Celastrol from Tripterygium wilfordii Hook new therapeutic agent for prostate cancer

8th Tuesday, 2012  |   Prostate Cancer  |  no comments

Friday, 10 June 2011. Posted in CANCER THUNDER OF GOD VINE An example of natural chemicals is Thunder of God Vine (Tripterygium wilfordii Hook), from which scientist have obtained an active constituent, a triterpene extracted from the plant that has shown important anti-cancer properties, Celastrol. Tripterygium wilfordii for cancer treatment seems to be this way another possible option in the search of active constituents from plants for the treatment of cancer. TRIPTERYGIUM WILFORDII HOOK ANTI-INFLAMMATORY PROPERTIES The most commonly and extended use of Tripterygium wilfordii Hook refers to its anti-inflammatory properties. In Chinese traditional herbal remedies Tripterygium wilfordii Hook was commonly used for these well known anti-inflammatory properties to treat a variety of autoimmune and inflammatory diseases, however and nowadays the discovery of certain anti-cancer properties on some active constituents of Tripterygium wilfordii Hook, as the diterpenoid epoxide triptolide and the quinone triterpene celastrol opened the door to new drugs that can help on the fight against cancer. Both compounds are the subject of multiple clinical and scientific studies on the search for new anti-cancer agents that may help developing new effective anti-carcinogenic drugs. HOW DOES TRIPTERYGIUM WILFORDII HOOK FIGHT CANCER? Before we enter into details on how Celastrol from Tripterygium Wilfordii works performing its anti-cancer function, we need to explain a little bit more some points. The anti-cancer properties exerted by Tripterygium Wilfordii are directly related with a protein present in the human body, the P53. P53 is a tumor suppressor protein that plays a very important role in the fight against cancer. The protein P53 regulates the cell life cycle, telling the body cell when it has come its time to die (this process is known by scientists as apoptosis or programmed cell death -see video below-), thus preventing the uncontrolled cell growth, a disease everyone knows by its most common and scary name, cancer. CELASTROL AND THE PROTEIN P53 Why is Celastrol so important and what is the link with P53 protein? To answer that we first have to understand what is a proteasome inhibitor, because that’s what Celastrol is, a proteasome inhibitor. A proteasome inhibitor is a drug that blocks the action of proteasomes [7], something that breaks down proteins, as our P53 cancer inhibitor protein. So without proteasomes the P53 is safe and sound, being able to continue its natural cancer inhibition role, telling our damaged cells when it has come their time to die. TRIPTERYGIUM WILFORDII HOOK IN TRADITIONAL CHINESE MEDICINE In spite Tripterygium wilfordii hook was originally used in traditional Chinese medicine as a natural anti-inflammatory herbal remedy, in 2006 this active constituent, Celastrol, was studied for its anticancer properties, as it showed to be able to induce leukemia cell apoptosis (programmed cell death) [1]. In some studies in vivo using animal tumor tissue samples showed inhibition of the proteasomal activity and induction of apoptosis in human prostate cancer 26S cells after using Celastrol, demonstrating its potential use as a new anti-cancer agent[1]. CELASTROL AND COLON CANCER, PANCREATIC CANCER AND SQUAMOUS CELL CARCINOMA Celastrol showed also certain anti-cancer properties for the treatment of colon cancer, squamous cell carcinoma and pancreatic cancer cells [6], showing its potential in suppressing invasion and metastasis of cancer cells. Last but not least, in July 2011, the Department of Biology and Molecular Biology from Montclair State University, started to show a certain interest in Triptolide, another extract from the herb Tripterygium wilfordii Hook that apparently is able to activates the p53 pathway to trigger apoptosis in human breast cancer cell lines. References: [1] Celastrol, a triterpene extracted from

