Scientific Researches On:
Betulinic Acid (Birch Bark Extract)
USA National Center for
Biotechnology Information
1:
Mol
Carcinog. 2008 Apr 28. [Epub ahead of
print]
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Betulinic acid suppresses constitutive and
TNFalpha-induced NF-kappaB activation and
induces apoptosis in human prostate carcinoma
PC-3 cells.
Rabi T,
Shukla S,
Gupta S.
Department of Urology, The James & Eillen Dicke
Research Laboratory, Case Western Reserve
University, Cleveland, Ohio.
Development of chemoresistance in
androgen-refractory prostate cancer cells is
partly due to constitutive activation of Rel/NF-kappaB
transcription factors that regulate several cell
survival and anti-apoptotic genes. In this study
we examined whether betulinic acid (BetA), a
pentacyclic triterpene from the bark of white
birch, is effective in inhibiting NF-kappaB
expression in androgen-refractory human prostate
cancer cells exhibiting high constitutive NF-kappaB
expression. Treatment of PC-3 cells with BetA
inhibited DNA binding and reduced nuclear levels
of the NF-kappaB/p65. BetA-mediated NF-kappaB
inhibition involved decreased IKK activity and
phosphorylation of IkappaBalpha at serine 32/36
followed by its degradation. Reporter assays
revealed that NF-kappaB inhibition by BetA is
transcriptionally active. These effects were
found to correlate with a shift in Bax/Bcl-2
ratio and cleavage of poly(ADP)ribose polymerase
more towards apoptosis. BetA also inhibited
TNFalpha-induced activation of NF-kappaB via the
IkappaBalpha pathway, thereby sensitizing the
cells to TNFalpha-induced apoptosis. Our studies
demonstrate that BetA effectively inhibits
constitutive NF-kappaB activation and supports
the rationale for targeting NF-kappaB through
combination protocols with BetA in
androgen-refractory prostate cancer. (c) 2008
Wiley-Liss, Inc.
PMID: 18444250 [PubMed - as supplied by
publisher]
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Cytotoxic triterpenoids from the root bark of
Helicteres angustifolia.
Pan MH,
Chen CM,
Lee SW,
Chen ZT.
Department of Seafood Science, National
Kaohsiung Marine University, No. 142, Hai-Chuan
Rd, Nan-Tzu, Kaohsiung 811, Taiwan, R.O.C.
Three new triterpenoids,
3beta-acetoxy-27-[(E)-cinnamoyloxy]lup-20(29)-en-28-oic
acid methyl ester (1),
3beta-acetoxy-27-[(4-hydroxybenzoyl)oxy]lup-20(29)-en-28-oic
acid (2), and
3beta-acetoxy-27-[(4-hydroxybenzoyl)oxy]olean-12-en-28-oic
acid methyl ester (3), together with nine known
triterpenoids, 4-12, were isolated from the root
bark of Helicteres angustifolia. The structures
of these compounds were established on the basis
of spectroscopic methods including 2D-NMR
experiments. All twelve compounds were tested
for their cytotoxic activities against human
colorectal cancer (COLO 205), human hepatoma (Hep
G2), and human gastric cancer (AGS) cell lines
in vitro. Among them, compounds 2, 3,
3beta-O-[(E)-coumaroyl]betulinic acid (6), and
pyracrenic acid (7) showed significant cytotoxic
activities against human cancer cells COLO 205
and AGS.
Publication Types:
PMID: 18421748 [PubMed - in process]
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Synthesis of lupane-type saponins bearing
mannosyl and 3,6-branched trimannosyl residues
and their evaluation as anticancer agents.
Cmoch P,
Pakulski Z,
Swaczynová J,
Strnad M.
Institute of Organic Chemistry, Polish Academy
of Sciences, Kasprzaka 44/52, PL-01-224
Warszawa, Poland.
The saponins modified with mono- or trimannosyl
residues can provide a convenient means of
delivering drugs to certain human cells via
interactions with mannose receptors. In the
study reported therein, we developed a
convenient approach for the synthesis of
3-O-mannoside and branched trimannoside
derivatives of the saponin lupeol and of C-28
acyl esters of 3-O-acetyl-betulinic acid bearing
the same mannosyl entities. Lupeol and
3-O-acetyl-betulinic acid were mannosylated with
tetra-O-benzoyl- or tetra-O-acetyl-alpha-D-mannopyranosyl
trichloroacetimidates. De-esterification
followed by regioselective dimannosylation of
the unprotected monosaccharide derivatives with
2equiv of tetra-O-benzoyl-alpha-D-mannopyranosyl
trichloroacetimidate selectively yielded
O-3,O-6-linked trimannosides. The cytotoxic
activity of selected lupane-type saponins
(derivatives of lupeol, betulinic acid, and
betulin) toward normal human fibroblasts and
various cancer cell lines was also compared.
