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Old 07-10-2010, 03:22 PM   #1
Rich66
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Betulinic Acid (Birch, Chaga etc)

Supplement available: Herbal Extracts Plus
More info on Birch/Betulin: http://www.betulin.ca/betulin-products.html
Chaga mushroom as source for Betulinic acid: http://www.chagatrade.ru/cchagamushroom.html, http://eartherbs.com/index.php?page=144&


Int J Mol Sci. 2008 Jun;9(6):1096-107. Epub 2008 Jun 27.
Betulinic Acid for cancer treatment and prevention.

Fulda S.
University Children's Hospital, Ulm, Germany. simone.fulda@uniklinik-ulm.de


FREE TEXT

Abstract

Betulinic acid is a natural product with a range of biological effects, for example potent antitumor activity. This anticancer property is linked to its ability to induce apoptotic cell death in cancer cells by triggering the mitochondrial pathway of apoptosis. In contrast to the cytotoxicity of betulinic acid against a variety of cancer types, normal cells and tissue are relatively resistant to betulinic acid, pointing to a therapeutic window. Compounds that exert a direct action on mitochondria present promising experimental cancer therapeutics, since they may trigger cell death under circumstances in which standard chemotherapeutics fail. Thus, mitochondrion-targeted agents such as betulinic acid hold great promise as a novel therapeutic strategy in the treatment of human cancers.

PMID: 19325847 [PubMed]PMCID: PMC2658785Free PMC Article


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Betulinic acid exerts a number of biological activities. For example, betulinic acid has been shown to have antitumor properties. To this end, it is interesting to note that white birch bark (Betula alba) which contains betulinic acid, has been used by Native Americans as a folk remedy.
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The antitumor cytotoxicity of betulinic acid has been extensively studied in a panel of cancer cell lines, primary tumor samples and xenograft mouse models (Table 1). While initial reports suggested that betulinic acid is selectively cytotoxic against melanoma cell lines [33], anticancer activity was subsequently also reported against other types of human cancers including neuroblastoma, glioblastoma, medulloblastoma, Ewing tumor, leukemia as well as several carcinoma, i.e. head and neck, colon, breast, hepatocellular, lung, prostate, renal cell, ovarian or cervix carcinoma [12, 14, 18, 22, 23, 34-39]. In addition to tumor cell lines, Betulinic acid was also cytotoxic against primary cancer cells isolated from tumor specimens obtained from neuroblastoma, glioblastoma and leukemia [14, 23, 38, 39]. Also, betulinic acid was cytotoxic in different models of drug resistance, for example primary pediatric acute leukemia samples that were refractory to standard chemotherapeutic agents [14, 23].
Thus, betulinic acid may overcome certain forms of drug resistance. Further, there is evidence that betulinic acid is preferentially cytotoxicity against metastatic over non-metastatic melanoma cell lines [32]. Moreover, betulinic acid cooperated with different cytotoxic stimuli to suppress tumor growth, including ionizing radiation [16], chemotherapeutic drugs [40] [41] or the death recpetor ligand TRAIL [42]. This suggests that betulinic acid may be used as sensitizer in combination regimens to enhance the efficacy of anticancer therapy. By comparison, normal cells of different origin have been reported to be much more resistant to betulinic acid than cancer cells pointing to some tumor selectivity [16, 22, 38, 39].
Besides its potent antitumor activity in vitro, betulinic acid also suppressed tumor growth in several animal models of human cancer. In a xenograft mouse model of ovarian cancer administration of betulinic acid significantly increased the survival time [22]. Also, betulinic acid suppressed tumor growth in a melanoma xenograft model [33]. Also in vivo, betulinic acid cooperated with chemotherapeutic agents such as vincristin to reduce lung metastasis in a metastatic melanoma model [41]. Of note, no systemic toxicities or weights loss were observed in betulinic acid-treated mice even at high systemic doses of betulinic acid [22, 33]. Pharmacokinetic studies in mice bearing melanoma xenografts demonstrated that betulinic acid was well absorbed and distributed with highest concentrations found within the tumor [43, 44]. Phase I/II studies of 3-o-(3',3'-dimethylsuccinyl) betulinic acid (bevirimat) in patients with human immunodeficiency virus (HIV) infection demonstrated that single oral doses of bevirimat were well tolerated and that plasma concentrations ranged from 8 to 58 μg/ml [45, 46]. This indicates that plasma levels of betulinic acid could be achieved after oral administration in humans that correspond to concentrations, which were found to exert antitumor activity in vitro.
Furthermore, betulinic acid was reported to harbor anticarcinogenic properties that could be exploited in cancer prevention settings. To this end, betulinic acid was shown already more than a decade ago to inhibit tumor formation in mouse skin two-stage carcinogenesis [47]. Betulinic acid is currently under evaluation as a topical agent in a phase I/II clinical trial for the treatment of dysplastic nevi with the potential to transform into melanoma.
In addition to betulinic acid, a variety of betulinic acid derivatives were developed with the aim to increase the anticancer potency and to improve the pharmacokinetic properties. For example, replacing the cyano group with a methoxycarbonyl was reported to markedly enhance the apoptosis-inducing
activities of betulinic acid [48]. In addition, these new BA analogues showed higher plasma and tissue levels compared to betulinic acid [48]. Further, C-3 modified Betulinic acid derivatives proved to have better in vivo anti-tumor efficacy as compared to betulinic acid in vivo against human colon cancer and also displayed favorable pharmacokinetic properties [49]. Moreover, 17-carboxylic acid modified 23-hydroxy betulinic acid ester derivatives demonstrated for cytotoxic activity on five cancer cell lines in vitro: all tested compounds showed higher cytotoxic activity as compared to 23-hydroxy betulinic acid and betulinic acid in vitro and also in vivo [50].
Anticancer Drugs. 2010 Mar;21(3):215-27.
Betulinic acid, a natural compound with potent anticancer effects.