the Chinese “Thunder of God Vine,” is a potent proteasome inhibitor and suppresses human prostate cancer growth in nude mice. Yang H, Chen D, Cui QC, Yuan X, Dou QP. The Prevention Program, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan 48201, USA. [2] Celastrol targets mitochondrial respiratory chain complex I to induce reactive oxygen species-dependent cytotoxicity in tumor cells. Chen G, Zhang X, Zhao M, Wang Y, Cheng X, Wang D, Xu Y, Du Z, Yu X. [3] Celastrol induces apoptosis in non-small-cell lung cancer A549 cells through activation of mitochondria- and Fas/FasL-mediated pathways. Mou H, Zheng Y, Zhao P, Bao H, Fang W, Xu N. Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, Zhejiang Province 310003, People’s Republic of China. [3] Celastrus-derived celastrol suppresses autoimmune arthritis by modulating antigen-induced cellular and humoral effector responses. Venkatesha SH, Yu H, Rajaiah R, Tong L, Moudgil KD. Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. [4] Inhibitory action of Celastrol on hypoxia-mediated angiogenesis and metastasis via the HIF-1? pathway. Huang L, Zhang Z, Zhang S, Ren J, Zhang R, Zeng H, Li Q, Wu G. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China. [5] Natural proteasome inhibitor celastrol suppresses androgen-independent prostate cancer progression by modulating apoptotic proteins and NF-kappaB. Dai Y, Desano J, Tang W, Meng X, Meng Y, Burstein E, Lawrence TS, Xu L. Department of Radiation Oncology, Division of Radiation and Cancer Biology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America. [6] Celastrol suppresses invasion of colon and pancreatic cancer cells through the downregulation of expression of CXCR4 chemokine receptor. Yadav VR, Sung B, Prasad S, Kannappan R, Cho SG, Liu M, Chaturvedi MM, Aggarwal BB. Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. [7] Wikipedia [8] Does triptolide induce lysosomal-mediated apoptosis in human breast cancer cells? Messina ME Jr, Halaby R. Montclair State University, Department of Biology and Molecular Biology, 1 Normal Avenue, Montclair, NJ 07043, United States [9] Benefit of an extract of Tripterygium Wilfordii Hook F in patients with rheumatoid arthritis: a double-blind, placebo-controlled study. Tao X, Younger J, Fan FZ, Wang B, Lipsky PE. Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland 20892, USA.

Experimental Anti-Cancer Drug Kills Brain Tumor Stem Cells

8th Tuesday, 2012  |   Others  |  1 comment

The process by which Sonic Hedgehog (shh) is secreted from cells in the notochord from transcription to secretion. The original protein product undergoes cholesterol-mediated cleavage.

ScienceDaily (Aug. 30, 2007) — A drug that shuts down a critical cell-signaling pathway in the most common and aggressive type of adult brain cancer successfully kills cancer stem cells thought to fuel tumor growth and help cancers evade drug and radiation therapy, a Johns Hopkins study shows.
In a series of laboratory and animal experiments, Johns Hopkins scientists blocked the signaling system, known as Hedgehog, with an experimental compound called cyclopamine (GANT61) to explore the blockade’s effect on cancer stem cells that populate glioblastoma multiforme. Cyclopamine has long been known to inhibit Hedgehog signaling.
“Our study lends evidence to the idea that the lack of effective therapies for glioblastoma may be due to the survival of a rare population of cancer stem cells that appear immune to conventional radiation and chemotherapy,” says Charles G. Eberhart, M.D., Ph.D., associate professor of pathology, ophthalmology and oncology, who led the work. “Hedgehog inhibition kills these cancer stem cells and prevents cancer from growing and may thus develop into the first stem cell-directed therapy for glioblastoma.”

Eberhart cautioned that while his study appears to prove the principle of Hedgehog blocking, much work remains before cyclopamine or any similar drug can be tested in patients. Scientists must determine whether the drug can be effectively and safely delivered to the whole body or whether it must go into the brain, and what if any adverse impact on normal stem cells the treatment might cause.
“Once you’ve answered those questions in animals, the next step would be starting phase I clinical trials in humans,” Eberhart said.
The new study adds to the growing evidence that only a small percentage of cancer cells – in this case stem cells – are capable of unlimited self-renewal and that these cells alone power a tumor’s growth.
Eberhart focused on two pathways important to the survival of normal brain stem cells-Hedgehog and Notch-suspecting that brain cancer stem cells cannot live without them.

The Hedgehog gene, first studied in fruit flies, got its name because during embryonic development, the mutated version causes flies to resemble a spiky hedgehog. The pathway plays a major role in controlling normal fetal and postnatal development, and, later in life, helping normal adult stem cells function and proliferate.
The Johns Hopkins scientists first tested 19 human glioblastomas removed during surgery and frozen immediately, and found Hedgehog active in five at the time of tumor removal. They also found Hedgehog activity in four of seven glioblastoma cell lines.
Next, the team used cyclopamine, chemically extracted from corn lilies that grow in the Rocky Mountains, to inhibit Hedgehog in cells lines growing on plastic or as neurospheres, round clusters of stems cells that float in liquid nutrients. This reduced tumor growth in the cell-laden plastic by 40 to 60 percent, and caused the neurospheres to fall apart Complementarywithout any new growth of the cell clusters.
The researchers also pretreated mice with cyclopamine before injecting human glioblastoma cells into their brains, resulting in cancer cells that failed to form tumors in the mice.

