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Guggul

1/30/02 Guggul (Commiphora mukul) Historical or traditional use (may or may not be supported by scientific studies): The classical treatise on Ayurvedic medicine, Sushrita Samhita, describes the use of guggul for a wide variety of conditions, including arthritis and obesity. One of its primary indications was a condition known as medoroga. This ancient diagnosis is similar to the modern description of atherosclerosis. Guggul was primarily used to prevent this condition by lowering serum cholesterol and triglyceride levels.
5/10/02 Gugulipid Research - clinical trails and background info on Guggul
1/30/02 New triterpenes, myrrhanol A and myrrhanone A, from guggul-gum resins, and their potent anti-inflammatory effect on adjuvant-induced air-pouch granuloma of mice. Bioorg Med Chem Lett 2001 Apr 23;11(8):985-9 PMID: 11327606 Myrrhanol A, a new triterpene isolated from guggul (Balsamodendron or Commiphora mukul Hook.)-gum resin, displays a potent anti-inflammatory effect on exudative pouch fluid, angiogenesis, and granuloma weights in adjuvant-induced air-pouch granuloma of mice. Its effects were more marked than those of hydrocortisone and the 50% aqueous methanolic extract of the crude drug. Myrrhanol A is a plausible candidate for a potent anti-inflammatory agent.
1/30/02 Comparison of the anti-inflammatory activity of Commiphora mukul (an indigenous drug) with those of phenylbutazone and ibuprofen in experimental arthritis induced by mycobacterial adjuvant Arzneimittelforschung 1977 Jul;27(7):1455-7 PMID: 578471 Anti-inflammatory agents such as phenylbutazone, ibuprofen and fraction "A" of gum-guggual from Commiphora mukkul were administered orally at a daily dose of 100, 100 and 500 mg/kg, respectively, for a period of five months. All three drugs decreased the thickness of the joint swelling during the course of drug treatment. These results indicate the beneficial role of phenylbutazone, ibuprofen and fraction "A" of gum-guggul in experimental arthritis.
5/10/02 Ancient Folk Remedy Points Toward Possible New Way To Control Cholesterol, Researchers Say May 2, 2002 In studies at his Baylor lab, Moore and Nancy L. Urizar showed the guggul resin compound, called guggulsterone, acted on the FXR receptor.
5/10/02 A Natural Product That Lowers Cholesterol as an Antagonist Ligand for the FXR. Science 2002 May 2 PMID: 11988537 Extracts of the resin of the guggul tree (Commiphora mukul) lower LDL (low-density lipoprotein) cholesterol levels in humans. The plant sterol guggulsterone (4,17(20)-pregnadiene-3,16-dione) is the active agent in this extract. We show that guggulsterone is a highly efficacious antagonist of the farnesoid X receptor (FXR), a nuclear hormone receptor that is activated by bile acids. Guggulsterone treatment decreases hepatic cholesterol in wild type mice fed a high cholesterol diet, but is not effective in FXR null mice. Thus, we propose that inhibition of FXR activation is the basis for the hypolipidemic activity of guggulsterone. Other natural products with specific biologic effects may modulate the activity of FXR or other relatively promiscuous nuclear hormone receptors.
10/3/02 Bile acids stimulate invasion and haptotaxis in human colorectal cancer cells through activation of multiple oncogenic signaling pathways. Oncogene 2002 Oct 3;21(44):6740-50 PMID: 12360401 BA-induced invasion was associated with activation of the Rac1 and RhoA GTPases and expression of the farnesoid X receptor. We conclude that bile acids stimulate invasion and haptotaxis in colorectal cancer cells via several cancer invasion signaling pathways.