Publication Types:
PMID: 18328468 [PubMed - in process]
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Betulinic acid, a catalytic inhibitor of
topoisomerase I, inhibits reactive oxygen
species-mediated apoptotic topoisomerase I-DNA
cleavable complex formation in prostate cancer
cells but does not affect the process of cell
death.
Ganguly A,
Das B,
Roy A,
Sen N,
Dasgupta SB,
Mukhopadhayay S,
Majumder HK.
Molecular Parasitology Laboratory, Indian
Institute of Chemical Biology, Kolkata, India.
The ubiquitious enzyme topoisomerase I can be
targeted by drugs which turn these enzymes into
cellular poisons and subsequently induce cell
death. Drugs like staurosporine, which do not
target topoisomerase I directly, can also lead
to stabilization of topoisomerase I-DNA
cleavable complexes by an indirect process of
reactive oxygen species (ROS) generation and
subsequent oxidative DNA damage. In this study,
we show that betulinic acid, a catalytic
inhibitor of topoisomerases, inhibits the
formation of apoptotic topoisomerase I-DNA
cleavable complexes in prostate cancer cells
induced by drugs like camptothecin,
staurosporine, and etoposide. Although events
like ROS generation, oxidative DNA damage, and
DNA fragmentation were observed after betulinic
acid treatment, there is no topoisomerase I-DNA
cleavable complex formation, which is a key step
in ROS-induced apoptotic processes. We have
shown that betulinic acid interacts with
cellular topoisomerase I and prohibits its
interaction with the oxidatively damaged DNA.
Using oligonucleotide containing 8-oxoguanosine
modification, we have shown that betulinic acid
inhibits its cleavage by topoisomerase I in
vitro. Whereas silencing of topoisomerase I gene
by small interfering RNA reduces cell death in
the case of staurosporine and camptothecin, it
cannot substantially reduce betulinic
acid-induced cell death. Thus, our study
provides evidence that betulinic acid inhibits
formation of apoptotic topoisomerase I-DNA
complexes and prevents the cellular
topoisomerase I from directly participating in
the apoptotic process.
Publication Types:
PMID: 18089815 [PubMed - indexed for MEDLINE]
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Cimicifuga foetida extract inhibits
proliferation of hepatocellular cells via
induction of cell cycle arrest and apoptosis.
Tian Z,
Pan R,
Chang Q,
Si J,
Xiao P,
Wu E.
Institute of Medicinal Plant Development,
Chinese Academy of Medical Sciences, Peking
Union Medical College, Beijing 100094, China.
ze.tian@childrens.harvard.edu
The purpose of this study is to determine
whether the ethyl acetate fraction (EAF) from
the aerial part of Cimicifuga foetida Linnaeus
possesses the anti-tumor action on hepatoma, and
therefore, provide evidence for the traditional
use of the plant as a detoxification agent. EAF
was extracted and its cytotoxicity was evaluated
on a panel of Hepatocytes by MTT assay. The
IC(50) values of EAF on HepG2, R-HepG2 and
primary cultured normal mouse hepatocytes were
21, 43 and 80 microg/mL, respectively.
Morphology observation, Annexin V-FITC/PI
staining, cell cycle analysis and western blot
were used to further elucidate the cytotoxic
mechanism of EAF. EAF induced G(0)/G(1)cell
cycle arrest at lower concentration (25 microg/mL),
and triggered G(2)/M arrest and apoptosis at
higher concentrations (50 and 100 microg/mL,
respectively). An increase in the ratio of Bax/Bcl-2,
activation of downstream effector Caspase 3, and
cleavage of poly-ADP-ribose polymerase (PARP)
were implicated in EAF-induced apoptosis. In
addition, EAF inhibited the growth of the
implanted mouse H(22) tumor in a dose-dependent
manner with the growth inhibitory rate of 63.32%
at 200 mg/kg. In conclusion, EAF may potentially
find use as a new therapy for the treatment of
hepatoma.