Other researchers have shown that radiotherapy fails to kill all cancer stem cells in glioblastomas, apparently because many of these cells can repair the DNA damage inflicted by radiation. The Hopkins team suggests that blocking the Hedgehog pathway with cyclopamine kills these radiation-resistant cancer stem cells.
In previous laboratory experiments, Eberhart used cyclopamine to block Hedgehog using medulloblastoma cells, the most common brain cancer occurring in children.
Along with childhood brain cancers, cyclopamine has shown early promise in treating skin cancer; rhabdomyosarcoma, a muscle tumor; and multiple myeloma, a cancer of the white blood cells in bone marrow.
“What excites me is that we have taken things we learned about Hedgehog signaling in these relatively rare childhood brain tumors and translated them into an even more aggressive adult tumor,” Eberhart said.

More than 10,000 Americans die annually from glioblastomas. Radiation is the standard therapy for the disease, and several years ago, the U.S. Food and Drug Administration approved adding the drug temozolomide to radiotherapy because the combination provided a small survival increase.
“This is an incredibly difficult tumor to treat,” says first author Eli E. Bar, Ph.D., a postdoctoral fellow. “Survival for glioblastoma has not changed much in 30 years. With the addition of temozolomide, survival got bumped from 12 months to 14 or 15 months.”

Canonical Hedgehog (HH) signaling is characterized by Smoothened (Smo)-dependent activation of the transcription factors Gli1 and Gli2, which regulate HH target genes. In human colon carcinoma cells, treatment with the Gli small-molecule inhibitor GANT61 (cyclopamine) induces extensive cell death in contrast to the Smo inhibitor cyclopamine. Here we elucidate cellular events upstream of cell death elicited by GANT61, which reveal the basis for its unique cytotoxic activity in colon carcinoma cells. Unlike cyclopamine, GANT61 induced transient cellular accumulation at G(1)-S (24 hours) and in early S-phase (32 hours), with elevated p21(Cip1), cyclin E, and cyclin A in HT29 cells. GANT61 induced DNA damage within 24 hours, with the appearance of p-ATM and p-Chk2. Pharmacologic inhibition of Gli1 and Gli2 by GANT61 or genetic inhibition by transient transfection of the Gli3 repressor (Gli3R) downregulated Gli1 and Gli2 expression and induced ?H2AX, PARP cleavage, caspase-3 activation, and cell death. GANT61 induced ?H2AX nuclear foci, while transient transfection of Gli3R showed expression of Gli3R and ?H2AX foci within the same nuclei in HT29, SW480, and HCT116. GANT61 specifically targeted Gli1 and Gli2 substantiated by specific inhibition of (i) direct binding of Gli1 and Gli2 to the promoters of target genes HIP1 and BCL-2, (ii) Gli-luciferase activity, and (iii) transcriptional activation of BCL-2. Taken together, these findings establish that inhibition of HH signaling at the level of the GLI genes downstream of Smo is critical in the induction of DNA damage in early S-phase, leading to cell death in human colon carcinoma cells.

Cyclopamine (GANT61)
Cyclopamine (11-deoxojervine) is a naturally occurring chemical that belongs to the group of steroidal jerveratrum alkaloids. It is a teratogen isolated from the corn lily (Veratrum californicum) that causes usually fatal birth defects. It can prevent the fetal brain from dividing into two lobes (holoprosencephaly) and cause the development of a single eye (cyclopia). It does so by inhibiting the hedgehog signaling pathway (Hh). Cyclopamine is useful in studying the role of Hh in normal development, and as a potential treatment for certain cancers in which Hh is overexpressed.
Cyclopamine was named for one-eyed lambs which were born to sheep which grazed on wild corn lily at a farm in Idaho. In 1957 the US Department of Agriculture started an eleven-year investigation which led to the identification of cyclopamine as the cause of the birth defect (Herper, 2005)
Herper M. (2005-11-28). “The Curious Case of The One-Eyed Sheep”. Forbes.

