Betulinic acid against cancer and HIV

Betulinic acid is found in various herbs including birch and chagas.  All of the herbs that I am aware of containing betulinic acid have been used historically for the treatment of cancers.  Medical studies have confirmed the anti-cancer effects of betulinic acid:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells.
   
"Betulinic acid is a triterpene with selective cytotoxicity against melanoma, neuroectodermal and malignant brain tumor cell lines. In this study the betulinic acid activity was evaluated, in comparison with doxorubicin, on different human neoplastic and non-neoplastic cell lines and on proliferating normal lymphocytes. Growth inhibition was evident in all the neoplastic cell lines independently on p53 status and histotype. Antiproliferative activity of betulinic acid was related to a cytotoxic effect on two p53 wild-type and on one p53 mutant cell lines and to a cytostatic effect on one p53 mutant melanoma clone. At the same concentrations, normal cells were unaffected indicating a selective effect of this agent. A cytotoxic activity of doxorubicin was evident on all the tested systems."

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"Conventional chemotherapeutic agents elicit mitochondrial permeabilization in an indirect fashion by induction of endogenous effectors that are involved in the physiologic control of apoptosis. However, an increasing number of experimental anticancer drugs, including lonidamine, arsenite, betulinic acid, CD437, and several amphipathic cationic alpha-helical peptides, act directly on mitochondrial membranes and/or on the PTPC. Such agents may induce apoptosis in circumstances in which conventional drugs fail to act because endogenous apoptosis induction pathways, such as those involving p53, death receptors, or apical caspase activation, are disrupted. "

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"Betulinic acid is a naturally occurring pentacyclic triterpenoid. Betulinic acid has recently been selected by the National Cancer Institute for addition into the RAID (Rapid Access to Intervention in Development) programme. The agent exhibits potential anti-tumour activity and functions in this regard via apoptosis. "    

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"Recently, betulinic acid was identified as a highly selective inhibitor of human melanoma growth and was reported to induce apoptosis in these cells. We have investigated the growth-inhibitory properties of this compound alone and in combination with ionizing radiation in a panel of established human melanoma cell lines as well as in normal human melanocytes. Betulinic acid strongly and consistently suppressed the growth and colony-forming ability of all human melanoma cell lines investigated."    

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"Neuroblastoma has long been recognized to show spontaneous regression during fetal development and in the majority of stage 4s infants < 1 year of age with disseminated disease. Stage 4s disease regresses with no chemotherapy in 50% of the patients. The mechanism by which this occurs is not understood but may be programmed cell death or apoptosis. Betulinic acid (BA) has been reported to induce apoptosis in human melanoma with in vitro and in vivo model systems. Melanoma, like neuroblastoma, is derived from the neural crest cell. We hypothesised that neuroblastoma cells have the machinery for programmed cell death and that apoptosis could be induced by betulinic acid. Nine human neuroblastoma cell lines were treated in vitro with BA at concentrations of 0-20 micrograms/ml for 0-6 days. Profound morphological changes were noted within 3 days. Cells withdrew their axonic-like extensions, became non-adherent and condensed into irregular dense spheroids typical of apoptotic cell death (ED50 = 14-17 micrograms/ml). DNA fragmentation analysis showed ladder formation in the 100-1200 bp region in 3/3 neuroblastoma cell lines treated with BA for 24-72 h. Thus, apparently BA does induce AP in neuroblastoma in vitro."

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"BACKGROUND AND PROCEDURE: We identified BetA as a new cytotoxic agent active against neuroectodermal tumor cells including neuroblastoma, medulloblastoma, glioblastoma and Ewing sarcoma cells, representing the most common solid tumors of childhood. RESULTS: BetA induced apoptosis by a direct effect on mitochondria independent of accumulation of wild-type p53 protein and independent of death-inducing ligand/receptor systems such as CD95. Mitochondrial perturbations on treatment with BetA resulted in the release of soluble apoptogenic factors such as cytochrome c or AIF from mitochondria into the cytosol, where they induced activation of caspases. Overexpression of the anti-apoptotic proteins Bcl-2 or Bcl-X(L) that blocked loss of the mitochondrial membrane potential and cytochrome c release from mitochondria also conferred resistance to BetA. Most importantly, BetA exhibited potent antitumor activity on neuroblastoma cells resistant to CD95- or doxorubicin-triggered apoptosis and on primary tumor cells from patients with neuroectodermal tumors. CONCLUSIONS: Thus, BetA may be a promising new agent in the treatment of neuroectodermal tumors including neuroblastoma in vivo. "    