5/10/02 Nuclear receptors What are they? Nuclear receptors (NRs) are transcription factors that are regulated by the binding of small, lipid-soluble ligands, such as steroid hormones, retinoids and thyroid hormones. A growing number of proteins have been identified that possess the structural features of nuclear receptors, but that lack known ligands. Known as orphan receptors, these proteins represent targets for novel signaling molecules. The study of nuclear orphan receptors has led to several important discoveries with major impacts on the fields of endocrinology, pharmacology, and molecular biology, and with immediate clinical relevance. These discoveries have pointed to the existence of previously unknown signaling pathways and created new paradigms to study transcriptional regulation of gene expression. Orphan receptors for which the signaling molecules (i.e., ligands) and biological functions have been elucidated, and which can be called "adopted" orphans, include the retinoid X receptor (RXR), the peroxisome proliferator activated receptors (PPAR), the liver X receptors (LXR), the pregnane X receptor or steroid and xenobiotic receptor (PXR/SXR), and the farnesol X receptor (FXR also termed bile acid receptor). In order to activate transcription, nuclear receptors, like most transcription factors, rely on cofactors. Initially it was thought that cofactors simply bridge transcription factors with the basic transcription machinery. Although this bridging function is definitely important, several cofactors also have enzymatic activities, suggesting that they could control gene expression by specifically modifying chromatin and DNA structure. In general, unactivated nuclear receptors form a complex with corepressors, which inhibit their transcriptional activity, whereas activation of the receptor (by ligand binding and/or phosphorylation) induces a conformational change which results in the dissociation of the corepressors and the recruitment of coactivator complexes that facilitate target gene transcription. These cofactors are hence an integral part of the nuclear receptor signaling pathways, and most likely affect many crucial metabolic pathways. The signaling pathways controlled by these "adopted" orphan receptors, as well as some "true" orphan receptors, play a predominant role in metabolism. Unlike the ligands for the classical hormone receptors, which are endocrine signaling molecules produced in minute quantities by endocrine organs (concentrations in the nanomolar range), ligands for these metabolic receptors are products from dietary origin or intermediates in metabolic pathways controlled by these "metabolic" receptors, and are present in large quantities in cells and tissues (concentrations in the micromolar range). Consistent with this observation, also larger concentrations of ligands are required to activate these metabolic receptors. These ligands include fatty acids (PPARs), sterols (LXRs), cholesterol-derived metabolites, such as bile acids (FXR), but also drugs and xenobiotics (SXR, PXR). Interestingly, these ligands are often found in excess in people exposed to an industrialized westernized life style (high caloric intake and lack of physical exercise). These receptors seem therefore receptors for excess and coordinate a thrifty response. Aberrant signaling by these "metabolic" receptors underpins many common disorders in our industrialized societies, such as obesity, insulin resistance, type 2 diabetes, hyperlipidemia, gallbladder disease, etc,…., often referred to as "syndrome X" or the metabolic syndrome. The receptor / cofactor complexes hence also constitute excellent therapeutic targets. This fact has been emphasized by the new avenues for the prevention and treatment of metabolic disorders which have been opened thanks to the careful dissection of signaling pathways controlled by the PPARs.
5/10/02 The nuclear receptors FXR and LXRalpha: potential targets for the development of drugs affecting lipid metabolism and neoplastic diseases Curr Pharm Des 2001 Mar;7(4):231-59 PMID: 11254888 The natural and synthetic FXR agonists trigger differentiation, inhibit cell proliferation and are potent inducers of apoptosis. The 1,1-bisphosphonate ester SR-45023A (Apomine) is presently being developed as an antineoplastic drug.
5/10/02 ILEX Oncology APOMINE appears to induce death of cancer cells. It also appears to be active in multiple drug-resistant cancer cells. In Phase I trials, the compound was well-tolerated and has demonstrated antitumor activity in heavily pretreated cancer patients with melanoma and ovarian cancer. Phase II trials are under way in patients with melanoma and patients with breast cancer. Based on its oral bioavailability, tolerability and efficacy, APOMINE is believed to have potential for broad use in a variety of cancers —alone or in combination with other chemotherapeutic agents. In addition to its anticancer activity, APOMINE, which was originally identified from a class of agents (similar to the statins) that lower cholesterol, appears to inhibit bone metastasis, a significant issue in the management of certain cancers, including breast and prostate cancer. Preclinical tests have not only shown APOMINE's ability to reduce the incidence and progression of breast cancer metastasis into bone tissue but also to increase the survival time of treated animals.