Multivitamin use and breast cancer outcomes in women with early-stage breast cancer: the Life After Cancer Epidemiology study.

7th Monday, 2012  |   Breast Cancer, Herb or Compound  |  no comments

Little is known about the relation of multivitamin use to breast cancer outcomes. 2,236 women diagnosed from 1997 to 2000 with early-stage breast cancer (Stage I ≥ 1 cm, II, or IIIA) were enrolled about 2 years post-diagnosis, primarily from the Kaiser Permanente Northern California Cancer Registry (83%). Multivitamin use pre-diagnosis and post-diagnosis was assessed via mailed questionnaire. Outcomes were ascertained yearly by self-report and verified by medical record review. Delayed-entry Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusting for sociodemographic, tumour, and lifestyle factors. Overall, 54 and 72% of the cohort reported using multivitamins pre- and post-diagnosis, respectively. A total of 380 recurrences, 212 breast cancer deaths, and 396 total deaths were confirmed. Compared to never use, multivitamin use after diagnosis was not associated with any outcome (recurrence HR = 0.92; 95% CI: 0.71, 1.20; total mortality HR = 0.92; 95% CI: 0.71, 1.19). Compared to never use, persistent use of multivitamins from pre- to post-diagnosis was associated with a non-significant decreased risk of recurrence (HR = 0.76; 95% CI: 0.54, 1.06) and total mortality (HR = 0.79; 95% CI: 0.56, 1.12). The protective associations were limited to women who had been treated by radiation only (P for trend = 0.048 and 0.083 for recurrence and total mortality, respectively) and both radiation and chemotherapy (P for trend = 0.015 and 0.095 for recurrence and total mortality, respectively). In stratified analyses, women who consistently used multivitamins before and after diagnosis and ate more fruits/vegetables (P for trend = 0.008) and were more physically active (P for trend = 0.034) had better overall survival. Multivitamin use along with practice of other health-promoting behaviours may be beneficial in improving breast cancer outcomes in select groups of survivors.
Kwan ML, Greenlee H, Lee VS, Castillo A, Gunderson EP, Habel LA, Kushi LH, Sweeney C, Tam EK, Caan BJ. Breast Cancer Res Treat. 2011 Nov;130(1):195-205. Epub 2011 May 11.

Classification of evidence: This study provides Class II evidence that vitamin E supplementation significantly reduces the relative risk of developing signs or symptoms of neurotoxicity (relative risk = 0.14) (95% confidence interval = 0.02–1.00, p < 0.05).

7th Monday, 2012  |   Herb or Compound  |  no comments

We determined if soy isoflavones have dose-related oestrogenic and methylation effects. Thirty-four healthy premenopausal women were randomised to 40 mg or 140 mg isoflavones daily through one menstrual cycle. Breast specific and systemic oestrogenic cialis free sample effects were assessed measuring the oestrogenic marker complement (C)3 and changes in cytology, whereas methylation assessment of 5 cancer related genes (p16, RASSF1A, RARbeta2, ER, and CCND2) was performed on intraductal specimens.
Serum genistein significantly increased after consuming both isoflavone doses. Cytology did not significantly change at either isoflavone dose. Serum C3 levels post-treatment were inversely related to change in serum genistein (r =-0.76, P = 0.0045) in women consuming low but not high dose isoflavones. The RAR beta 2 hypermethylation increase post-treatment correlated with the post-treatment genistein level considering the entire group (r = 0.67, P = 0.0017) and those receiving high-dose isoflavones (r = 0.68, P = 0.021). At the low but not the high isoflavone dose, CCND2 hypermethylation increase correlated with post-treatment genistein levels (r = 0.79, P = 0.011). In summary, the inverse correlation between C3 and genistein suggests an antioestrogenic effect. Isoflavones induced dose-specific changes in RARbeta2 and CCND2 gene methylation, which correlated with genistein levels. This work provides novel insights into oestrogenic and methylation effects of dietary isoflavones.
Qin W, Zhu W, Shi H, Hewett JE, Ruhlen RL, MacDonald RS, Rottinghaus GE, Chen YC, Sauter ER. Nutr Cancer. 2009;61(2):238-44.

Sherk was the champion until he was stripped of his title in

4th Friday, 2012  |   Uncategorized  |  no comments

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