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...
"For this purpose we used betulinic acid, a cytotoxic agent selective for melanoma, straightly perturbing mitochondrial functions. In fact, betulinic acid induced mitochondrial cytochrome c release and DNA fragmentation in both CD95-resistant and CD95-sensitive melanoma cell populations, independent of the Bax/Bcl-2 ratio."

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"Betulinic acid (BA) was identified by our group as a selective inhibitor of melanoma that functions by inducing apoptosis."

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"The crude chloroform bark extract of Syncarpia glomulifera (Myrtaceae) shows antibacterial and cytotoxic activity. Bioactivity-directed separation led to the isolation of oleanolic acid-3-acetate, ursolic acid-3-acetate and betulinic acid. The relatively large abundance (10% of the crude extract) and high degree of activity of betulinic acid are responsible for the bioactivity of the crude bark extract."

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"23-Hydroxybetulinic acid, a derivative of betulinic acid, was investigated for its apoptotic effect and the associated telomerase activity in human leukemia HL-60 cells. Apoptosis and bcl-2 were determined by flow cytometry analysis. A PCR-based telomeric repeat amplification protocol assay was used to detect telomerase activity. Results showed that 23-hydroxybetulinic acid induced growth arrest and apoptotic cell death in HL-60 cells. The apoptotic events were associated with concurrent down-regulation of bcl-2 and the telomerase activity. Our data suggest that 23-hydroxybetulinic acid may be a potential cytotoxic agent for treatment of cancer."
   

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"Three triterpenoids, betulinic acid, oleanolic acid, and ursolic acid, were isolated as their methyl esters (treatment with diazomethane) from diethyl ether extracts of almond hulls (Nonpareil variety) using flash chromatography and preparative high-performance liquid chromatography. The triterpenoids, which comprised approximately 1% of the hulls, were characterized using chromatographic and spectroscopic methods. These studies demonstrate that almond hulls are a rich source of these triterpenoids, which have reported anti-inflammatory, anti-HIV, and anti-cancer activities."

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"Betulinic acid (11), its methyl ester (12), lup-28-al-20(29)-ene-3beta-ol (9), and lup-28-al-20(29)-en-3-one (10) inhibited B16 2F2 cell proliferation by induction of apoptosis. "

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"Malignant brain tumors are the most common solid tumors in children. The overall prognosis for this group of patients is still poor, emphasizing the importance of more effective therapies. Betulinic acid (Bet A) has been described as a novel cytotoxic compound active against melanoma and neuroblastoma cells."
"Since Bet A did not exhibit cytotoxicity against murine neuronal cells in vitro, these findings suggest that Bet A may be a promising new agent for the treatment of medulloblastoma and glioblastoma cells that clearly warrants further pre-clinical and clinical evaluation."

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"The chloroform extract of Vauquelinia corymbosa Correa has shown activity against the P-388 lymphocytic leukemia test system. The constituents responsible for this activity were identified as uvaol, ursolic acid, and betulinic acid. Their identity was proven by melting point; mixed melting point; elemental analysis; IR, PMR, and mass spectra; and preparation of derivatives."

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"Microbial transformation studies of the antimelanoma agent betulinic acid (1) were conducted."     