Publication Types:
PMID: 17881166 [PubMed - indexed for MEDLINE]
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Pharmacological evaluation of C-3 modified
Betulinic acid derivatives with potent
anticancer activity.
Rajendran P,
Jaggi M,
Singh MK,
Mukherjee R,
Burman AC.
Experimental Oncology Lab, Dabur Research
Foundation, 22, Site-IV, Sahibabad, Ghaziabad,
Uttar Pradesh, 201010, India.
In vitro and in vivo pharmacological screening
of Betulinic acid (BA) and five dihydro-BA
derivatives modified at C-3 position
[4-nitrobenzyl-oximino (1),
2-4-difluoro-benzoyloxy (2),
2-4-difluoro-benzylidene-amino (3),
benzoyl-hydrazono (4), and
4-fluorophenyl-hydrazono (5)], having potent in
vitro anti-cancer activity was carried out using
ADME, animal PK and tumor studies. We found that
BA and the derivatives had poor aqueous
solubility (<0.1 microg/ml), low to moderate
permeability (log Pe<-5.0) and high plasma
protein binding (>70%). Although BA and 5 were
metabolized by human liver microsomes,
derivatives 1, 2, 3 and 4 possessed good in
vitro metabolic stability. Except 3 which
inhibited CYP1A2 isoform by more than 50% none
of the other compounds inhibited key cytochrome
P450 enzyme isoforms (CYP1A2, CYP2C9, CYP2D6 and
CYP3A4) at 10 microM. Based on in vitro results
one derivative 1 was tested in rodent PK and
tumor studies. We found that 1 exhibited
favorable pharmacokinetic characteristics of a
systemically administered drug and showed better
in vivo anti-tumor efficacy as compared to BA in
a human colon cancer xenograft model. Our
results show that BA derivatives are potential
anti-cancer compounds which need to be explored
in detail.
PMID: 17851638 [PubMed - in process]
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Effect of betulinic acid on anticancer
drug-resistant colon cancer cells.
Jung GR,
Kim KJ,
Choi CH,
Lee TB,
Han SI,
Han HK,
Lim SC.
Department of Pharmacology, College of Medicine,
Chosun University, 488 Seosuk-dong, Dong-gu,
Gwangju 501-140, Korea.
Primary or acquired resistance of tumours to
established chemotherapeutic regimens is a major
concern in oncology. Attempts to improve the
survival of cancer patients largely depend on
strategies to prevent tumour cell resistance.
5-Fluorouracil (5-FU)-based chemotherapy with a
combination of other drugs such as irinotecan (IRT)
and oxaliplatin (OXT) has been reported to be
effective, even though an optimal regimen has
yet to be defined due to the relatively high
toxicity of the procedure. The aim of this study
was to examine the effect of betulinic acid (BetA)
as a chemosensitizer for anticancer drug
treatment in chemoresistant colon cancer cell
lines. A chemoresistant cell line to
5-fluorouracil (SNU-C5/5FU-R), irinotecan
(SNU-C5/IRT-R) and oxaliplatin (SNU-C5/OXT-R)
treatment were derived from the wild-type colon
adenocarcinoma cell line (SNU-C5/WT). The effect
of BetA or a combination of anticancer drugs and
BetA on the multidrug resistance-related genes,
caspases, Bcl-2, Bad and cell death in the
SNU-C5/WT and SNU-C5/R cell lines was analysed.
BetA alone was an effective chemotherapeutic
drug for the SNU-C5/WT, SNU-C5/5FU-R and SNU-C5/OXT-R
cells. The combination of BetA with IRT or OXT
was effective against SNU-C5/5FU-R cells, and
the combination of BetA with 5-fluorouracil, IRT
or OXT was effective against SNU-C5/OXT-R cells.
BetA induced cancer cell death by apoptosis
through the mitochondrial pathway. These
findings indicate that the use of BetA as a
chemosensitizer may be a new strategy to enhance
the efficacy of chemotherapy. However, further
studies will be needed for confirmation.
Publication Types:
PMID: 17845510 [PubMed - indexed for MEDLINE]
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2-cyano-lup-1-en-3-oxo-20-oic acid, a cyano
derivative of betulinic acid, activates
peroxisome proliferator-activated receptor gamma
in colon and pancreatic cancer cells.
