Saturday, June 01, 2013

Ursolic Acid for Cancer Prevention and Treatment

There is a new natural substance (well, not really new) that has been getting serious attention from the cancer research world. Ursolic Acid has been around for more than a decade, but it the last few years its prominence as a chemopreventive agent has increased considerably.

Via Wikipedia (follow the links for citation information):
Ursolic acid (sometimes referred to as 3-beta-3-hydroxy-urs-12-ene-28-oic-acid or 3-β-hydroxy-urs-12-en-28-oic acid) is a pentacyclic triterpene acid capable of inhibiting various cancer cell types by inhibiting the STAT3 activation pathway,[2][3] one of which includes human fibrosarcoma by reducing expression of matrix metalloproteinase-9 via glucocorticoid receptors. It may also decrease proliferation of cancer cells and induce apoptosis.[4] Ursolic acid has also been shown to inhibit JNK expression and IL-2 activation of JURKAT leukemic T Cells leading to the reduction in proliferation and T cell activation.[5] Ursolic acid is present in many plants, including apples, basil, bilberry, cranberries, elder flower, peppermint, rosemary, lavender, oregano, thyme, hawthorn, and prunes. Apple peels contain large quantities of ursolic acid and related compounds.[6]

Ursolic acid can serve as a starting material for synthesis of more potent bioactive derivatives, such as antitumor agents.[7] It has been found to reduce muscle atrophy and to stimulate muscle growth in mice.[8][9] Ursolic acid has potential use as a cardioprotective compound.[10]

Ursolic acid was found to be a weak aromatase inhibitor (IC50 = 32 μM).[11]

Ursolic acid has been shown to increase the amount of muscle and brown fat and decrease white fat obesity and associated conditions when added to diets fed to mice.[12]
If you look for this in health food stores, most of the supplements you'll find are from apple skins or from basil and rosemary. The problem with these supplements is that ursolic acid content is relatively low. For example, NOW Foods Holy Basil Extract (2% standardized) only offers 10 mg per 500 mg capsule; Nature's Way Holy Basil Extract (2.5% standardized) only offers 11.25 mg per 450 mg capsule.

However, in the sports supplement world, this substance has been known for a while as a potential aromatase inhibitor (aromatase converts testosterone to estrogen, especially when T levels are too high) and as a possible "nutrient partitioning" agent (switches metabolism from fat storage to muscle building in the presence of weight training and excess calories). Supplements in this area are dosed much higher: Urso-X contains 600 mg of rosemary leaf per two-capsule dose, being 25% ursolic acid, or 150 mg of ursolic acid per two-capsules; Ursolix is dosed at 225 mg of ursolic acid per 3 capsules (Holy Basil extract, 25% standardized).

Cancer Research


Over the last ten or so years, there has been an increasing amount of research into the use of ursolic acid (or modified pharmaceutical versions of the molecule) in treating and preventing cancer. It turns out that ursoic acid has potent chemopreventive properties.

A study last year (March, 2012) showed that ursolic acid inhibits the initiation and progression of Prostate Cancer by modulating pro-Inflammatory pathways. This puts ursolic acid in the same top tier category as curcumin and resveratrol (the two best researched and validated natural chemopreventive supplements for prostate cancer.

A more recent article (May, 2013) showed that ursolic acid simultaneously targets multiple signaling pathways to suppress proliferation and induce apoptosis (programmed cell death) in colon cancer cells.

Finally, a study from June, 2012, looked at how ursolic acid increases skeletal muscle and brown fat and decreases diet-induced obesity, glucose intolerance, and fatty liver disease in mice fed a high-fat diet with ursolic acid. The results were striking:
[U]rsolic acid increased skeletal muscle mass, fast and slow muscle fiber size, grip strength and exercise capacity. Interestingly, ursolic acid also increased brown fat, a tissue that shares developmental origins with skeletal muscle. Consistent with increased skeletal muscle and brown fat, ursolic acid increased energy expenditure, leading to reduced obesity, improved glucose tolerance and decreased hepatic steatosis.
First up, the two cancer articles, then last the article the ergogenic and metabolic effects of ursolic acid. All of these articles are Open Access via PLoS ONE.

Ursolic Acid Inhibits the Initiation, Progression of Prostate Cancer and Prolongs the Survival of TRAMP Mice by Modulating Pro-Inflammatory Pathways



Muthu K. Shanmugam, Tina H. Ong, Alan Prem Kumar, Chang K. Lun, Paul C. Ho, Peter T. H. Wong, Kam M. Hui, Gautam Sethi


Abstract


Prostate cancer is one of the leading causes of cancer death among men worldwide. In this study, using transgenic adenocarcinoma of mouse prostate (TRAMP) mice, the effect of diet enriched with 1% w/w ursolic acid (UA) was investigated to evaluate the stage specific chemopreventive activity against prostate cancer. We found that TRAMP mice fed with UA diet for 8 weeks (weeks 4 to 12) delayed formation of prostate intraepithelial neoplasia (PIN). Similarly, mice fed with UA diet for 6 weeks (weeks 12 to 18) inhibited progression of PIN to adenocarcinoma as determined by hematoxylin and eosin staining. Finally, TRAMP mice fed with UA diet for 12 weeks (weeks 24 to 36) demonstrated markedly reduced tumor growth without any significant effects on total body weight and prolonged overall survival. With respect to the molecular mechanism, we found that UA down-regulated activation of various pro-inflammatory mediators including, NF-κB, STAT3, AKT and IKKα/β phosphorylation in the dorsolateral prostate (DLP) tissues that correlated with the reduction in serum levels of TNF-α and IL-6. In addition, UA significantly down-regulated the expression levels of cyclin D1 and COX-2 but up-regulated the levels of caspase-3 as revealed by immunohistochemical analysis of tumor tissue sections. Finally, UA was detected in serum samples obtained from various mice groups fed with enriched diet in nanogram quantity indicating that it is well absorbed in the GI tract. Overall, our findings provide strong evidence that UA can be an excellent agent for both the prevention and treatment of prostate cancer.

