http://www.eurekalert.org/pub_releas...w-pm082409.php
'Hedgehog' pathway may hold key to anti-cancer therapy
Research into the role of pathway gene could provide novel method to treat cancer metastases
Scientists in Switzerland have discovered a way to block the growth of human colon cancer cells, preventing the disease from reaching advanced stages and the development of liver metastases. The research, published today in
EMBO Molecular Medicine, shows that
blocking the so-called Hedgehog-GLI pathway can prevent the growth of tumours, metastatic lesions and cancer stem cells, the cells thought to lie at the root of cancer growth.
Colon cancer often begins in a treatable form when it is confined to the bowel wall, but in frequent cases it can develop to an incurable metastatic stage. A Geneva-based research team has discovered the essential role played by HH-GLI in the progression of colon cancer to these late and incurable stages. HH-GLI is a signalling pathway used by cells to communicate with each other, often used to determine position, growth and survival.
"Previous works hinted at the possible role of HH-GLI in colon cancer, but this was denied by other studies, so its involvement was never entirely clear," said lead researcher Professor Ariel Ruiz i Altaba of Geneva University.
"In this study we have proven that HH-GLI is essential for the development and growth of colon cancers. The research demonstrates the active presence of HH-GLI signalling in epithelial cells of colon cancers. Moreover,
we find that metastatic tumours rely on this pathway for sustained growth. This identifies HH-GLI as a target for novel anti-cancer therapies against so far incurable forms of colon cancer in distant organs, such as the liver."
This research opens the possibility of new anti-cancer therapies, specifically the use of RNA interference and of Cyclopamine, a plant product known to block Hedgehog pathway activity. This and other similar molecules can now be considered for future research as a treatment for terminal patients with metastatic disease and to fight resurgent forms of the disease.
"Recurrence is a major problem in cancer treatment. Even after a patient has displayed an apparent complete recovery from a primary tumour, recurrence at nearby or distal locations has a poor prognosis," said Ruiz i Altaba.
"While monitoring recovering mice we noted that tumours began to recur in all cases except for those treated with Cyclopamine for a short period of time after tumour disappearance. The treated mice were kept for up to one year after the treatment and remained healthy and tumour free."
Using these genetic or pharmacologic methods to block HH-GLI activity also prevents cancer stem cell self-renewal. Using a new in vivo assay to test the participation of cancer stem cells in a growing tumour,
the research team demonstrated the essential role of this pathway for the maintenance and survival of cancer stem cells.
"This work firmly establishes the critical action of HH-GLI in human colon cancer cells, providing the platform for preclinical and future clinical work." concluded Ruiz i Altaba. "The finding that
a blockade of HH-GLI for a relatively short period was sufficient to eliminate the tumour and prevent recurrence, without negatively affecting the health of the mice, opens the possibility for the use of a therapeutic window to eradicate the tumour without major side effects."
Contact: Ben Norman
Benorman@wiley.com
44-124-377-0375
Wiley-Blackwell
Oncogene (
23 November 2009) |
doi:10.1038/onc.2009.392
Activation of the hedgehog-signaling pathway in human cancer and the clinical implications
L Yang , G Xie , Q Fan & J Xie
Abstract
The hedgehog pathway, initially discovered by two Nobel laureates Drs E Wieschaus and C Nusslein-Volhard in Drosophila, is a major regulator for cell differentiation, tissue polarity and cell proliferation. Studies from many laboratories reveal activation of this pathway in a variety of human cancer, including basal cell carcinomas (BCCs), medulloblastomas, leukemia, gastrointestinal, lung, ovarian, breast and prostate cancers. It is thus believed that targeted inhibition of hedgehog signaling may be effective in treatment and prevention of human cancer. Even more exciting is the discovery and synthesis of specific signaling antagonists for the hedgehog pathway, which have significant clinical implications in novel cancer therapeutics. In this review, we will summarize major advances in the last 2 years in our understanding of hedgehog signaling activation in human cancer, interactions between hedgehog signaling and other pathways in carcinogenesis, potential antagonists for hedgehog signaling inhibition and their clinical implications for human cancer treatment. Oncogene advance online publication, 23 November 2009; doi:10.1038/onc.2009.392
Combined Targeted Treatment to Eliminate Tumorigenic Cancer Stem Cells in Human Pancreatic Cancer.
Mueller MT,
Hermann PC,
Witthauer J,
Rubio-Viqueira B,
Leicht SF,
Huber S,
Ellwart JW,
Mustafa M,
Bartenstein P,
D'Haese JG,
Schoenberg MH,
Berger F,
Hidalgo M,
Heeschen C.