Chintharlapalli S,
Papineni S,
Liu S,
Jutooru I,
Chadalapaka G,
Cho SD,
Murthy RS,
You Y,
Safe S.
Institute of Biosciences and Technology, Texas
A&M University Health Science Center,Houston, TX
77030-3303, USA.
Betulinic acid (BA) is a phytochemical
triterpenoid acid from bark extracts and is
cytotoxic to cancer cells and tumors. We
modified the A-ring of BA to give a
2-cyano-1-en-3-one moiety and the effects of the
2-cyano-lup-1-en-3-oxo-20-oic acid (CN-BA),
2-cyano derivative of BA, and its methyl ester (CN-BA-Me)
were investigated in colon and pancreatic cancer
cells. Both CN-BA and CN-BA-Me were highly
cytotoxic to Panc-28 pancreatic and SW480 colon
cancer cells. CN-BA and CN-BA-Me also induced
differentiation in 3T3-L1 adipocytes, which
exhibited a characteristic fat droplet
accumulation induced by peroxisome proliferator-activated
receptor gamma (PPARgamma) agonists. Based on
these results, we investigated the activities of
CN-BA and CN-BA-Me as PPARgamma agonists using
several receptor-mediated responses including
activation of transfected PPARgamma-responsive
constructs, induction of p21 in Panc-28 cells
and induction of caveolin-1 and Krüppel-like
factor 4 in colon cancer cells. The results
clearly demonstrated that both CN-BA and CN-BA-Me
activated PPARgamma-dependent responses in colon
(caveolin-1) and pancreatic (p21) cancer cells,
whereas induction of KLF4 by these compounds in
colon cancer cells was PPARgamma independent and
also dependent on cell context. The PPARgamma
agonist activities of CN-BA and CN-BA-Me were
structure-, response/gene- and cell
context-dependent suggesting that these
compounds are a novel class of selective
PPARgamma modulators with potential for clinical
treatment of colon and pancreatic cancer.
Publication Types:
PMID: 17724373 [PubMed - indexed for MEDLINE]
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Novel semisynthetic analogues of betulinic
acid with diverse cytoprotective,
antiproliferative, and proapoptotic activities.
Liby K,
Honda T,
Williams CR,
Risingsong R,
Royce DB,
Suh N,
Dinkova-Kostova AT,
Stephenson KK,
Talalay P,
Sundararajan C,
Gribble GW,
Sporn MB.
Dartmouth Medical School, Hanover, NH 03755,
USA.
Betulinic acid (BA), a pentacyclic triterpene
isolated from birch bark and other plants,
selectively inhibits the growth of human cancer
cell lines. However, the poor potency of BA
hinders its clinical development, despite a lack
of toxicity in animal studies even at high
concentrations. Here, we describe six BA
derivatives that are markedly more potent than
BA for inhibiting inducible nitric oxide
synthase, activating phase 2 cytoprotective
enzymes, and inducing apoptosis in cancer cells
and in Bax/Bak(-/-) fibroblasts, which lack two
key proteins involved in the intrinsic,
mitochondrial-dependent apoptotic pathway.
Notably, adding a cyano-enone functionality in
the A ring of BA enhanced its cytoprotective
properties, but replacing the cyano group with a
methoxycarbonyl strikingly increased potency in
the apoptosis assays. Higher plasma and tissue
levels were obtained with the new BA analogues,
especially CBA-Im
[1-(2-cyano-3-oxolupa-1,20(29)-dien-28-oyl)imidazole],
compared with BA itself and at concentrations
that were active in vitro. These results suggest
that BA is a useful platform for drug
development, and the enhanced potency and varied
biological activities of CBA-Im make it a
promising candidate for further chemoprevention
or chemotherapeutic studies.
Publication Types:
PMID: 17620440 [PubMed - indexed for MEDLINE]
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Synthesis and structure-activity relationship
study of cytotoxic germanicane- and lupane-type
3beta-O-monodesmosidic saponins starting from
betulin.
Thibeault D,
Gauthier C,
Legault J,
Bouchard J,
Dufour P,
Pichette A.
Laboratoire d'Analyse et de Séparation des
Essences Végétales, Département des Sciences
Fondamentales, Université du Québec à Chicoutimi,
555 boul. de l'Université, Chicoutimi, Québec,
Canada.
