Pharmacogenomics and the Yin/Yang actions of ginseng: anti-tumor, angiomodulating and steroid-like activities of ginsenosides

Part 1 of an scientific article discussing the effects of ginseng in the treatment of cancer and cardiovascular disorders. Strong results are found to support the use of ginseng in these applications. Suggests that there is great potential for the future development of ginsenoside based drugs.

Abstract

In Chinese medicine, ginseng (Panax ginseng C.A. Meyer) has long been used as a general tonic or an adaptogen to promote longevity and enhance bodily functions. It has also been claimed to be effective in combating stress, fatigue, oxidants, cancer and diabetes mellitus. Most of the pharmacological actions of ginseng are attributed to one type of its constituents, namely the ginsenosides. In this review, we focus on the recent advances in the study of ginsenosides on angiogenesis which is related to many pathological conditions including tumor progression and cardiovascular dysfunctions.

Angiogenesis in the human body is regulated by two sets of counteracting factors, angiogenic stimulators and inhibitors. The 'Yin and Yang' action of ginseng on angiomodulation was paralleled by the experimental data showing angiogenesis was indeed related to the compositional ratio between ginsenosides Rg1 and Rb1. Rg1 was later found to stimulate angiogenesis through augmenting the production of nitric oxide (NO) and vascular endothelial growth factor (VEGF). Mechanistic studies revealed that such responses were mediated through the PI3K?Akt pathway. By means of DNA microarray, a group of genes related to cell adhesion, migration and cytoskeleton were found to be up-regulated in endothelial cells. These gene products may interact in a hierarchical cascade pattern to modulate cell architectural dynamics which is concomitant to the observed phenomena in angiogenesis. By contrast, the anti-tumor and anti-angiogenic effects of ginsenosides (e.g. Rg3 and Rh2) have been demonstrated in various models of tumor and endothelial cells, indicating that ginsenosides with opposing activities are present in ginseng. Ginsenosides and Panax ginseng extracts have been shown to exert protective effects on vascular dysfunctions, such as hypertension, atherosclerotic disorders and ischemic injury. Recent work has demonstrates the target molecules of ginsenosides to be a group of nuclear steroid hormone receptors. These lines of evidence support that the interaction between ginsenosides and various nuclear steroid hormone receptors may explain the diverse pharmacological activities of ginseng. These findings may also lead to development of more efficacious ginseng-derived therapeutics for angiogenesis-related diseases.

Panax ginseng

Background

Ginseng, Panax ginseng C.A. Meyer, a precious Chinese traditional medicinal herb, has been known clinically used in China for thousands of years. The genus name 'Panax' was derived from Greek. 'Pan' means 'all' and 'axos' means 'cure'. Literally 'Panax' can be translated as 'cure-all' or panacea. The herbal root is named ginseng because it is shaped like a man. Actually the term 'ginseng' represents two Chinese ideograms: 'gin' (pronounced ren) refers to 'man' and 'seng' (pronounced shen) refers to 'essence' It is believed to embody man's three mythical essences – body, mind and spirit. Thus it is also referred to as the lord or king of herbs [1]. Its medicinal efficacy was first documented in Shengnong Bencao Jing and it was later summarized by Li Shizhen in Bencao Gangmu and Zhongyao Zhi (Chinese Materia Medica) by People's Health Publishing House, Beijing, published in 1596 and 1959 respectively [1,2]. In the 18th century, the effectiveness of ginseng was recognized in the West, and subsequently, a large number of investigations were conducted on its botany, chemistry, pharmacology and therapeutic applications [3-7]. Ginseng has been used as a general tonic or adaptogen for promoting longevity especially in the Far East, especially China, Korea and Japan [8]. Ginseng is now one of the most popular herbal medicines used nutraceutically with an annual sale of over USD 200 million.

Ginseng is a deciduous perennial plant that belongs to the Araliaceae family. Currently, twelve species have been identified in the genus Panax (Table 1) [9]. Among them, Panax ginseng C. A. Meyer (Araliaceae), cultivated in China, Korea, Japan, Russia, and the US, P. quinquefolium L (American ginseng), grown in southern Canada and the US and P. notoginseng, cultivated in Yunnan and Guangxi provinces in China, represent the three most extensively investigated species. The pharmacological and therapeutic effects of ginseng have been demonstrated to affect the central nervous system (CNS), cardiovascular system, endocrine secretion, immune function, metabolism, biomodulating action, anti-stress, and anti-aging [5]. Recently, there have been controversies concerning the usefulness of ginseng in cancer therapy. Most studies claimed that the pharmacological effects of ginseng are attributed to its bioactive constituents such as ginsenosides, saponins, phytosterols, peptides, polysaccharides, fatty acids, polyacetylenes, vitamins and minerals [10]. In this review, we focus on the recent advances in the studies of ginsenosides on the modulation of angiogenesis (i.e. formation of blood vessels) which is a common denominator of many diseases, such as tumor and cardiovascular disorders (e.g. atherosclerosis).

Ginsenosides of ginseng

The most prominent constituent of ginseng is a saponin glycoside known as ginsenosides (Rx) (Figure 1). Recent research indicates that most of the pharmacological effects of ginseng are attributed to ginsenosides [11]. In general, the contents of ginsenosides vary widely ranging from 2 to 20% depending on the species, age and part of ginseng, and even vary with the preservation or extraction method [11-13]. More than 30 ginsenosides have been isolated, and characterized from various Panax species [14,15]. In terms of their chemical structural characteristics, ginsenosides can be classified into three major categories, namely protopanaxadiols (PPD) (e.g. Rb1, Rb2, Rc, Rd, Rg3, Rh2), protopanaxatriols (PPT) (e.g. Re, Rf, Rg1, Rg2, Rh1) and the oleanolic acid derivatives. Ginsenosides have a steroid-like skeleton consisting of four trans-rings, with modifications from each other depending the type (e.g. glucose, maltose and fructose), number of sugar moieties and the sites of attachment of the hydroxyl group (e.g. C-3, C-6, or C-20) (Figure 1). Ginsenosides are amphipathic in nature. The hydroxyl (-OH) group of ginsenosides allows both interactions between the polar head of the membrane phospholipids and the ?-OH group of cholesterol, while the hydrophobic steroid backbone can interact with the hydrophobic side chains of fatty acids and cholesterol. Indeed, these physiochemical interactions are greatly determined by the numbers and sites of polar hydroxyl groups on each ginsenoside. Moreover, ginsenosides have been shown to interact with numerous membrane proteins such as ion channels, transporters and receptors, which leads to a broad range of physiological activities [16].

[end of part 1]