Experimental Medicine, Department of Surgery, Ludwig-Maximilian-University, Munich, Germany.
BACKGROUND & AIMS:
Pancreatic cancers contain exclusively tumorigenic cancer stem cells (CSCs), which are highly resistant to chemotherapy, resulting in a relative increase in CSC numbers during gemcitabine treatment. Signaling through sonic hedgehog and mammalian target of rapamycin (mTOR), respectively, may be essential for CSC self-renewal and could represent putative targets for novel treatment modalities. METHODS: We used in vitro and in vivo models of pancreatic cancer to examine the effects of sonic hedgehog inhibition (cyclopamine/CUR199691) and mTOR blockade (rapamycin) on the tumorigenic CSC population. RESULTS:
Surprisingly, neither cyclopamine nor rapamycin alone or as supplements to chemotherapy were capable of effectively diminishing the CSC pool. Only the combined inhibition of both pathways together with chemotherapy reduced the number of CSCs to virtually undetectable levels in vitro and in vivo. Most importantly, in vivo administration of this triple combination in mice with established patient-derived pancreatic tumors was reasonably tolerated and translated into significantly prolonged long-term survival. CONCLUSIONS: The
combined blockade of sonic hedgehog and mTOR signaling together with standard chemotherapy is capable of eliminating pancreatic CSCs. Further preclinical investigation of this promising approach may lead to the development of a novel therapeutic strategy to improve the devastating prognosis of patients with pancreatic cancer.
August 31, 2000
Plant Compound Blocks Action of Cancer Genes
http://www.hhmi.org/news/beachy.html
Quote:
"It had long been known that animals that consumed plants containing cyclopamine suffered severe neural birth defects, including malformations that produced a single cyclopic eye," said Beachy. "And when we knocked out the mouse counterpart of the hedgehog gene, Sonic hedgehog, we saw an effect very much like that produced in animals by cyclopamine. So, that really rang a bell for us."
After initial experiments indicated that cyclopamine did not directly affect the Hedgehog protein, the scientists turned their attention to the two cellular targets that receive signals from Hedgehog-proteins produced by the genes Smoothened and Patched. While the Smoothened protein switches on cell division, the Patched protein acts as a cellular "brake," or tumor suppressor. Previous studies had shown that Hedgehog switches on cell division by binding to Patched, turning off its normal braking function, and allowing Smoothened to activate cell proliferation.
The scientists' experiments ruled out that cyclopamine might thwart proliferation by activating the Patched protein. They found instead that when they deleted the Patched gene from mouse cells, cyclopamine could still turn off cell division. "Thus, we'd eliminated two red herrings-that cyclopamine affected either Hedgehog or Patched," said Beachy.
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http://www.hhmi.org/research/investigators/beachy.html
Hedgehog Signaling in Development and Disease
Quote:
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Our studies show that treatment with the Hedgehog pathway antagonist cyclopamine can block cell proliferative effects associated with pathway activation and can cause complete regression of aggressive human and rodent cancers growing in mice. The use of cyclopamine or other pathway antagonists thus may represent a novel, nontoxic approach to therapies for lethal human cancers.
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1:
J Med Chem. 2009 Jul 23;52(14):4400-18.
Links
Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926).
Tremblay MR, Lescarbeau A, Grogan MJ, Tan E, Lin G, Austad BC, Yu LC, Behnke ML, Nair SJ, Hagel M, White K, Conley J, Manna JD, Alvarez-Diez TM, Hoyt J, Woodward CN, Sydor JR, Pink M, MacDougall J, Campbell MJ, Cushing J, Ferguson J, Curtis MS, McGovern K, Read MA, Palombella VJ, Adams J, Castro AC.
Infinity Pharmaceuticals, Inc, Cambridge, Massachusetts 02139, USA. Martin.Tremblay@infi.com
Recent evidence suggests that blocking aberrant hedgehog pathway signaling may be a promising therapeutic strategy for the treatment of several types of cancer. Cyclopamine, a plant Veratrum alkaloid, is a natural product antagonist of the hedgehog pathway. In a previous report, a seven-membered D-ring semisynthetic analogue of cyclopamine, IPI-269609 (2), was shown to have greater acid stability and better aqueous solubility compared to cyclopamine. Further modifications of the A-ring system generated three series of analogues with improved potency and/or solubility. Lead compounds from each series were characterized in vitro and evaluated in vivo for biological activity and pharmacokinetic properties. These studies led to the discovery of IPI-926 (compound 28), a novel semisynthetic cyclopamine analogue with substantially improved pharmaceutical properties and potency and a favorable pharmacokinetic profile relative to cyclopamine and compound 2. As a result, complete tumor regression was observed in a Hh-dependent medulloblastoma allograft model after daily oral administration of 40 mg/kg of compound 28.
