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Emerging Therapeutic Aspects in Oncology

Following is another brief/adaptation from the excellent  review article from ” Emerging Therapeutic Aspects in Oncology “.

Review

Curcumin: an orally bioavailable blocker of TNF and other pro-inflammatory biomarkers

  • Bharat B Aggarwal, Subash C Gupta and Bokyung Sung
  • Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

TNFs are major mediators of inflammation and inflammation-related diseases, hence, the United States Food and Drug Administration (FDA) has approved the use of blockers of the cytokine, TNF-a, for the treatment of osteoarthritis, inflammatory bowel disease, psoriasis and ankylosis.

These drugs include the chimeric TNF antibody (infliximab), humanized TNF-a antibody (Humira) and soluble TNF receptor-II (Enbrel) and are associated with a total cumulative market value of more than $20 billion a year.

As well as being expensive ($15 000–20 000 per person per year), these drugs have to be injected and have enough adverse effects to be given a black label warning by the FDA. In the current report, we describe an alternative, curcumin (diferuloylmethane), a component of turmeric (Curcuma longa) that is very inexpensive, orally bioavailable and highly safe in humans, yet can block TNF-a action and production in in vitro models, in animal models and in humans. In addition, we provide evidence for curcumin’s activities against all of the diseases for which TNF blockers are currently being used. Mechanisms by which curcumin inhibits the production and the cell signalling pathways activated by this cytokine are also discussed. With health-care costs and safety being major issues today, this golden spice may help provide the solution.

Thus, initially considered cartilage driven, OA is a much more complex disease with inflammatory mediators released by cartilage, bone and synovium.

 

Introduction

Extensive research during the past century has revealed that inflammation plays a major role in most chronic diseases.

It was Cornelius Celsus, a physician in first century Rome, who first attempted to  describe inflammation as heat (calor), pain (dolor), redness (rubor) and swelling tumour). Rudolf Virchow, a German scientist from Wurzburg, in 1850, was the first to observe a link between inflammation and various chronic diseases, which include cancer, atherosclerosis, arthritis, diabetes, asthma, multiple sclerosis and Alzheimer’s disease (Heidland et al., 2006). More than 200 different types of inflammatory disease have been described. When the name of a disease ends with ‘itis’, this means inflammation

of the affected organ. Thus, arthritis is inflammation of the joints, whereas bronchitis, sinusitis, gastritis, oesophagitis, pancreatitis, meningitis, rhinitis and gingivitis are, espectively, inflammation of the bronchi, sinuses, stomach, oesophagus, pancreas, brain, nose and gums.

Acute inflammation is thought to be therapeutic as it helps an organism to heal. Chronic inflammation, however, can lead to a disease; inflammation of the colon (colitis), for example, when persistant, for as long as 30 years, can finally lead to colon cancer.

During the past three decades, molecular mechanisms that lead to inflammation have been extensively examined.

Various enzymes, cytokines, chemokines and polypeptide hormones have been  identified, which can mediate inflammation. These include COX-2, 5-lipooxygenase (LOX),TNF-a, IL-1, IL-6, IL-8, Il-17, IL-21, IL-23 and monocyte chemotactic protein-1 (MCP-1). Among these, TNF-a is a major mediator of inflammation, which is the primary focus of this review.

Discovery of TNFs

TNF has at various times been called tumour necrosis serum, cachectin, lymphotoxin or monocyte cytotoxin based on work from our laboratory and others.

It is now clear that TNF is a 25 kDa transmembrane protein (17 kDa when secreted) produced primarily by activated macrophages.

The ability of tumours to undergo haemorrhagic necrosis after injection of endotoxin was first shown by Shear and Perrault (1944).O’Malley et al. (1962) reported that endotoxin injection into normal mice resulted in the appearance of tumour necrotizing activity in the circulating blood. This activity was renamed tumour necrosis factor by Carswell et al. (1975). The true chemical identity of TNF, however, was unclear until our group isolated two different molecules: one from macrophages, which we named TNF-alpha (Aggarwal et al., 1985b), and the other from lymphocytes, which we named TNF-b (Aggarwal et al., 1984). The current review primarily deals with TNF-alpha.

Because of the amino acid sequence homology between human TNF-alpha and endotoxin-induced murine cachectin, aprotein linked to endotoxin-mediated cachexia and shock (Beutler et al., 1985), it became clear that TNF-aalpha and cachectin were identical.

Soon thereafter, numerous groups independently identified the same molecule by using a variety of approaches (Haranaka et al., 1984; Old, 1985; Wang et al.,1985; Fiers et al., 1986; Wallach, 1986).

TNF-a is now known to bind to two different receptors, TNFRSF1A and TNFRSF1B,and to activate caspase-mediated apoptosis, NF-kB, activator protein-1 (AP-1), JNK, p38 MAPK and ERK signalling (Figure 1).

Our group demonstrated that both TNF-alpha and TNF-beta bind to identical receptors and with similar affinities (Aggarwal et al., 1985a). Although much is known about TNF-a, very little is understood about TNF-b (Aggarwal, 2003; Aggarwal et al., 2012).

Both overlapping and nonoverlapping activities of the two molecules have been reviewed (Stone-Wolff et al., 1984; Kuprash et al., 2002; Liepinsh et al., 2006).

Aside from originating in monocytes, it is now clear that TNF-alpha is also produced by a variety of other cell types including Kupffer cells in the liver, astrocytes in the brain, T-cells and beta cells in the immune system, and ovarian cells.

In general, under appropriate conditions, most cell types have the potential to produce TNF-a.

Figure 1

Regulation of the production and action of TNF by curcumin. TNFR1 and TNFR2 are TNF receptors TNFRSF1A and TNFRSF1B respectively. Targets highlighted as yellow are down modulated by curcumin.

Conclusions

Overall, all studies suggest that curcumin can suppress pro-inflammatory pathways linked with most chronic diseases. It can block both the production and the action of NF.Curcumin also binds to TNF directly. Evidence for curcumin as a TNF blocker has been obtained in both in vitro and in vivo studies. However, only a few studies have demonstrated that curcumin is effective at inhibiting TNF production in humans. Unlike most other TNF blockers, curcumin can be given orally. In addition, it is quite safe and affordable.However, more studies are needed in humans to prove that curcumin has the ability to be an effective treatment of various pro-inflammatory conditions.

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