Current Topics in Medicinal Chemistry - Volume 12, Issue 13, 2012

TNF-α was discovered more then 20 years ago as a cytokine implicated in a wide range of cell signaling pathways, many of which are known to lead to the activation of genes involved in inflammation and carcinogenesis. TNF-α is involved in the pathogenesis of many diseases, including Crohn’s disease, diabetes, septic shock, tumorigenesis, rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease. Multidisciplinary research endeavoring to understand the biomolecular and biomedicinal properties of TNF-α has never faded away, and the search for natural products able to inhibit TNF-α remains, to date, a hot topic of investigation. Over the last 10 years, many TNF-α-inhibiting natural compounds have been discovered, and their anti-TNF-α activities have been described. The present review describes the major cell signaling pathways activated by TNF-α and discusses the chemical and biological properties of TNF-α-inhibiting natural products, focusing on compounds that are able to inhibit TNF-α-related signal transduction pathways or TNF-α gene expression.

Tumor necrosis factor-α (TNF-α) is a major cytokine involved in the inflammatory response. Elevated TNF-α expression has been found to be associated with the development of diabetes, septic shock, tumorigenesis, cardiovascular diseases, rheumatoid arthritis and inflammatory bowel disease. In the past decade, the success of anti-TNF-α biologics has valuated the importance of the blockade of TNF-α production in the treatment of patients with various inflammatory diseases. Oxidative stress is another important element in oxidative/inflammatory responses that directly linked to oxidation of proteins, DNA and lipids. The increased oxidant levels could activate nuclear factor-kappaB (NFκ-B), signal transduction and gene expression of TNF-α, interleukin-1 (IL-1) and other pro-inflammatory cytokines. Therefore, TNF-α inhibitors with anti-oxidative stress activity may have multiple target effect that could exhibit excellent anti-inflammatory activities. The review briefly highlights the pathological roles of TNF-α and oxidative stress in inflammation, and covers those natural products as TNF-α inhibitors capable of anti-oxidative stress activity.

Tumor necrosis factor-alpha (TNF-α) is a multifunctional cytokine produced by monocytes, macrophages, neutrophils, T-cells, mast cells, epithelial cells, osteoblasts and dendritic cells. It can regulate numerous cellular and biological processes such as immune function, cell differentiation, proliferation, apoptosis and energy metabolism. It is also involved in the pathogenesis of multiple chronic inflammatory or autoimmune diseases. The biological activities of TNF-α mediated by two receptors TNFR1 and TNFR2. Its activity can be inhibited by neutralizing monoclonal antibodies or soluble TNF receptors. The inhibition of its biological activities using anti TNF-α antibodies represents an approved strategy for the treatment of various diseases like cancer, autoimmune diseases, inflammations etc. The involvement of TNF-α cytokine in the various types of diseases provide the therapeutic rationale for the development of TNF-α antagonist. A large number of natural and synthetic compounds are currently being investigated for TNF-α inhibitory activity. Since the synthetic molecules are always associated with their side effects hence it is beneficial to develop the natural strategies as the alternative sources. There are many medicinal plants which are traditionally used for the treatment of the diseases associated with TNF-α inhibition. Hence, in this review article we make an approach to provide a platform for the development of TNF-α antagonist from natural resources.

Thalidomide and its one analogue, lenalidomide (CC5103 or revlimid) are recently approved for the treatment of multiple myeloma. Multiple myeloma is characterized by an overproduction of malignant plasma cells in the bone marrow. The journey of thalidomide was started in 1956 when it was marketed as a non-barbiturate sedative agent. It was considered as a “wonder drug” that provided safe and sound sleep and hence, used to cure morning sickness in pregnant women. Later, in 1961, it was withdrawn from the world market due to its serious side effects, i.e., teratogenic activity. However, the recent decade has witnessed a true renaissance in interest in its broad biological activity. In particular, thalidomide was reevaluated and attracted significant attention due to its selective inhibitory activity of tumor necrosis factor-α (TNF-α), which is a clinically important activity against serious diseases such as rheumatoid arthritis, Crohn’s disease, leprosy, AIDS, and various cancers. The comeback of thalidomide to the legitimate status of a marketed drug came in 1998 when it received FDA approval for the treatment of erythema nodosum leprosum (ENL). Recently, the drug has got FDA approval for the treatment of multiple myeloma. In the last few years, number of thalidomide analogues have been synthesized and are in clinical development as a class of immunomodulatory drugs. Among these, lenalidomide is more potent than thalidomide, and is also non-neurotoxic. It was shown in vitro studies to induce apoptosis or arrest growth even in resistant multiple myeloma cell lines, decrease binding of the cells to bone marrow stromal cells, and stimulate host natural killer cell immunity. It also inhibits tumour growth and decreases angiogenesis. Earlier reviews have described the pharmacological aspects of thalidomide and a review has focused only on synthetic aspect of thalidomide. However, review focusing on chemistry and metabolism and mechanism of biological activity is still lacking. In this review, we will concisely describe the therapeutic aspects, metabolism and synthesis of thalidomide.

Tumor necrosis factor alpha (TNF-α) is a pleiotropic inflammatory cytokine. The cytokine possesses both growth stimulating properties and growth inhibitory processes, and it appears to have self regulatory properties as well. Agents like etanercept and infliximab showed beneficial effects against rheumatoid arthritis by modulationg TNF-α proteins, however, these agents are largely unable to penetrate the blood-brain barrier, which severely limits their use in different conditions. Thalidomide, an inhibitor of TNF-α protein synthesis is readily capable of crossing the blood-brain barrier and thus thalidomide and its analogs are excellent candidates for use in determining the potential value of anti-TNF-α therapies in a variety of diseases. Thalidomide blocks TNF-α expression by different possible mechanisms. Down regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), an essential transcription factor for TNF and other cytokines under thalidomide treatment leads to reduction in the TNF-α expression. Additionally, myeloid differentiation factor 88 (MyD88), an adapter protein regulates the expression of TNF under thalidomide treatment. Thalidomide treatment also leads to destruction of TNF-α mRNA thus, reducing the total expression of TNF-α protein. Thalidomide also targets reactive oxygen species (ROS) and α1- acid glycoprotein (AGP) to regulate TNF-α. In the present review, we discuss different possible mechanism that regulates TNF-α under thalidomide treatment. Additionally, we suggest novel strategies for the future targeting combination therapies of thalidomide and its analogs with different other anti-inflammatory drug to curb TNF-α associated diseases.