PMID: 19522463 [PubMed - indexed for MEDLINE
Discussion of how to get Cyclopamine and anecdotal patient success:
http://margaret.healthblogs.org/2008...n-cyclopamine/
Since Cyclopamine, though available, is an investigational substance, the natural alternatives:
Mol Carcinog. 2009 Dec 18. [Epub ahead of print]
Curcumin inhibits the Sonic Hedgehog signaling pathway and triggers apoptosis in medulloblastoma cells.
Elamin MH,
Shinwari Z,
Hendrayani SF,
Al-Hindi H,
Al-Shail E,
Khafaga Y,
Al-Kofide A,
Aboussekhra A.
Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Medulloblastoma is an aggressive primary brain tumor that arises in the cerebellum of children and young adults. The Sonic Hedgehog (Shh) signaling pathway that plays important roles in the pathology of this aggressive disease is a promising therapeutic target. In the present report we have shown that curcumin has cytotoxic effects on medulloblastoma cells. Curcumin suppressed also cell proliferation and triggered cell-cycle arrest at G(2)/M phase. Moreover, curcumin inhibited the Shh-Gli1 signaling pathway by downregulating the Shh protein and its most important downstream targets GLI1 and PTCH1. Furthermore, curcumin reduced the levels of beta-catenin, the activate/phosphorylated form of Akt and NF-kappaB, which led to downregulating the three common key effectors, namely C-myc, N-myc, and Cyclin D1. Consequently, apoptosis was triggered by curcumin through the mitochondrial pathway via downregulation of Bcl-2, a downstream anti-apoptotic effector of the Shh signaling. Importantly, the resistant cells that exhibited no decrease in the levels of Shh and Bcl-2, were sensitized to curcumin by the addition of the Shh antogonist, cyclopamine. Furthermore, we have shown that curcumin enhances the killing efficiency of nontoxic doses of cisplatin and gamma-rays. In addition, we present clear evidence that piperine, an enhancer of curcumin bioavailability in humans, potentiates the apoptotic effect of curcumin against medulloblastoma cells. This effect was mediated through strong downregulation of Bcl-2. These results indicate that curcumin, a natural nontoxic compound, represents great promise as Shh-targeted therapy for medulloblastomas. (c) 2009 Wiley-Liss, Inc.
PMID: 20025076 [PubMed - as supplied by publisher]
http://www.faqs.org/patents/app/20090054517
Patent application title:
Phytoestrogens As Regulators Of Hedgehog Signaling And Methods Of Their Use In Cancer Treatment
Abstract: A new method is provided for inhibiting tumor growth and for delaying the onset of cancer. Several estrogenic compounds from plants are capable of inhibiting cell proliferation both in cell cultures and in whole animals. These compounds likely exert their anti-proliferation effects by inhibiting the Hedgehog signaling pathway. Estrogen receptors may also play an essential role in the inhibitory effect of these compounds.
Chembiochem. 2008 May 5;9(7):1082-92.
Naturally occurring small-molecule inhibitors of hedgehog/GLI-mediated transcription.
http://www3.interscience.wiley.com/j...45574/abstract
Hosoya T,
Arai MA,
Koyano T,
Kowithayakorn T,
Ishibashi M.
Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 263-8522, Japan.
The aberrant hedgehog (Hh)/GLI signaling pathway causes the formation and progression of a variety of tumors. To search for Hh/GLI inhibitors, we screened for naturally occurring inhibitors of the transcriptional activator GLI1 by using a cell-based assay.
We identified zerumbone (1), zerumbone epoxide (2), staurosporinone (9), 6-hydroxystaurosporinone (10), arcyriaflavin C (11) and 5,6-dihydroxyarcyriaflavin A (12) as inhibitors of GLI-mediated transcription. In addition, we isolated physalins F (17) and B (18) from Physalis minima, which are also potent inhibitors. These compounds also inhibited GLI2-mediated transactivation. Semiquantitative RT-PCR and Western blotting analysis further revealed that
1, 9, 17, and 18 decreased Hh-related component expressions. We also show that inhibitors of GLI-mediated transactivation reduce the level of the antiapoptosis Bcl2 expression. Finally, these identified compounds were cytotoxic to PANC1 pancreatic cancer cells, which express Hh/GLI components. These results strongly suggest that the cytotoxicity of the compounds to PANC1 cells correlates with their inhibition of GLI-mediated transcription.