5/10/02 Preclinical and clinical activity of Apomine, a novel biophosphonate ester, in the prevention and treatment of melanoma AACR 2002 meeting abstract

Marianne Broome Powell, David S. Alberts, Maria Lluria-Prevatt, Amy Carrier, Ana Maria Lopez, Evan Hersh, Adam Kinsey, Susan Smith, Eric J. Niesor, Craig L. Bentzen, Stanford University, Stanford, CA; Arizona Cancer Center, Tucson, AZ; ILEX Oncology Research, Geneva, Switzerland. We have examined in both a preclinical model and in a phase I study the activity of a novel biophosphonate ester, Apomine, in the prevention and treatment of melanoma. Apomine (SR45023A) has been reported to activate the farnesoid X receptor, increase the rate of degradation of HMG-CoA reductase, and induce apoptosis in precancerous cells. It is active when administered orally and topically. In our TPras transgenic mouse melanoma model, we have studied the activity of topically administered Apomine (1.25m g/dose, 2-3X/week). We observed a 55% reduction in melanoma incidence in mice exposed to 50mg DMBA (1X/week for 5 weeks) and treated with Apomine. Treatment of TPras mouse melanoma cells with 10m M Apomine resulted in a reduction of activated Ras. In vitro studies demonstrated that Apomine blocked UV-induced reactive oxygen species in the melanoma cells and inhibited UV stimulation of phosphorylation of Akt, a downstream target of the Ras/PI3 kinase pathway. Additional downstream targets are under investigation. In a phase I study at the Arizona Cancer Center, Apomine has been administered orally (100mg BID continuously or 125 mg/m2 BID for 14 out of 21 days) to patients with chemotherapy resistant, metastatic melanoma. We observed a plasma Cmax of 17.1mg/ml and an AUC (0-12hr) of 183 mg.hr/ml. Two of 9 (22%) melanoma patients experienced prolonged disease stabilization; one patient with pulmonary metastases remains on study after 36 courses of Apomine therapy over 2.5 years. The results of these studies demonstrate that this novel agent's mechanism of action, in part, targets the Ras signaling pathway, oral and topical availability, and a non-myelosuppressive stability profile. We conclude that Apomine merits further clinical development for the prevention and treatment of melanoma.(This work was funded in part by NIH grant CA27502.
5/10/02 Apomine (SR-45023A) AACR 2000 Two preclinical studies for Apomine, under joint investigation by ILEX Oncology Inc and Symphar SA, were presented at the conference. In the first, Apomine was tested in human tumor specimens taken directly from patients. A total of 82 specimens, processed to give a single cell suspension, were continuously exposed to 10, 20 and 40 m g of Apomine. After 14 days, a colony count was performed. Inhibitory responses were seen in multiple tumor types; most notably breast, non-small cell lung and ovarian cancer specimens experienced 67%, 71% and 93% inhibition of colony formation, respectively. Cross-resistance experiments showed that samples resistant to standard agents, including cisplatin, taxol and etoposide, were sensitive to Apomine. Apomine is a potent activator of the farnesoid X activated receptor FXR. A clear correlation between this activity and induction of apoptosis has been demonstrated. In the second study, the relationship between the caspase-inducing and antiproliferative activities of Apomine were investigated. The results indicate that apomine inhibits the growth of a number of tumor cells lines with IC50 values ranging from 5 to 14 m g. This inhibition is correlated with a rapid induction of apoptosis. Caspase-3 activity, a key feature of apoptosis, was triggered by Apomine in HL60 cells. However, Apomine-induced apoptosis is not inhibited by caspase inhibitors suggesting that it activates additional antiproliferative mechanisms. The actions of Apomine are similar to those for the iosoprenoids and other FXR activators. Phase I studies are currently underway [363616].
5/10/02 ORPHAN & NUCLEAR RECEPTORS: Strategies for New Therapeutic Interventions June 27 - 28, 2002 • Holiday Inn On The Bay • San Diego, CA USA 11:30 Tissue Expression and Potential Role of LXRa and FXR In Neoplastic Tissues and Tumour Derived Cell Lines Eric J. Niesor, Director of Biosciences and Pharmacology, ILEX Oncology Research The orphan nuclear receptors LXRa and FXR have recently been shown to control a number of genes involved in bile acid and lipid metabolism. The role played by other orphan nuclear receptors such as RAR, RXR and PPARs in cell differentiation and proliferation is well established. LXRa and FXR might display similar activities and modulators of these receptors might be useful in the treatment of neoplastic diseases. The current status of studies on the expression of LXRa and FXR in normal, neoplastic tissues and tumour derived cell lines will be reviewed. The functional relationship between the expression these receptors, cell differentiation and malignancy will be discussed.