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"Microbial transformation of betulin (1), a lupane-type triterpene obtained from the bark extract of white birch (Betula platyphylla Sukatshev var. japonica), and its chemical oxidation product, betulonic acid (2), by the fungus Chaetomium longirostre yielded 4,28-dihydroxy-3,4-seco-lup-20(29)-en-3-oic acid (3) and 4-hydroxy-3,4-seco-lup-20(29)-ene-3,28-dioic acid (4) from 1, and 4,7beta,17-trihydroxy-3,4-seco-28-norlup-20(29)-en-3-oic acid (5) and 7 beta,15 alpha-dihydoxy-3-oxolup-20(29)-en-28-oic acid (6) from 2. The four metabolites, 3-6, along with 1 and 2, were evaluated for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells as a primary screening test for inhibitors of tumor promotion. All of the triterpenes tested showed potent inhibitory effects, with the four metabolites 3-6 exhibiting the more potent effects."

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"BACKGROUND: Betulinic acid, a naturally abundant, plant derived, pentacyclic triterpenoid possesses anti-HIV, anti-malarial and anti-inflammatory properties and has recently emerged as a potent anti-tumor compound."
"Dihydro betulinic acid is the most potent (IC50=0.5 mM) pentacyclic triterpenoid to inhibit eukaryotic topoisomerase I till date and can be exploited as a strong candidate for anti-tumor drug designing."

(Notice how the drug companies are planning on stealing another idea that herbalists have known and have been using for a long time?)

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"Six ceanothane and 1-norceanothane derivatives (1, 2, 8-11) were prepared from ceanothic acid dibenzyl ester. These ring-A homologues of betulinic acid exhibited cytotoxic effects. Among these, 1-decarboxy-3-oxo-ceanothic acid (2) was found to be the most cytotoxic against OVCAR-3 and HeLa cancer cell lines, with an IC50 of 2.8 and 6.6 microg/mL, respectively, and an IC50 of 11.3 microg/mL against normal cell line FS-5."
   

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"The finding supports the idea that betulinic acid acts as anti-melanoma agent via inhibition of aminopeptidase N activity."
   

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"We investigated the sequence of these events in SHEP neuroblastoma cells transfected with Bcl-2 or Bcl-X(L) using two different drugs, namely, doxorubicin (Doxo), which activates the CD95/CD95 ligand (CD95-L) system, and betulinic acid (Bet A), which does not enhance the expression of CD95 or CD95-L and which, as shown here, directly targets mitochondria. Apoptosis induced by both drugs was inhibited by Bcl-2 or Bcl-X(L) overexpression or by bongkrekic acid, an agent that stabilizes mitochondrial membrane barrier function, suggesting a critical role for mitochondria. "    

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"Betulinic acid has been modified at C-3, C-20, and C-28 positions and the toxicity of the derivatives has been evaluated against cultured human melanoma (MEL-2) and human epidermoid carcinoma of the mouth (KB) cell lines. This preliminary investigation demonstrates that simple modifications of the parent structure of betulinic acid can produce potentially important derivatives, which may be developed as antitumor drugs."    

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"This investigation demonstrates that amino acid conjugates of betulinic acid can produce potentially important derivatives, which may be developed as antitumor agents."
   
( Why does betulinic acid have to be developed in to an antitumor agent since it is already an antitumor agent?)

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"Betulinic acid (BetA), a pentacyclic triterpene, is a selective apoptosis-inducing agent that works directly in mitochondria."

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"Betulinic acid is a known inducer of apoptosis in human melanoma that is most effective under conditions of low pH."    

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"Indeed, unlike conventional anti tumour drugs which trigger pro-apoptotic signal transduction pathways upstream mitochondria, several compounds were shown to act directly on mitochondria to induce apoptosis. These drugs include betulinic acid, lonidamine, arsenic trioxide and two retinoids like CD437/AHPN and fenretinide/4-HPR. This review summarizes new data concerning these drugs targetted to mitochondria and highlights the new perspective they may offer in cancer therapy."

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"CONCLUSIONS: Lupeol and betulin suppress superoxide generation by preventing tyrosyl phosphorylation of a 45.0-kDa protein in human neutrophils, and may have pharmaceutical applications."
 