Germanicane-type triterpenes allobetulin (3) and
28-oxoallobetulin (4) can be obtained by the
Wagner-Meerwein rearrangement of the more
available lupane-type triterpenes betulin (1)
and betulinic acid (2), respectively. The
medical uses of betulinic acid (2) and its
derivatives are limited because of their poor
hydrosolubility and pharmacokinetics properties.
In order to overcome this major problem, we
synthesized and studied the in vitro anticancer
activity of a series of 3beta-O-monodesmosidic
saponins derived from betulin (14-16), betulinic
acid (20-22), allobetulin (23-28) and
28-oxoallobetulin (29-34) based on six different
natural sugar residues (d-glucose, l-rhamnose,
d-arabinose, d-galactose, d-mannose and d-xylose).
This structure-activity relationship study
confirmed that betulinic acid saponins are
generally better in vitro anticancer agents than
those derived from betulin with the exception of
betulin 3beta-O-alpha-d-mannopyranoside (15)
which exerted a potent cytotoxic activity
against lung carcinoma (A-549) and colorectal
adenocarcinoma (DLD-1) human cell lines with
IC(50) ranging from 7.3 to 10.1mumol/L.
Furthermore, although the synthesis of novel
germanicane-type saponins was carried out with
success, the bioactivity measured for these
glycosides was not as high as we anticipated
since only the 3beta-O-beta-d-glucopyranoside
and 3beta-O-beta-d-galactopyranoside of
allobetulin (23,24) showed moderate anticancer
activity (IC(50) 30-40 micromol/L).
Publication Types:
PMID: 17614290 [PubMed - indexed for MEDLINE]
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Betulin binds to melanocortin receptors and
antagonizes alpha-melanocyte stimulating hormone
induced cAMP generation in mouse melanoma cells.
Muceniece R,
Saleniece K,
Riekstina U,
Krigere L,
Tirzitis G,
Ancans J.
Faculty of Medicine, University of Latvia, Riga,
Latvia. Ruta.Muceniece@lu.lv
Betulin is a principal component of birch bark
and is known to possess a broad range of
biological activities, including
antiinflammatory, antiviral and anticancer
actions. The present study was carried out in
vitro to clarify the influence of betulin on
melanocortin (MC) receptor-ergic signalling by
using COS-7 cells transfected with corresponding
human MC receptor DNA. The results showed that
betulin binds to the human melanocortin MC1,
three to five receptors with selectivity to the
MC1 subtype (K(i) value 1.022 +/- 0.115 microM).
Betulin binds to the MC receptors with the
following potency order-MC > MC3 > MC5 > MC4.
Betulin itself does not stimulate cAMP
generation, however, it slightly antagonizes
alpha-melanocyte-stimulating hormone (alpha-MSH)-induced
cAMP accumulation in the mouse melanoma cell
line B16-F1. As a water-insoluble substance,
betulin was dissolved in DMSO therefore DMSO
competition with the labelled ligand NDP-MSH for
the binding to the MC receptors was tested in
the identical experimental set-up. We found that
DMSO competes for binding to all the MC receptor
subtypes, at 20% concentration and above.
Selectivity for one or another receptor subtype
was not observed. We have demonstrated for the
first time, the ability of the plant compound
betulin to bind to the MC receptors. One may
suggest MC receptor MC1 subtype as the essential
target for the antimelanoma action of betulin
and its structurally close molecules such as
betulinic acid. Moreover, we have found a new
non-peptide small molecule MC mimetic, that is
betulin. Thus, we report a new chemical motif
for the binding to the MC receptors that could
be used as a template for the search of more
selective MC mimetics.
Publication Types:
PMID: 17605140 [PubMed - indexed for MEDLINE]
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Triterpenoid pyrazines and benzopyrazines
with cytotoxic activity.
Urban M,
Sarek J,
Kvasnica M,
Tislerova I,
Hajduch M.
Department of Organic and Nuclear Chemistry,
Faculty of Science, Charles University in
Prague, Hlavova 8, 128 43 Prague 2, Czech
Republic.
Twelve lupane, 18alpha-oleanane, and des-E-lupane
derivatives (1a-5b) were either extracted from
natural sources or synthesized from betulinic
acid (1a) and betulin (2). Compounds 1b, 1c, 3b,
3c, 4b, 4c, 5a, and 5b were then used as
starting materials for further synthesis of a
series of pyrazines and benzopyrazines (6a-18);
20 of them are new (6a-6e, 7a-7d, and 10a-18).