5/10/02 Hypocholesterolaemic and antiatherosclerotic effects of tetra-iso-propyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethyl-1,1-diphosphonate (SR-9223i). Arzneimittelforschung 2000 Apr;50(4):380-6 PMID: 10800637 This report not only describes the cholesterol-lowering properties in four species of animals fed normocholesterolaemic diets but also reductions in lipid deposition in the arteries of cholesterol-fed New Zealand white rabbits following the administration of SR-9223i...At the higher dose, the cholesteryl ester content of the aorta was half that of control animals. SR-9223i, at both doses, also inhibited the accumulation of cholesterol in the liver. SR-9223i has been shown to suppress HMG CoA reductase activity, inhibit ACAT activity and prevent lipid oxidation. These activities, demonstrated in vitro, have now been shown to translate into lipid lowering and antiatherosclerotic activities in vivo.
5/10/02 Phase I pharmacokinetic trial and correlative in vitro phase II tumor kinetic study of Apomine (SR-45023A), a novel oral biphosphonate anticancer drug Clin Cancer Res 2001 May;7(5):1246-50 PMID: 11350890 In vitro assay results showed that 63 and 91% of the ovarian cancers were sensitive (i.e., >70% inhibition of tumor cell growth) to Apomine at concentrations of 10 and 20 microM. The sensitivity rates were 91% for carboplatin (270 microM), 88% for cisplatin (33 microM), 41% for paclitaxel (5.9 microM), and 85% for topotecan (2.2 microM). CONCLUSIONS: These in vitro assay results, taken together with our preliminary plasma pharmacokinetic data, suggest that Apomine should be clinically active at the 125 mg/m(2) dose level.
5/10/02 The mevalonate/isoprenoid pathway inhibitor apomine (SR-45023A) is antiproliferative and induces apoptosis similar to farnesol Biochem Biophys Res Commun 2000 Apr 2;270(1):240-6 PMID: 10733934 Apomine (SR-45023A) is a new antineoplastic compound which is currently in clinical trials and representative of the family of cholesterol synthesis inhibitors 1,1-bisphosphonate esters. Apomine inhibits growth of a wide variety of tumor cell lines with IC(50) values ranging from 5 to 14 microM. The antiproliferative activity of apomine was studied in comparison with that of other inhibitors of the mevalonate/isoprenoid pathway of cholesterol synthesis, simvastatin, farnesol, and 25-hydroxycholesterol. All these compounds inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity. Apomine (IC(50) = 14 microM), simvastatin (IC(50) = 3 microM), farnesol (IC(50) = 60 microM), and 25-hydroxycholesterol (IC(50) = 2 microM) inhibited HL60 cell growth. Growth inhibition due to simvastatin was reverted by mevalonate, whereas the antiproliferative activity of apomine, farnesol, and 25-hydroxycholesterol was not. Apomine triggered apoptosis in HL60 cells in less than 2 h. Apomine and farnesol induced caspase-3 activity at concentrations similar to their IC(50) values for cell proliferation, whereas a 10-fold excess of simvastatin was necessary to trigger apoptosis compared to its potency on proliferation. Caspase-3 activity was not induced by 25-hydroxycholesterol. The overall similar profile on mevalonate synthesis inhibition, cell growth inhibition, and apoptosis suggests that apomine acts as a synthetic mimetic of farnesol.