Mullauer FB, Kessler JH, Medema JP.
Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
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Abstract


New therapies using novel mechanisms to induce tumor cell death are needed with plants playing a crucial role as a source for potential anticancer compounds. One highly promising class of natural compounds are the triterpenoids with betulinic acid (BetA) as the most prominent representative. In-vitro studies have identified this agent as potently effective against a wide variety of cancer cells, also those derived from therapy-resistant and refractory tumors, whereas it has been found to be relatively nontoxic for healthy cells. In-vivo preclinically applied BetA showed some remarkable anticancer effects and a complete absence of systemic toxicity in rodents. BetA also cooperated with other therapies to induce tumor cell death and several potent derivatives have been discovered. Its antitumor activity has been related to its direct effects on mitochondria where it induces Bax/Bak-independent cytochrome-c release.

PMID: 20075711 [PubMed - indexed for MEDLINE]



Mol Nutr Food Res. 2009 Jan;53(1):140-6.
Betulinic acid: a natural product with anticancer activity.

Fulda S.
University Children's Hospital, Ulm, Germany. simone.fulda@uniklinik-ulm.de



Abstract

Betulinic acid (BA) is a naturally occurring pentacyclic triterpene that exhibits a variety of biological activities including potent antitumor properties. This anticancer activity has been linked to its ability to directly trigger mitochondrial membrane permeabilization, a central event in the apoptotic process that seals the cell's fate. In contrast to the potent cytotoxicity of BA against a variety of cancer types, nonmalignant cells and normal tissue remained relatively resistant to BA, indicating a therapeutic window. Since agents that exert a direct action on mitochondria may trigger cell death under circumstances in which standard chemotherapeutics fail, there is increasing interest to develop such compounds as experimental cancer therapeutics. Thus, mitochondrion-targeted agents such as BA hold great promise as a novel approach to bypass certain forms of drug resistance in human cancers.

PMID: 19065582 [PubMed - indexed for MEDLINE]



Strahlenther Onkol. 2010 Feb 22. [Epub ahead of print]
Betulinic Acid a Radiosensitizer in Head and Neck Squamous Cell Carcinoma Cell Lines.

Eder-Czembirek C, Erovic BM, Czembirek C, Brunner M, Selzer E, Pötter R, Thurnher D.
Department of Cranio-, Maxillofacial and Oral Surgery, Medical University of Vienna, Vienna, Austria.


Abstract

BACKGROUND AND PURPOSE: : Betulinic acid, a pentacyclic triterpene, is a new cytotoxic compound active on melanoma, neuroblastoma, glioblastoma and head and neck squamous cell carcinoma (HNSCC) cells. In combination with irradiation it has been shown to have an additive effect on growth inhibition in melanoma cells. In this study, the radiosensitizing effect of betulinic acid on sequential irradiation was investigated in HNSCC cell lines. MATERIAL AND METHODS: : Two HNSCC cell lines, SCC9 and SCC25, were treated with increasing doses of betulinic acid and sequentially irradiated with a single boost of 4 Gy from a conventional radiation source. The cells were counted, the surviving fraction was determined, and colony-forming assays were performed. RESULTS: : It could be shown that betulinic acid alone inhibits cell survival, affects cell survival additively in combination with irradiation and decreases clonogenic survival in both cell lines when applied alone. CONCLUSION: : Betulinic acid could be a promising treatment agent in radioresistant head and neck cancer. A combination of betulinic acid with radiotherapy seems to be beneficial.

PMID: 20339825 [PubMed - as supplied by publisher]



Cancer Res. 2007 Mar 15;67(6):2816-23.
Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors.

Chintharlapalli S, Papineni S, Ramaiah SK, Safe S.
Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77843-4466, USA.
Online TEXT
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Abstract

Betulinic acid is a pentacyclic triterpene natural product initially identified as a melanoma-specific cytotoxic agent that exhibits low toxicity in animal models. Subsequent studies show that betulinic acid induces apoptosis and antiangiogenic responses in tumors derived from multiple tissues; however, the underlying mechanism of action is unknown. Using LNCaP prostate cancer cells as a model, we now show that betulinic acid decreases expression of vascular endothelial growth (VEGF) and the antiapoptotic protein survivin. The mechanism of these betulinic acid-induced antiangiogenic and proapoptotic responses in both LNCaP cells and in tumors is due to activation of selective proteasome-dependent degradation of the transcription factors specificity protein 1 (Sp1), Sp3, and Sp4, which regulate VEGF and survivin expression. Thus, betulinic acid acts as a novel anticancer agent through targeted degradation of Sp proteins that are highly overexpressed in tumors.

