion molecules such as intercellular adhesion molecule-1 and P-selectin, and acute-phase proteins such as C-reactive protein, fibrinogen and amyloid. Other studies have shown an over expression of cyclooxygenase enzymes (COX 1 and COX 2). These changes may signal a chronic inflammatory process in an individual predisposed to a multitude of degenerative diseases and cancers.

Although synthetic drugs effectively reduce inflammation and pain in both acute and chronic inflammatory conditions, they work in a very selective way that may be counterproductive to the purpose of treatment. Recent research reveals that selective COX-2 inhibitors (pharmaceutical) may induce metabolic imbalances that can result in the over production of toxic cytokines, TNF-alpha and certain interleukins that are involved in the inflammatory process (McKellar 2007).

In the emerging trend to search for natural therapies, turmeric root (Curcuma longa), ginger root (Zingiber officinale), rosemary leaves (Rosmarinus officinalis), green tea leaves (Camellia spp) and their active phytochemical constituents are reported to be effective COX-2 inhibitors that also inhibit the formation of inflammatory leukotrienes and toxic cytokines. These herbs do not irritate the gastrointestinal lining (mucosa) and have a safe medicinal record spanning centuries. Furthermore no adverse effects have been reported with these herbs in clinical studies performed to validate various therapeutic properties. In fact many of these compounds are included on the so called GRAS list (generally recognised as safe)--which means that they are safe to use in daily nutrition. Based on the current body of scientific evidence, turmeric's curcuminoids are considered the most promising food derived compound to fight inflammation and related diseases (Table 1) (Santangelo 2007, Shishodia 2005).

[FIGURE 1 OMITTED]

Curcumin (chemically diferuloylmethane) and its derivatives demethoxycurcumin and bisdemethoxy-curcumin, collectively known as curcuminoids, are responsible for the yellow pigment derived from the roots of the perennial herb turmeric (Curcuma longa L.) (Fig 1). The same ground dried roots of turmeric which have been used for centuries as a spice (curry), food preservative and a colouring agent, have been found to be a rich source of phenolic compounds (curcuminoids) with versatile biological mechanisms (Shishodia 2005). In dietary supplement practice and in a growing body of scientific research, an extract of turmeric roots is being utilised that is standardised for a high purity of curcuminoids, e.g. 95% curcuminoids (see references).

Curcuminoids in prevention and treatment of cancer

In the last three years alone there have been several pioneering IND (Investigational New Drug) studies granted by the FDA and other NIH funded studies for the investigation of curcumin and its derivatives in the treatment of patients with cancer and Alzheimer's disease (Dhillon 2007, Vadhan 2007, Azra 2007, Ringman 2008). Some of the leading clinical research centres in the US, including MD Anderson Hospital in Houston Texas, are involved in pre-clinical and clinical research of the anti-cancer mechanism and application of curcuminoids in conditions including multiple myeloma, colon, pancreatic, breast, prostate, head and neck and respiratory tract cancers. These cancer conditions are either currently being studied in clinical experiments or considered next in line for systematic evaluation with curcuminoid therapy.

Potential mechanisms of action

Curcuminoids act by inhibiting several processes that contribute to the survival, proliferation, invasion and metastasis of tumor cells (Kuttan 2007). Curcuminoids act by interfering with signalling mechanisms (critical for tumor growth), regulation of apoptosis (cell death), and tumor angiogenesis (new blood vessel formation which feeds tumors). Current research is designed to determine which of these fundamental processes in cancer development account for the clinical effects of curcumin and its derivatives.

Curcuminoids have significant immunomodulating and anti-inflammatory effects, in part due to the inhibition of cyclooxygenase type 2 enzyme (COX-2) and its subsequent arachidonic acid metabolism (Gautam 2007, Rao 2007). Curcuminoids, like several other immunomodulators, inhibit the activation of the nuclear factor kappa-B (NF-kB) family of transcription factors that are known to be activated in a wide variety of solid tumors and leukemias (Graph 1*, Table 2*) (Garg 2002, 2003, Takada 2004). The activation of NF-kB may shield tumor cells from apoptosis, or programmed cell death, promote tumor growth factors and those factors that facilitate invasion and metastasis of tumors. Curcuminoids block the NF-kB mediated gene expression responsible for the chain of events leading to tumor development, progression and expansion. A probable mechanism of curcuminoids seems to be blocking the degradation of the inhibitors of NF-kB (Graph 1*) (Garg 2002). In vitro, curcuminoids induce apoptosis, and thus inhibit tumor growth in a broad range of tumor cells including cell lines from colon, breast, prostate, squamous cell, renal cell, hepatocellular carcinomas, B and T-cell lymphomas, leukemias, melanoma and sarcoma cells (Aggarwal 2007).