5/10/02 CHOLESTEROL WARS: CITY OF HOPE SCIENTISTS DISCOVER BODY’S OWN MECHANISM FOR DESTROYING CHOLESTEROL LOS ANGELES, May 20, 1999 -- City of Hope scientists have discovered the molecular mechanism underlying the body's main method for destroying cholesterol. The discovery suggests novel therapies for lowering blood cholesterol--a key element in maintaining a healthy heart. The research, published in the May 21, 1999 issue of the journal Molecular Cell, was led by Barry M. Forman, MD, PhD, assistant professor of Molecular Medicine at City of Hope’s Gonda Diabetes and Genetic Research Center. It focuses on a process that takes place in the liver, which destroys cholesterol by converting it into compounds known as "bile acids." The bile acids are secreted into the intestine and removed from the body. In principle, cholesterol levels can be kept at a low level by increasing the activity for the cholesterol degradation pathway. This is more easily said than done, since the body carefully controls this process by a feedback loop -- the biological equivalent of a thermostat. Instead of maintaining a constant temperature, this feedback loop maintains constant levels of cholesterol. This can be a problem for individuals with high cholesterol. In effect, their "cholesterol thermostat" may be set too high. Until now, scientists had been unable to determine the exact nature of the molecules that control the cholesterol thermostat. Dr. Forman's group has uncovered this mechanism. First, the researchers discovered that the cholesterol degradation products (bile acids) bind to a sensor molecule known as FXR. Dr. Forman’s research had previously shown that the FXR sensor was a member of a class of molecules known as "nuclear receptors" that can switch genes on and off. In the next phase of research, Dr. Forman's group demonstrated that bile acids caused the FXR sensor to shut down genes involved in cholesterol metabolism. With these findings, the steps controlling the cholesterol thermostat became clear: The liver first tries to remove cholesterol by converting it to bile acids. As more and more bile acids are made, they bind to FXR. This binding in turn stimulates FXR to act on cholesterol-related genes, halting the further degradation of cholesterol. Through this process, the cholesterol thermostat limits the amount of cholesterol that the body can destroy. This works well in healthy people but can be a problem for people with high cholesterol. "By understanding this mechanism, we can now begin to develop new treatments that could lower blood cholesterol," says Dr. Forman. "In effect, we can search for drugs that will lower the cholesterol thermostat. The type of drug that would be required is known as an antagonist--a molecule that would prevent bile acids from binding to FXR. Blocking FXR in this way would allow the degradation of cholesterol to proceed more efficiently." Dr. Forman notes that antagonists to other nuclear receptors have been successfully used to treat other diseases. The breast cancer drug Tamoxifen, for example, used to prevent breast cancer, is an antagonist that prevents the hormone estrogen from binding to the estrogen receptor. A cholesterol-lowering therapy based on this approach could significantly benefit a large number of patients who suffer from high cholesterol. These people are at high risk for heart disease, which is the leading cause of mortality in the United States.
5/10/02 Researchers reveal cholesterol control mechanisms September 15, 2000 Scientists have long suspected that mammals have a sensor that controls the elimination and absorption of dietary cholesterol, but how to activate the sensor remained a mystery. Researchers have now identified three proteins—retinoid, faresnoid and liver X receptors, or RXR, FXR and LXR—that act as a sort of biological switch, according to findings published in a recent issue of Science. The receptors work in teams to rid the body of too much cholesterol and inhibit lipid absorption. LG268, as it turns out, activates RXR, which in turn activates LXR and FXR. Already under consideration for clinical use for chemotherapy and diabetes, LG268 enhances FXR's ability to repress a gene crucial for bile acid synthesis in the liver and cholesterol absorption in the intestine. It also activates LXR's ability to speed up production of ABC1, a reverse cholesterol transporter that moves excess cholesterol out of cells to the liver for excretion.
5/10/02 A New Approach for Lowering Cholesterol The new idea is to rid cells of excess cholesterol through control of a nuclear master switch, the retinoid X receptor (RXR), which combines with other proteins to activate genes involved in cholesterol metabolism. In the liver, for instance, RXR combines with the liver X receptor (LXR) to activate a gene whose product breaks down cholesterol into bile acids. At the University of Texas Southwestern Medical Center, Dallas, pharmacologists used a drug called LG268 to activate RXR. Tested in animals fed a high-cholesterol diet, the treatment not only reduced elevated liver cholesterol levels but also exerted a powerful block on cholesterol absorption from the gut. Further experiments revealed that the drug increased enterocyte production of a protein called ABC1, which is known to pump cholesterol out of cells. (Tangier disease, in which intracellular cholesterol retention produces severe, premature atherosclerosis, is caused by a mutation in the ABC1 gene.) By the same mechanism, the drug pumped cholesterol out of macrophages. Last, the drug boosted the activity of RXR paired with a protein called FXR, a partnership that reduced hepatic production of bile acids, inhibiting bile-acid-dependent absorption of cholesterol and other lipids. The bile-acid-decreasing RXR/FXR pathway appears to be physiologically dominant over the bile-acid-increasing RXR/LXR pathway.
6/10/02 Guggul CAM Intellihealth

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