PMID: 17363604 [PubMed - indexed for MEDLINE]Free Article


Quote:
The results indicate that the antitumorigenic effects of betulinic acid are associated with targeted degradation of Sp transcription factors that are overexpressed in many tumors, and this results in activation of proapoptotic and antiangiogenic responses in tumor but not in non-target tissues (e.g., liver) that exhibit low Sp protein expression.
Quote:
Betulinic acid is a natural product identified in various bark extracts and is readily synthesized from betulin, a major component in bark from birch trees ( 19). Pisha et al. ( 20) initially reported that this triterpenoid inhibited growth of several melanoma cell lines, and ED50 values for cytotoxicity varied from 4.8 to 1.1 μg/mL, whereas the corresponding values for a series of colon, prostate, breast, lung, squamous, and glioma cancer cells were >20 μg/mL. However, other reports also show that betulinic acid inhibits growth and induces apoptosis in several different cancer cell lines ( 19), and this corresponds to results of this study in which IC50 values (growth inhibition) for melanoma and prostate cancer cells were 5 to 10 μmol/L and 1 to 5 μmol/L, respectively, and similar results were obtained in other cancer cell lines. It has also been reported that betulinic acid derivatives and related lupane analogues are more cytotoxic than betulinic acid to cancer cells ( 19); however, a major advantage in using the latter compound for cancer chemotherapy is the low toxicity. Doses as high as 500 mg/kg every 4th day (×6) exhibited no detectable toxic side effects ( 20).
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Quote:
The critical role for Sp proteins in regulating expression of antiapoptotic and proangiogenic genes/proteins in tumors is supported by results of this study that also highlights the efficacy of anticancer drugs that target specific transcription factors, such as Sp proteins, that are overexpressed in tumors. The effects of betulinic acid in this study were also observed for the closely related derivative betulonic acid (data not shown), and we conclude that betulinic acid and similar derivatives represent a novel class of transcription factor–targeting anticancer drugs. Moreover, because betulinic acid induces many other cytotoxic and proapoptotic effects in cancer cell lines ( 3647), it is likely that down-regulation of Sp proteins differentially contributes to the overall effect of this compound.
Method for treating cancer using betulinic acid rich herbal extract description/claims (Patent)

http://www.freshpatents.com/Method-f...0060159783.php

Quote:
This invention relates to an orally effective herbal extract-based composition having broad-spectrum anticancer activity, more specifically a method of treating, inhibiting and/or preventing malignant tumors of the colon, intestine, stomach, breast, melanoma, glioblastoma, lung, cervix, ovary, prostate, oral cavity, larynx, liver, pancreas, kidney, bladder, endothelial cells, leukemia and myeloma using a herbal extract of Zizyphus, rich in betulinic acid as well as having low systemic toxicity. The extract inhibits Protein Kinase C activity of cancer cells and induces apoptosis.
Use Of Betulinic Acid And Its Derivatives For Inhibiting Cancer Growth And A Method Of Monitoring This - Patent 6048847

http://www.docstoc.com/docs/46420400...Patent-6048847



Basic Clin Pharmacol Toxicol. 2009 Dec;105(6):425-32. Epub 2009 Oct 12.
Betulin elicits anti-cancer effects in tumour primary cultures and cell lines in vitro.

Rzeski W, Stepulak A, Szymański M, Juszczak M, Grabarska A, Sifringer M, Kaczor J, Kandefer-Szerszeń M.
Department of Virology and Immunology, Maria Curie-Sklodowska University, Lublin, Poland. rzeskiw@hektor.umcs.lublin.pl


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Abstract

Betulin is a pentacyclic triterpene found in many plant species, among others, in white birch bark. The aim of the study was in vitro characterization of the anticancer activity of betulin in a range of human tumour cell lines (neuroblastoma, rhabdomyosarcoma-medulloblastoma, glioma, thyroid, breast, lung and colon carcinoma, leukaemia and multiple myeloma), and in primary tumour cultures isolated from patients (ovarian carcinoma, cervical carcinoma and glioblastoma multiforme). In this study, we demonstrated a remarkable anti-proliferative effect of betulin in all tested tumour cell cultures. Neuroblastoma (SK-N-AS) and colon carcinoma (HT-29) were the most sensitive to the anti-proliferative effect of betulin. Furthermore, betulin altered tumour cells morphology, decreased their motility and induced apoptotic cell death. These findings demonstrate the anti-cancer potential of betulin and suggest that they may be applied as an adjunctive measure in cancer treatment.

PMID: 19821831 [PubMed - indexed for MEDLINE]

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Old 07-10-2010, 03:57 PM   #2
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Re: Betulinic Acid (Birch)

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Old 08-15-2010, 01:54 AM   #3
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Re: Betulinic Acid (Birch)

sounds very good!
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