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"Three triterpenes were isolated from Diospyros leucomelas and identified as betulin, betulinic acid, and ursolic acid. They showed anti-inflammatory activity in the carrageenan and serotonin paw edema tests and TPA and EPP ear edema tests.    "

(Remember that inflammation has been shown to play a role in cancer formation)

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"A new pentacyclic lupane-type triterpene derivative, 3-O-[9(Z)-octadecenoyl]betulinic acid (1), and betulinic acid (2) were also isolated and identified. All isolates as well as pure linoleic, oleic and stearic acids were evaluated for their inhibitory effects against both cyclooxygenases-1 (COX-1) and -2 (COX-2)."

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"Cold-pressed, non-raffinated evening primrose oil was found to contain lipophilic radical scavengers. A highly enriched fraction of these compounds could be obtained from the oil by extraction with aqueous ethanol and subsequent liquid-liquid partitioning with petroleum. LC-DAD-MS analysis revealed that the fraction contained three aromatic compounds with identical UV and ESI-MS spectra. The compounds were isolated by RP-HPLC and their structures established by chemical and spectroscopic means as 3-O-trans-caffeoyl derivatives of betulinic, morolic, and oleanolic acid. The morolic acid derivative was a new compound. The three esters exhibited pronounced radical scavenging activity against the stable 2,2-diphenyl-1-picrylhydrazyl radical and were potent inhibitors of neutrophil elastase and cyclooxygenase-1 and -2 in vitro. "

(Cold pressed evening primrose oil is readily available in health food stores)

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"Conclusions: These results suggest that in human melanoma cells Mcl-1 is (i) of functional relevance for survival and (ii) subject to dual regulation by the MAP- kinase pathway and a pathway involving protein kinase B/Akt, the latter of which is modulated in response to betulinic acid."    

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"DNA topoisomerases (Topos) are enzymes that play a crucial role in DNA metabolism events such as replication, transcription, recombination, and chromosome segregation at mitosis. Thus, Topo inhibitors could be expected to have antitumor effects. Naturally occurring lupane- and oleanane-type triterpenoids isolated from the bark of Phyllanthus flexuosus were screened for human Topos I and II inhibitory activities. Olean-12-en-3 beta,15 alpha-diol (1), olean-12-en-3 beta,15 alpha,24-triol (3), lupeol (4), and betulin (6) were found to be selective catalytic inhibitors of human Topo II activity with IC(50) values in the range of 10-39 microM."

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"The new phenolic compound, 3,5-dihydroxy-4-methoxy phenethyl alcohol, named alphitol, and betulinic acid were from the bark of Alphitonia zizyphoides. The chemical structure of alphitol was determined by mass spectrometry in combination with one and two dimensional NMR, including HMBC. Both compounds inhibited prostaglandin biosynthesis in vitro, alphitol with an IC50 value of 0.66mM, which is of the same magnitude as acetyl salicylic acid."

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"Our data suggest that betulinic acid exerts its inhibitory effect partly by increasing p53 without a comparable effect on p21WAF1."
   

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

"Betulinic acid might be promising as an antitumor agent toward solid tumors because the interior pH of tumor tissues is generally lower than in normal tissues."
   

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&...

Sterol and triterpene derivatives from plants inhibit the effects of a tumor promoter, and sitosterol and betulinic acid inhibit tumor formation in mouse skin two-stage carcinogenesis.

"A single topical application of 1 microgram of 12-O-tetradecanoylphorbol- 13-acetate (TPA) to the ears of mice was shown to induce edema, and this TPA-induced inflammation was inhibited by 4-methylsterol and triterpene derivatives. The ED50 of these compounds against TPA-induced inflammation was 0.1-3 mumol. Phytosterols had only slight inhibitory effects. Furthermore, application of 5 micrograms TPA to mouse skin rapidly caused accumulation of ornithine decarboxylase (ODC). Similarly, sitosterol and lupane-type triterpene derivatives markedly inhibited this TPA-induced ODC accumulation. In addition, 5 mumol betulinic acid markedly inhibited the promoting effect of 2.5 micrograms TPA applied twice weekly on skin tumor formation in mice initiated with 50 micrograms of 7,12-dimethylbenz[a]anthracene, and 5 mumol of sitosterol caused slight suppression. Thus, the inhibitory effects of sterol and triterpene derivatives on TPA-induced inflammation roughly parallelled their inhibitory activities against tumor promotion."

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