Curcuminoids also affect a signalling mechanism that involves expression and activation of certain growth factor receptors that promote tumor growth. For example HER-2/neu is a member of the Epidermal Growth Factor Receptor family, which is over expressed in approximately 30% of breast cancer patients. HER-2/neu positive breast cancer cells, when exposed to curcumin, were found to have decreased expression of the HER-2 receptor (Aggarwal 2007, Mehta 1997, Hong 1999).

This ability makes curcumin a promising agent for combination with paclitaxel (Taxol [R]) (Agarwal 2007). Taxol [R] is an alkaloid derived from the Pacific yew tree (Taxus brevifolia) and is used as first line chemotherapy in breast cancer. It induces the apoptosis (programmed cell death) of various breast tumor cell lines, but over expression of HER2/neu may block these apoptotic effects and induce resistance to Taxol [R]. Further HER2/neu and Taxol [R] can activate anti-apoptotic pathways through activation of NF kB. Thus agents such as curcuminoids that can down regulate NF kB activation and decrease HER2/neu over expression and other markers of tumorigenesis augment the therapeutic effects of Taxol [R] against breast cancer (Figs 2, 3, 4, 5*).

Interestingly curcuminoids may have a comparable mechanism of action to the drug therapy involving Herceptin [R] for breast cancer patients with HER-2 receptor positive cancer cells. Herceptin [R] is an antibody against HER-2 receptors; binding, blocking and inactivating those receptors. In vitro the growth of breast cancer cells with multi-drug resistance (MDR) characteristics is inhibited by these turmeric phenolics; the stimulation of estrogen receptor (ER) positive cell lines by estrogenic pesticides is also inhibited by curcuminoids (Hong 1999, Poma 2007). Curcuminoids have also been found to inhibit epidermal growth factor receptor expression and/or activation in skin cancer cell lines as well as in androgen sensitive and androgen insensitive prostate cancer cell lines (Dorai 2004).

An important anti-cancer mechanism of curcuminoids is restriction of vital blood supply to the rapidly growing tumor (Kiran 2008, Bhandarkar 2007). In vitro these compounds inhibit the blood vessel endothelial and smooth muscle cell growth and proliferation which is the basis for inhibition of angiogenesis (new blood vessel formation). Curcuminoids also inhibit new vessel formation induced by growth factors such as fibroblast growth factor-2 (FGF-2) (Kiran 2008). Furthermore curcuminoids inhibit the production of vascular endothelial growth factor (VEGF) in human melanoma cells (Lao 2006a).

The anti-angiogenic effect of turmeric compounds can be explained by the aforementioned selective COX-2 inhibition with curcuminoids. COX-2 enzyme activity may contribute to tumor growth (inhibition of apoptosis) along with increased production of the new vessel growth factors (VEGF, FGF) and the formation of new blood vessels. An in vivo study showed tumor regression in response to cyclooxygenase inhibitors in experimental models of human colon, prostate, gastric, lung and certain types of head and neck tumors. In vitro experiments show cyclooxygenase inhibitors inhibited the growth of human pancreatic, liver and breast cancer cell lines.

Therapeutic trials

While there are still limited human trials involving curcuminoids, in animal models curcuminoids prevent tumor formation in genetically predisposed animals, i.e. animals prone to develop precancerous multiple intestinal adenomas, a model for the human condition known as familial adenomatous polyposis (FAP) (Telang 2007, Cruz-Correa 2006). Dietary enrichment with curcuminoids inhibited polyp growth in these animals by over 60%. A study with human subjects is currently underway evaluating the effects of curcuminoids on aberrant crypt foci (ACF) development in the colon (Badmaev personal communication 2008). Curcuminoids have also been successfully tested in several other intervention trials (Sharma 2004, Aoki 2007, Vadhan 2007, Raza 2007, Kyle 2005, Kunnumakkara 2008).

In one study mice inoculated with melanoma cells responded to dietary curcumin intervention with a reduction in the number of lung tumor nodules of 90% compared with sham fed controls. In a dose escalation study 15 patients with advanced colorectal cancer refractory to standard chemotherapy received curcuminoids in doses between 0.45 and 3.6 g daily for up to 4 months (Sharma 2004).