PMID: 18357592 [PubMed - indexed for MEDLINE]
High content of zerumbone in volatile oils of Zingiber zerumbet from southern India and Malaysia
http://www3.interscience.wiley.com/j...17925/abstract
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| Sabulal Baby 1 *, Mathew Dan 2, Abdul R. M. Thaha 2, Anil J. Johnson 1, Rajani Kurup 1, Prasanth Balakrishnapillai 1, Chong Keat Lim 3 |
1Phytochemistry and Phytopharmacology Division, Tropical Botanic Garden and Research Institute, Pacha-Palode, Thiruvananthapuram 695 562, Kerala, India
2Plant Genetic Resources Division, Tropical Botanic Garden and Research Institute, Pacha-Palode, Thiruvananthapuram 695 562, Kerala, India
3Folia Malaysiana, 215 Macalister Road, 10450 Penang, Malaysia
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| email: Sabulal Baby (sabulal@gmail.com) |
*Correspondence to Sabulal Baby, Phytochemistry and Phytopharmacology Division, Tropical Botanic Garden and Research Institute, Pacha-Palode, Thiruvananthapuram 695 562, Kerala, India
Abstract
| Zerumbone is a sesquiterpene phytochemical with potential anticancer, anti-inflammatory, anti-HIV and other biological activities, most abundantly found in Zingiber zerumbet (L.) Smith. Previous studies reported 12.6-73.1% of zerumbone in Z. zerumbet rhizome oils from various geographical locations. In a careful review of the literature, we found that most of the previous gas chromatographic profiling studies on volatile oils of Z. zerumbet were inadequate, since they were based on poor identification and quantification procedures and also on single-sample data. In this study, we report the chemical profiles of volatile oils of Z. zerumbet rhizomes from six locations in the southern Indian state of Kerala and also from Penang in Malaysia. Chemical profiling of volatiles was carried out by extensive GC-FID, GC-MS and associated techniques, supported by 1H-NMR, 13C-NMR, FABMS and HPTLC. The full chemical profiles of rhizome oils of these seven accessions of Z. zerumbet were elucidated. The south Indian accessions of Z. zerumbet reported 76.3-84.8% zerumbone content in their rhizome oils. The Malaysian accession recorded the lowest content of zerumbone (68.9%). This study reveals the high content of the bioactive compound zerumbone in Z. zerumbet from Kerala. Copyright © 2009 John Wiley & Sons, Ltd. |
Received: 3 February 2009; Revised: 9 June 2009; Accepted: 12 June 2009
Zerumbone possibly better, discussed:
http://margaret.healthblogs.org/2008...bone/#comments
Cyclopamine and Zerumbone sourced and informally trialed here:
http://www.curingourselves.com/
Evid Based Complement Alternat Med. 2009 Jun 18. [Epub ahead of print]
Cytotoxic Activities of Physalis minima L. Chloroform Extract on Human Lung Adenocarcinoma NCI-H23 Cell Lines by Induction of Apoptosis.
http://ecam.oxfordjournals.org/cgi/content/full/nep057v1
Leong OK,
Muhammad TS,
Sulaiman SF.
School of Biological Sciences, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia.
shaida@usm.my.
Physalis minima L. is reputed for having anticancer property. In this study, the chloroform extract of this plant exhibited remarkable cytotoxic activities on NCI-H23 (human lung adenocarcinoma) cell line at dose- and time-dependent manners (after 24, 48 and 72 h of incubation). Analysis of cell-death mechanism demonstrated that the extract exerted apoptotic programed cell death in NCI-H23 cells with typical DNA fragmentation, which is a biochemical hallmark of apoptosis. Morphological observation using transmission electron microscope (TEM) also displayed apoptotic characteristics in the treated cells, including clumping and margination of chromatins, followed by convolution of the nuclear and budding of the cells to produce membrane-bound apoptotic bodies. Different stages of apoptotic programed cell death as well as phosphatidylserine externalization were confirmed using annexin V and propidium iodide staining. Furthermore, acute exposure to the extract produced a significant regulation of c-myc, caspase-3 and p53 mRNA expression in this cell line.
Due to its apoptotic effect on NCI-H23 cells, it is strongly suggested that the extract could be further developed as an anticancer drug.
PMID: 19541726 [PubMed - as supplied by publisher]