Full Citation: 
Shanmugam MK, Ong TH, Kumar AP, Lun CK, Ho PC, et al. (2012). Ursolic Acid Inhibits the Initiation, Progression of Prostate Cancer and Prolongs the Survival of TRAMP Mice by Modulating Pro-Inflammatory Pathways. PLoS ONE 7(3): e32476. doi:10.1371/journal.pone.0032476

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Ursolic Acid Simultaneously Targets Multiple Signaling Pathways to Suppress Proliferation and Induce Apoptosis in Colon Cancer Cells



Jingshu Wang, Liqun Liu, Huijuan Qiu, Xiaohong Zhang, Wei Guo, Wangbing Chen, Yun Tian, Lingyi Fu, Dingbo Shi, Jianding Chengl, Wenlin Huang, Wuguo Deng


Abstract


Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid distributed in medical herbs, exerts antitumor effects and is emerging as a promising compound for cancer prevention and therapy, but its excise mechanisms of action in colon cancer cells remains largely unknown. Here, we identified the molecular mechanisms by which UA inhibited cell proliferation and induced apoptosis in human colon cancer SW480 and LoVo cells. Treatment with UA led to significant inhibitions in cell viability and clone formation and changes in cell morphology and spreading. UA also suppressed colon cancer cell migration by inhibiting MMP9 and upregulating CDH1 expression. Further studies showed that UA inhibited the phosphorylation of Akt and ERK proteins. Pretreatment with an Akt or ERK-specific inhibitor considerably abrogated the proliferation inhibition by UA. UA also significantly inhibited colon cancer cell COX-2 expression and PGE2 production. Pretreatment with a COX-2 inhibitor (celecoxib) abrogated the UA-induced cell proliferation. Moreover, we found that UA effectively promoted NF-κB and p300 translocation from cell nuclei to cytoplasm, and attenuated the p300-mediated acetylation of NF-κB and CREB2. Pretreatment with a p300 inhibitor (roscovitine) abrogated the UA-induced cell proliferation, which is reversed by p300 overexpression. Furthermore, UA treatment induced colon cancer cell apoptosis, increased the cleavage of PARP, caspase-3 and 9, and trigged the release of cytochrome c from mitochondrial inter-membrane space into cytosol. These results indicate that UA inhibits cell proliferation and induces apoptosis in colon cancer cells through simultaneous modulation of the multiple signaling pathways such as MMP9/CDH1, Akt/ERK, COX-2/PGE2, p300/NF-κB/CREB2, and cytochrome c/caspase pathways.

Full Citation: 
Wang J, Liu L, Qiu H, Zhang X, Guo W, et al. (2013) Ursolic Acid Simultaneously Targets Multiple Signaling Pathways to Suppress Proliferation and Induce Apoptosis in Colon Cancer Cells. PLoS ONE 8(5): e63872. doi:10.1371/journal.pone.0063872

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Ursolic Acid Increases Skeletal Muscle and Brown Fat and Decreases Diet-Induced Obesity, Glucose Intolerance and Fatty Liver Disease 

Steven D. Kunkel, Christopher J. Elmore, Kale S. Bongers, Scott M. Ebert, Daniel K. Fox, Michael C. Dyle, Steven A. Bullard, Christopher M. Adams

Abstract

Skeletal muscle Akt activity stimulates muscle growth and imparts resistance to obesity, glucose intolerance and fatty liver disease. We recently found that ursolic acid increases skeletal muscle Akt activity and stimulates muscle growth in non-obese mice. Here, we tested the hypothesis that ursolic acid might increase skeletal muscle Akt activity in a mouse model of diet-induced obesity. We studied mice that consumed a high fat diet lacking or containing ursolic acid. In skeletal muscle, ursolic acid increased Akt activity, as well as downstream mRNAs that promote glucose utilization (hexokinase-II), blood vessel recruitment (Vegfa) and autocrine/paracrine IGF-I signaling (Igf1). As a result, ursolic acid increased skeletal muscle mass, fast and slow muscle fiber size, grip strength and exercise capacity. Interestingly, ursolic acid also increased brown fat, a tissue that shares developmental origins with skeletal muscle. Consistent with increased skeletal muscle and brown fat, ursolic acid increased energy expenditure, leading to reduced obesity, improved glucose tolerance and decreased hepatic steatosis. These data support a model in which ursolic acid reduces obesity, glucose intolerance and fatty liver disease by increasing skeletal muscle and brown fat, and suggest ursolic acid as a potential therapeutic approach for obesity and obesity-related illness.

Full Citation: 
Kunkel SD, Elmore CJ, Bongers KS, Ebert SM, Fox DK, et al. (2012) Ursolic Acid Increases Skeletal Muscle and Brown Fat and Decreases Diet-Induced Obesity, Glucose Intolerance and Fatty Liver Disease. PLoS ONE 7(6): e39332. doi:10.1371/journal.pone.0039332

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