Three biomarkers of the potential activity of curcuminoids were translated from preclinical models and measured in patient blood leukocytes: glutathione S-transferase activity (GST), levels of M1G, and prostaglandin E2 (PGE2) production induced ex vivo. Dose limiting toxicity was not observed. A daily dose of 3.6 gm curcuminoids resulted in a significant decrease in PGE2 production in the blood samples while showing no effect on GST and M1G formation. In conclusion of this study, a daily oral dose of 3.6 gm of curcuminoids is advocated for Phase II evaluation in the prevention or treatment of colorectal cancer. PGE2 production in blood and target tissue may indicate biological activity. It should be noted that other studies indicate the anti-cancer mechanism of curcuminoids is related to induction of GST enzymes, inhibition of PGE2 production or suppression of oxidative genetic material damage (DNA adduct (M1G) formation).

The potential role of curcuminoids in plasma cell dyscrasias/paraproteinaemia is currently under-going clinical trials at St George Hospital, Australia. Patients with monoclonal gammopathy of undetermined significance (MGUS) are typified by a serum M-protein value of < 30g/L, fewer than 10% plasma cells in the bone marrow, none or a small amount of M protein in the urine, and absence of lytic bone lesions, anemia, hypercalcemia or renal insufficiency related to the plasma cell proliferative process (Kyle 2005). While MGUS occurs in association with a variety of diseases, it can also precede the onset of multiple myeloma.

There is no current treatment for these patients. Management includes the regular clinical observation for changes in clinical and immunochemical status at 4-6 month intervals.

In a single blind randomised control pilot study, curcuminoids or placebo was administered orally, 2 grams twice daily to a cohort of 26 MGUS patients. A 5-30% decrease in serum paraprotein concentrations occurred in MGUS patients after only one week of therapy compared with stable or increased paraprotein concentrations in controls. Serum paraprotein levels continued to remain suppressed after 3 months of 'active' curcumin therapy. A double blind randomised cross over controlled trial is currently underway.

Curcuminoids in prevention and treatment of neurodegenerative conditions

Aging can be described as a decline in function and performance of body organs and systems which enhances the likelihood of wear-and-tear damage, inflammation and pain. One of the most challenging fields in anti-aging medicine is the management and treatment of chronic degenerative conditions as exemplified by Alzheimer's disease. This disease is increasingly seen as a defective response to the aging immune system (Fiala 2007a).

The aging immune system becomes progressively less efficient in dealing with inflammation. This is because both innate and adaptive (acquired during lifetime) immune responses show age related changes that could be decisive for healthy aging and survival. Natural or innate immunity is particularly important in the aging process and is based on foot soldier type cells called macrophages which are crucial for defence against microbes and removal of cellular and metabolic debris. Innate immunity is our first line of defence. It functions by the ability of macrophages to recognise a pattern of a pathogenic (harmful) molecule through a code system called pathogen associated molecular patterns (PAMPs).

These potentially harmful molecules, e.g. amyloid protein, when recognised by macrophages, trigger responses that also guide an appropriate adaptive immune response.

The interaction between the innate and adaptive immune systems is critical for the clinical outcome of a pathogen molecule challenge to an organism. A harmonious response to the challenge of a pathogen molecule changes with aging and may lead to a defective or misguided response of macrophages--a difference between macrophages contributing to the body injury or to the healing process.

In Alzheimer's disease (AD), there is increasing evidence supporting a role for macrophages and the dependent innate immunity system in disease origins and progression (Fiala 2007a). Brain amyloidosis is hypothesised to be a crucial pathogenic mechanism in the AD brain and many investigators of AD pathogenesis believe that accumulation of amyloid-[beta] (A[beta]) is toxic to neurons. The immune system of patients with AD is generally poorly responsive to A[beta].

The amyloid hypothesis of AD has increased interest in developing therapies that promote clearance of brain amyloidosis by macrophages leading to a novel strategy of immunotherapy with A[beta] vaccine, or antibodies against the amyloid protein. It was established that the anti-A[beta] antibodies were sufficient for reducing A[beta] in the brain, and that these reductions were accompanied by improvement in cognitive function in animal models of AD. Importantly since the 1990s macrophages have been considered as perpetrators of inflammatory damage in neurodegenerative diseases, parallel to cardiovascular disorders. Consequently anti-inflammatory therapies with different drugs and nutritional compounds have been tested with positive but also negative results (Ringman 2008).

Recently a group of researchers from UCLA has tested a hypothesis that curcuminoids, which have epidemiologic and experimental rationale for use in AD, may improve the innate immune system and increase amyloid clearance from the brain of patients with sporadic AD (Zhang 2006). Macrophages of a majority of AD patients do not ingest (phagocytose) and do not efficiently clear amyloid from the brain, although they phagocytose bacteria (Figs 6 and 7*).

