Approaches for Polygenic Disorders Using Medicinal Plants: A New Battle Against Old Adversaries

Rational Multi Target Selections

Target selection plays vital role and considered to be a heart of the drug discovery programme. Reynold and Elliot (2006) reported that the combined genetic and molecular studies and lawful use of whole animal models with properly performed epidemiology analysis are mandatory to select the appropriate targets.

Duscica Pavlovic et al. (2007) reported that genes involved in redox modification is a key mechanism in mediating pathological process such as inflammation, tumor formation, diabetes, atherosclerosis, aging, etc. and stressed the importance of antioxidant therapy with existing monotherapies. Figure 11.2 described the cross talk between genes involved in oxidative stress, cancer, diabetes and inflammation. The activation of NF-κB–a transcription factor has been associated with a wide variety of human diseases, including cancer, AIDS, rheumatoid arthritis, diabetes, asthma, atherosclerosis, osteoporosis, and Alzheimer’s disease (Kwang and Aggarwal, 2005). Kinases are primary regulators of many vital processes in intricate signaling pathways to control every aspect of cellular function cells. There are approximately 500 different kinases encoded in the human genome, and many human diseases have been linked to these enzymes including all forms of autoimmune disorders. Cyclin Dependent Kinases in cancer and Glycogen synthase kinases in diabetes are the successful models of anti kinase approach in current drug discovery programme (Baier et al., 2007). In summary, target selection in drug discovery is a complex scientific, strategic concern and it needs thorough understanding of cell signaling pathways, and the key mediators involved in the diseases.

Figure 11.2

An Appraisal of Herbal as Multi-Targeted Therapy

Free radicals are the main cause of many deleterious reactions in the pathogenesis of auto-immune diseases. Oxygen free radicals are not only generated during diabetes, ischemia, tissue damage, cancer, inflammation and aging conditions but also from exogenous sources such as UV light, pollution, life style changes and various medications (Atawodi, 2005). Protection of cellular constituents is one of the most important targets for modern medicine. Nowadays, plant-based products are widely commercialized as a nutrition supplement by rationalizing its antioxidant potential. Tannins, polyphenols and flavonoids are the main antioxidants present in most of the plants and their significance in treating various diseases like cancer (Cicilio et al., 2003), diabetes (Xueqing Liu et al., 2005), etc are well documented. Since, most of the plants exhibit anti oxidant activity it can be used as one of the target in multi targeting approach of autoimmune diseases.

Apart from antioxidant potential, herbals also play specific role in managing autoimmune disorders. Extensive studies have been carried out on evaluation of multi functional potential of medicinal plants. A classical example is Pterocarpus marsupium a well-studied plant for Diabetes (Figure 11.3). The constituents isolated from this plant are an antioxidant (-) epicatechin, which causes an ATP dependent enhancement of glucose, stimulated insulin secretion from islets (Hii et al., 1984), Myricetin and Quercetin which shows similar activity with protein tyrosine kinase inhibition (Robert et al., 1989). In addition, the phenolics isolated from this plant are Marsupsin, Pterosupin and Pterostilbene which enhances insulin secretion (Manickam et al., 1997) and an isoflavone namely 7-O-α-l-rhamnopyranosyl oxy-4’-methoxy-5-hydroxy which activates Glut-4, PPARg and PI3 kinase (Anandharajan et al., 2005).

Most of the chemopreventive agents currently being studied are natural products or their derivatives. Many natural compounds, particularly plant products and dietary constituents, have been found to exhibit cancer chemopreventive activities both in vitro and in vivo (Lee et al., 2001) (Figure 11.4). Podophyllotoxin from Podophyllum peltatum was the first natural product anticancer compound isolated in the year 1947. Though Podophyllotoxin is too toxic for use as an anticancer agent, etoposide and teniposide, which are modifications of an analog, 4’–demethylepipodophyllotoxin, are used clinically to treat certain solid tumors (Hartwwll and Shear, 1947). The ‘vinca alkaloids’, vinblastine and vincristine from the Madagascan periwinkle, Catharanthus roseus are considered antimitotic drugs because they inhibit cell division. They act by binding to tubulin and preventing it from polymerizing into microtubules and found to be very effective in the treatment of Hodgkin’s disease and childhood leukemia, respectively (Dewick, 1997). Later Paclitaxel, a blockbuster drug, was isolated from Pacific yew tree, Taxus brevifolia (Wani et al., 1971). Though Paclitaxel acts as an antimitotic drug, it is the first anticancer drug discovered that stabilized microtubules and thus promotes their polymerization and used in the treatment of lung, ovarian, and breast cancer and Kaposi’s sarcoma (Shu, 1998)). Hayley and Susan (2001) demonstrated the beneficial multi-targeted mechanisms of paclitaxel on modulating various kinases and transcription factors involved in apoptosis. Undoubtedly, more effort is needed to search for new cancer drugs with the aid of better screening methods from plants and other natural sources either in the form of crude extracts or as components isolated from them.

Figure 11.3

Evaluations of medicinal plants for inflammatory disorders provide us so many successful molecules like curcumin from Curcuma longa, andrographolide from Andrographis paniculata, etc. Ramanathan et al. (2006) described the mode of action and possible multi targeted mechanisms of Curcumin. Curcumin inhibits cytokine with increasing an index of phagocytosis. Curcumin abrogated the expression of cytokines (TNF-alpha and IL-1beta) and chemokines (MIP-1beta, MCP-1and IL-8) in both peripheral blood monocytes (Yang, 2005). It is also observed that curcumin inhibited MAP kinase activation and the phosphorylation of ERK–1/2 and its downstream target Elk-1. (Giri et al., 2004). Curcumin down-regulates the expression of COX2, lipooxygenase, nitric oxide synthase inhibitors and inhibits the activity of c-Jun-N-terminal kinase, protein tyrosine kinases and protein serine/threonine kinases (Lin and Lin-Shiau, 2001) to produce potent anti-inflammatory activity. In addition curcumin modifies the expression of MMP-9, uPA, chemokines, cell surface adhesion molecules, cyclin D1, growth factor receptor EGFR (Nishino et al., 2004) to yield an effective anti tumor activity. These studies clearly show that curcumin can act on multiple targets thereby exhibit therapeutic and prophylactic activities on the treatment of polygenic disorders. The structural resemblance of Curcumin with Diarylheptanoids from Alpinia officinarum, and Gingerol from Zingiber officinale illustrates the similarity in biological activity of these compounds (Figure 11.5).