[MPWG] Inflammation, Cancer, and Targets of Ginseng -- Hofseth and Wargovich 2007 -- Journal of Nutrition 137 (1): 183S

[Patricia_DeAngelis at fws.gov]

Another recent research article that was provided by a listmember (thanks, 
Bob!).

Here are some highlights...

>Chronic inflammation is associated with a high cancer risk.
>...there are many natural food and herbal products that target the 
inflammatory cascade.
>We have been examining the role of ginseng on the inflammatory cascade.
>There is evidence that ginseng has potent effects on key players in the 
inflammatory cascade.

Another potential use for cultivated ginseng!?!

-Patricia

- - - - - - 

Inflammation, Cancer, and Targets of Ginseng -- Hofseth and Wargovich 137 
(1): 183S -- Journal of Nutrition 
© 2007 The American Society for Nutrition J. Nutr. 137:183S-185S, January 
2007

Supplement: International Research Conference on Food, Nutrition, and 
Cancer
Inflammation, Cancer, and Targets of Ginseng1­3, 
Lorne J. Hofseth4,* and Michael J. Wargovich5 
4 Department of Basic Pharmaceutical Sciences, South Carolina College of 
Pharmacy and 5 Department of Pathology and Microbiology, School of 
Medicine, 
University of South Carolina, Columbia, SC 29208 
* To whom correspondence should be addressed. E-mail: hofseth at cop.sc.edu.

         A
 
Chronic inflammation is associated with a high cancer risk. At the 
molecular 
level, free radicals and aldehydes, produced during chronic inflammation, 
can 
induce deleterious gene mutation and posttranslational modifications of 
key 
cancer-related proteins. Other products of inflammation, including 
cytokines, 
growth factors, and transcription factors such as nuclear factor B, 
control the 
expression of cancer genes (e.g., suppressor genes and oncogenes) and key 
inflammatory enzymes such as inducible nitric oxide synthase and 
cyclooxygenase-2. These enzymes in turn directly influence reactive oxygen 

species and eicosanoid levels. The procancerous outcome of chronic 
inflammation 
is increased DNA damage, increased DNA synthesis, cellular proliferation, 
disruption of DNA repair pathways and cellular milieu, inhibition of 
apoptosis, 
and promotion of angiogenesis and invasion. Chronic inflammation is also 
associated with immunosuppression, which is a risk factor for cancer. 
Current 
treatment strategies for reactive species overload diseases are frequently 
aimed 
at treating or preventing the cause of inflammation. Although these 
strategies 
have led to some progress in combating reactive species overload diseases 
and 
associated cancers, exposure often occurs again after eradication, 
treatment to 
eradicate the cause fails, or the treatment has long-term side effects. 
Therefore, the identification of molecules and pathways involved in 
chronic 
inflammation and cancer is critical to the design of agents that may help 
in 
preventing the progression of reactive species overload disease and cancer 

associated with disease progression. Here, we use ginseng as an example of 
an 
antiinflammatory molecule that targets many of the key players in the 
inflammation-to-cancer sequence. 


Overall, chronic inflammation is bad for human health. Extensive 
laboratory and 
clinical evidence shows that chronic inflammation contributes to cancer 
(1). 
Information on the key molecules involved in inflammation-driven 
carcinogenesis 
is emerging. These molecules include nuclear factor B (NF-B)6; toll-like 
receptors; reactive oxygen and nitrogen species (RONS); cyclooxygenases 
(COXs); 
nitric oxide synthases (NOSs); pro- and antiinflammatory cytokines; 
metals; 
antioxidant enzymes; peroxisome proliferator-activated receptor ligands; 
kinases; growth factors; and the tumor suppressor proteins, p53 and 
retinoblastoma (pRb) proteins. Because we recently reviewed these key 
players in 
inflammation (1), here we present a summary table and figure (Table 1 and 
Fig. 
1). All are potential targets for cancer chemoprevention and treatment. 
Many 
specific and general mediators of these targets have strong potential to 
be used 
as chemopreventive agents in inflammation-mediated carcinogenesis. 
Successful 
applications include the use of tumor necrosis factor- inhibitors 
(monoclonal 
antibodies) for Crohn disease (6) and interferon- for hepatitis (7). More 
general medicines that have consistently been found to inhibit many 
diseases 
associated with chronic inflammation (cancer, cardiovascular disease, 
diabetes) 
are nonsteroidal antiinflammatory drugs such as acetylsalicylic acid. A 
derivative, 5-acetylsalicylic acid, has been used with remarkable success 
in 
ameliorating inflammatory bowel disease (8). The mechanisms of 
5-acetylsalicylic 
acid are not fully understood, but it inhibits COX weakly, activates 
apoptosis, 
inhibits proliferation and NF-B, scavenges RONS, and inhibits 
RON-associated 
base damage (1). 

 

              Figure 1  The ubiquitous effects of ginseng on key players 
            involved in the inflammation-to-cancer sequence. 
Abbreviations: COX, 
            cyclooxygenase; MMP, matrix metalloprotease; NF-B, nuclear 
factor B; 
            NO, nitric oxide; NOS, nitric oxide synthase; pRb, 
retinoblastoma 
            protein; PPAR, peroxisome proliferators activated receptor; 
RONS, 
            reactive oxygen and nitrogen species; ROS, reactive oxygen 
species; 
            TLR, Toll-like receptor.


 
To this end, there are many natural food and herbal products that target 
the 
inflammatory cascade. These include red wine (9,10), raw fruits and 
vegetables 
(11,12), and fiber (13,14). Many others, such as green tea (15), curcumin 
(16), 
and garlic (17), have strong antiinflammatory properties. We have been 
examining 
the role of ginseng on the inflammatory cascade. The following is evidence 
in 
support of the ability of ginseng to target multiple players in this 
cascade. 