In contrast macrophages of normal subjects phagocytose amyloid. Upon amyloid stimulation, macrophages of normal subjects accelerate synthesis of molecules which participate in the previously discussed system of pathogen recognition, specifically MGAT3 (beta-1,4-mannosyl-glycoprotein 4-N-acetylglucosaminyl-transferase) and toll like receptors (TLRs), whereas mononuclear cells of AD patients generally down regulate these genes. Defective phagocytosis of the amyloid may be related to suppression of these pathogen recognition molecules.

In mononuclear (macrophage like) cells isolated from peripheral blood in AD patients, curcuminoids, especially bisdemethoxycurcumin, may enhance defective phagocytosis of amyloid (Figs 8 and 9*) while restoring synthesis critical for phagocytic function molecules, MGAT3 and TLRs (Fiala 2007b). Therefore curcuminoids may provide a novel approach to AD immunotherapy which is safer than the recently suggested vaccine therapy.

Curcuminoids clinical use, safety and pharmacokinetics

Current clinical experience indicates that oral supplementation of curcuminoids is tolerated without toxicity at doses of up to 8 gm daily for up to 12 months (Sharma 2004, Dhillon 2007, Raza 2007, Kyle 2005). Curcuminoids are poorly absorbed from the gastrointestinal tract, with low nanogram levels of circulating curcuminoids detected in the plasma (Lao 2006b). Nonetheless biological activity is beyond question, with indices of inflammation like NF-kB and COX-2 suppressed by oral administration of curcuminoids as well as clinical improvement in the treated condition (Sharma 2004, Dhillon 2007, Vadhan 2007, Raza 2007, Kyle 2005, Kurd 2008).

Preclinical data suggests that curcumin can be more effective if higher levels of exposure are achieved. As hydrophobic and lypophilic compounds, curcuminoids cannot be given directly intravenously but can be encapsulated in a liposome for intravenous administration (Li 2005). This method would theoretically achieve higher circulating levels of curcuminoids. Another possibility under consideration involves a nano-emulsion form of curcuminoids to bypass the gastrointestinal barrier to achieve higher plasma concentrations.

It is now well established that curcumin exists in rodent and human plasma largely in conjugated forms with the glucuronide conjugate present in much greater abundance than the sulfate conjugate (Cheng 2001, Sharma 2001, Ireson 2001). However even plasma concentrations of curcumin released from conjugated forms are surprisingly low. Interestingly there is little evidence for the biological activity of curcumin conjugates, e.g. against malignant cell growth (Ireson 2001).

Possibly there are other forms of conjugated curcuminoids or derivatives of curcuminoids that can better explain their biological activity and provide future formulae for more effective clinical application.

* Additional tables, graphs and coloured slide figures available on request by emailing a.cowper@nhaa.org.au

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Vladimir Badmaev MD PhD (1), Bharat B Aggarwal PhD (2), Milan Fiala MD, PhD (3), Muhammed Majeed PhD (1), T. Golombick PhD, Dipl Nutr (4), T Diamond MB.BCh MRCP FRACP (4)

(1) Sabinsa Corporation

(2) Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center

(3) UCLA Schools of Medicine and Dentistry, Los Angeles, California. Neurobiology; Harry Vinters, Pathology (Neuropathology), UCLA

(4) Dept Endocrinology, St George Hospital, Sydney, Australia
Table 1

Comparison of cancer incidence in the US (curcumin non-users)
and India (curcumin users)

 US India

Cancer Cases Deaths Cases Deaths

Breast 660 160 79 41
Prostate 690 130 20 9
Colon/rectum 530 220 30 18
Lung 660 580 38 37
Head and neck SCC 140 44 153 103
Liver 41 44 12 13
Pancreas 108 103 8 8
Stomach 81 50 33 30
Melanoma 145 27 1.8 1
Testis 21 1 3 1
Bladder 202 43 15 11
Kidney 115 44 6 4
Brain, nervous system 65 47 19 14
Thyroid 55 5 12 3
Endometrial 163 41 132 72
Ovary 76 50 20 12
Multiple myeloma 50 40 6 5
Leukemia 100 70 19 17
Non-Hodgkin's lymphoma 180 90 17 15
Hodgkin's disease 20 5 7 4

Showing cases per 1 million persons calculated on the basis
of current consensus

Endometrial cancers include cervix uteri and corpus uteri

Globocan. 2000. Cancer Incidence, mortality and prevalence
worldwide, V 1.0

IARC. 2001. Cancer Base No 5. Lyon: IARC Press.
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Author:Bamaev, Vladimir; Aggarwal, Bharat B.; Fiala, Milan; Majeed, Muhammed; Golombick, T.; Diamond, T.
Publication:Australian Journal of Medical Herbalism
Article Type:Report
Geographic Code:8AUST
Date:Jun 22, 2008
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