Source and Structure of Triterpenoids

2. Source and Structure of Triterpenoids

The variety of triterpenoids in nature is a result of the evolution of a large terpene synthase superfamily. One study analyzed the amino acid sequences of terpene synthase genes and found that all originated from an ancestral diterpene synthase. It was also found that the diversity of these triterpenoids is due to the structural features of their catalyst enzymes. Terpenes and their metabolites are widely distributed in various plant systems that depend on various biotic and abiotic environmental factors. Terpenes and their metabolites are used in several developmental and physiological functions on the basis of the differential expression profiles of terpene synthase genes. Terpenes and their metabolites play a very important role in a plant’s defense mechanism. They protect the plants from both constitutive and induced defensive responses against insects and environmental stress [141,142]. Hence, triterpenoids provide a very good protection shield for plants, indicating their potential for use in the prevention of various cancers and inflammatory diseases in humans.

3. Molecular Targets of Triterpenoids

In 1856, Rudolf Virchow for the first time showed inflammation to be a predisposing factor for various types of cancer. Today, the data suggest that at least one in seven malignant tumors diagnosed worldwide results from chronic inflammation and infection. Recognition of this fact has led to greater interest in research for molecular targets involved in the inflammatory pathways that trigger cancer and to find novel markers that restrain cancer progression along these pathways.

The conventional methods of treatment of cancer include surgery, chemotherapy and/or radiotherapy; the mode of treatment depends largely upon the type of cancer the patient has. Innovative, so-called multitargeting therapies from natural resources are urgently needed to target the various steps of cancer progression or the processes involved in cancer cell survival and metastasis to other parts of the body.

It is clear now that cancer is not a simple disease involving a single gene, but a complex disease involving interaction between multiple genes, either within the same cell or with those of neighboring tissues. The prevention or progression of human cancer depends on the integrity of a complex network of defense mechanisms in which 300–500 genes have gone wrong, leading to the upregulation of undesired products such as antiapoptotic proteins or the downregulation of tumor suppressor proteins.

3.1. NF-κB

NF-κB, a ubiquitous transcription factor, was discovered in 1986 as a nuclear factor that binds to the enhancer region of the κB chain of immunoglobulin in B cells. It is present in all cells, and in its resting stage, this factor resides in the cytoplasm as a heterotrimer consisting of p50, p65, and inhibitory subunit IκBα. NF-κB is activated by free radicals, inflammatory stimuli, cytokines, carcinogens, tumor promoters, endotoxins, γ-radiation, ultraviolet light, and x-rays [143]. On activation, the IκBα protein, an inhibitor of NF-κB, undergoes phosphorylation, ubiquitination, and degradation. p50 and p65 are then released to be translocated to the nucleus, bind to specific DNA sequences present in the promoters of various genes, and initiate the transcription of more than 400 genes. The kinase that causes the phosphorylation of IκBα is called IκBα kinase (IKK). Whereas the IKKβ mediates the classic/canonical NF-κB activation pathway, the IKKκ mediates the noncanonical pathway. IKK itself must be activated before it can activate IκBα. More than a dozen kinases have been described that can activate IKK, including protein kinase B (Akt), mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEKK1), MEKK3, transforming growth factor (TGF)–activating kinase 1 (TAK1), NF-κB–activating kinase, NF-κB–inducing kinase, protein kinase C, and the double-stranded RNA-dependent protein kinase (PKR).

3.2. STAT3

Signal transducer and activator of transcription 3 (STAT3), one of the major molecular targets of triterpenoids, was first identified in 1994 as a DNA-binding factor that selectively binds to the IL-6-responsive element in the promoter. The activation of STAT3 is regulated by the phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases, including epidermal growth factor receptor (EGFR) kinase [144], Src [145], Janus-activated kinases (JAK) [146,147], and extracellular signal-regulated kinase (ERK) [148]. The phosphorylation of STAT3 in the cytoplasm leads to its dimerization, translocation into the nucleus, and DNA binding, which results in the regulation of several genes involved in cell proliferation, differentiation, and apoptosis.

3.3. Other Pathways

A large body of evidence signifies the role of inflammation in cancer development through mediators such as reactive oxygen species (ROS), free radicals, and inflammatory cytokines like tumor necrosis factor-α (TNFα), lymphotoxins, and angiogenic factors. Also known to influence oncogenesis are signaling pathways that in normal cells are involved in tissue homeostasis, such as the NF-κB, prostaglandin/cyclooxygenase-2 (COX-2), and p53 pathways; the DNA repair machinery; and a family of the Toll-like receptor proteins.

Some of the most commonly known molecular targets of triterpenoids involved in the treatment and prevention of cancer have been targeted according to comprehensive knowledge of tumor growth and metastasis. This approach will maximize the effect of triterpenoids and minimize side effects by multitargeting the cells or processes that enable cancer to survive and spread in humans.

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