Unconventional treatment: ginseng as a dietary supplement
Several types of ginseng are found throughout the world, and all are part 
of the 
Araliaceae family, species in the genus Panax. The name ginseng comes from 
the 
Chinese words "Jen Sheng," meaning "man-herb," because of the humanoid 
shape of 
the root or rhizome of the plant, which is the part of the plant most 
commonly 
consumed. The name Panax means "all healing," which describes the 
traditional 
belief that ginseng has properties to heal all aspects of the body. There 
are 
several different species of ginseng: 2 of the most commonly used are P. 
ginseng 
(Chinese ginseng) and P. quinquefolius (American ginseng) (18). P. ginseng 
has 
been used in the Orient for thousands of years, and P. quinquefolius has 
been 
used by Native Americans for hundreds of years (19). Ginseng is prepared 
and 
used in several ways: as fresh ginseng (sliced and eaten, or brewed in a 
tea), 
white ginseng (peeled and dried), or red ginseng (peeled, steamed, and 
dried). 
Traditional medicine suggests that red ginseng has the most potency but 
modern 
research has shown that all forms have many beneficial properties 
(18,20,21). 
Ginseng is believed to be most potent when harvested after 4­5 y of growth 
(22). 

Studies indicate that ginseng has potential as a chemopreventive agent or 
adjuvant treatment. Some of the cancers shown to decrease significantly 
with 
ginseng use include cancers of the pharynx, stomach, liver, pancreas, and 
colon 
(22,23). Mechanisms include inhibition of DNA damage (24), induction of 
apoptosis (25), and inhibition of cell proliferation (26). It is also 
becoming 
increasingly clear that ginseng has potent effects on the inflammatory 
cascade 
and may inhibit the inflammation-to-cancer sequence. 

Ginseng targets the inflammatory players
There is evidence that ginseng has potent effects on key players in the 
inflammatory cascade (Fig. 1). For example, ginsan, a polysaccharide 
extracted 
from P. ginseng, showed inhibition of s, the p38 MAP kinase pathway, and 
NF-B in 
vitro and inhibition of proinflammatory cytokines in vivo (27). The 
ginsenoside 
Rg3 was shown to inhibit phorbol ester­induced COX-2 and NF-B induction 
(28). 
BST204, a fermented ginseng extract, can inhibit inducible NOS (iNOS) 
expression 
and subsequent nitric oxide production from lipopolysaccharide-stimulated 
RAW264.7 murine macrophages. In contrast, others showed that incubation of 
the 
same cells with P. ginseng showed a dose-dependent stimulation of iNOS 
(29). We 
are currently examining the effects of P. quinquefolius on nitric oxide 
production in both ANA-1 mouse macrophages and colon cells as a part of 
ongoing 
investigations into the potential for ginseng to inhibit colon cancer. We 
(25) 
recently showed that P. ginseng can inhibit chemically induced abberant 
crypt 
foci in mice. As mentioned, a cytokine storm is associated with active 
inflammation. It is therefore interesting to find that ginseng inhibits 
the 
lipopolysaccharide-induced production of tumor necrosis factor- and other 
proinflammatory cytokines by cultured macrophages (30). Such an effect, 
therefore, may have a chemopreventive outcome. 

Ginseng can also inhibit other mediators of the inflammation-to-cancer 
sequence, 
such as matrix metalloproteases and kinase pathways (31). Recently it was 
also 
shown to activate peroxisome proliferator-activated receptor- (32) and 
transforming growth factor-ß1 (33), which have the potential to inhibit 
the 
inflammation-to-cancer sequence (1). Finally, studies have found an effect 
of 
ginseng on key tumor suppressor proteins. For example, the ginsenoside Rs3 

induces p53 and p21 (34) and other proapoptotic molecules (35). Ginseng 
can also 
cause the dephosphorylation and activation of the retinoblastoma tumor 
suppressor protein (36). The influence of various forms of ginseng on 
these 
molecules has the ultimate effect of stimulating apoptosis and inhibiting 
cell 
cycle progression. Overall, this is a good example of a natural herb that 
has 
ubiquitous properties that are conducive to stopping inflammatory-mediated 

carcinogenesis. Clinical studies on free radical overload diseases are 
warranted. 

         FOOTNOTES 
 
1 Published in a supplement to The Journal of Nutrition. Presented as part 
of 
the International Research Conference on Food, Nutrition, and Cancer held 
in 
Washington, DC, July 13­14, 2006. This conference was organized by the 
American 
Institute for Cancer Research and the World Cancer Research Fund 
International 
and sponsored by (in alphabetical order) the California Walnut Commission; 

Campbell Soup Company; Cranberry Institute; Hormel Institute; IP-6 
International, Inc.; Kyushu University, Japan Graduate School of 
Agriculture; 
National Fisheries Institute; and United Soybean Board. Guest editors for 
this 
symposium were Vay Liang W. Go, Susan Higginbotham, and Ivana Vucenik. 
Guest 
Editor Disclosure: V.L.W. Go, no relationships to disclose; S. 
Higginbotham and 
I. Vucenik are employed by the conference sponsor, the American Institute 
for 
Cancer Research. 
2 Author Disclosure: No relationships to disclose. 
3 This work was supported in part by NIH grant 1 R21 DK071541-01A1 and the 
COBRE 
funded Center for Colon Cancer Research, NIH Grant P20 RR17698-01. 
6 Abbreviations used: COX, cyclooxygenase; NF-B, nuclear factor B; NOS, 
nitric 
oxide synthase; MMP, matrix metalloprotease; PPAR, peroxisome 
proliferators 
activated receptor; RONS; reactive oxygen and nitrogen species. 

         LITERATURE CITED 
      TOP
      ABSTRACT
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