Activity of pyrazine 6a against the T-lymphoblastic
leukemia cell line CEM encouraged us to
synthesize several new esters (6b-6d) to study
structure-activity relationships with respect to
substitution of the carboxyl group at position
28. The synthesized compounds were tested for
cytotoxicity against a variety of cancer cell
lines of different histogenetic origin, and the
results were compared with cytotoxicity of the
known starting compounds. Significant cytotoxic
activity against A 549, K 562, and multidrug-resistant
K 562-tax cell lines was found in pyrazines 6a,
6d, and 6e.
Publication Types:
PMID: 17371067 [PubMed - indexed for MEDLINE]
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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.
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.
Publication Types:
PMID: 17363604 [PubMed - indexed for MEDLINE]
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Synthesis and cytotoxic activity of
17-carboxylic acid modified 23-hydroxy betulinic
acid ester derivatives.
Bi Y,
Xu J,
Wu X,
Ye W,
Yuan S,
Zhang L.
Department of Medicinal Chemistry, China
Pharmaceutical University, Nanjing 210009,
China.
New 17-carboxylic acid modified 23-hydroxy
betulinic acid ester derivatives were prepared
and tested for cytotoxic activity on five cancer
cell lines in vitro: all tested compounds showed
stronger cytotoxic activity than 23-hydroxy
betulinic acid and betulinic acid. In addition,
compound 5a was tested for anti-tumor activity
in vivo: it had much better anti-tumor activity
than 23-OH betulinic acid and had similar
anti-tumor activity with cyclophosphamide and
5-fluorouracil.
Publication Types:
PMID: 17275295 [PubMed - indexed for MEDLINE]
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Biotransformation of betulinic and betulonic
acids by fungi.
Bastos DZ,
Pimentel IC,
de Jesus DA,
de Oliveira BH.
Universidade Federal do Paraná, Departamento de
Química, CP19081, 81531-970 Curitiba-PR, Brazil.
Betulinic acid (1), a triterpenoid found in many
plant species, has attracted attention due to
its important pharmacological properties, such
as anti-cancer and anti-HIV activities. The
closely related, betulonic acid (2) also has
similar properties. In order to obtain
derivatives potentially useful for detailed
pharmacological studies, both compounds were
submitted to incubations with selected
microorganisms. In this work, both were
individually metabolized by the fungi
Arthrobotrys, Chaetophoma and Dematium, isolated
from the bark of Platanus orientalis as well as
with Colletotrichum, obtained from corn leaves;
such fungal transformations are quite rare in
the scientific literature. Biotransformations
with Arthrobotrys converted betulonic acid (2)
into 3-oxo-7beta-hydroxylup-20(29)-en-28-oic
acid (3),
3-oxo-7beta,15alpha-dihydroxylup-20(29)-en-28-oic
acid (4) and
3-oxo-7beta,30-dihydroxylup-20(29)-en-28-oic
acid (5); Colletotrichum converted betulinic
acid (1) into
3-oxo-15alpha-hydroxylup-20(29)-en-28-oic (6)
acid whereas betulonic acid (2) was converted
into the same product and
3-oxo-7beta,15alpha-dihydroxylup-20(29)-en-28-oic
acid (4); Chaetophoma converted betulonic acid
(2) into 3-oxo-25-hydroxylup-20(29)-en-28-oic
acid (7) and both Chaetophoma and Dematium
converted betulinic acid (1) into betulonic acid
(2). Those fungi, therefore, are useful for
mild, selective oxidations of lupane substrates
at positions C-3, C-7, C-15, C-25 and C-30.
Publication Types:
PMID: 17258248 [PubMed - indexed for MEDLINE]
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Broad in vitro efficacy of plant-derived
betulinic acid against cell lines derived from
the most prevalent human cancer types.
Kessler JH,
Mullauer FB,
de Roo GM,
Medema JP.
Laboratory for Experimental Oncology and
Radiobiology, Center for Experimental and
Molecular Medicine, Academic Medical Center,
Meibergdreef 9, 1105 AZ Amsterdam, The
Netherlands.
Betulinic acid (BA) is a widely available
plant-derived triterpene with reported activity
against cancer cells of neuroectodermal origin
and leukaemias. Treatment with BA was shown to
protect mice against transplanted human melanoma
and led to tumor regression. In contrast, cells
from healthy tissues were resistant to BA and
toxic side-effects in animals were absent. These
findings have raised interest in the
chemotherapeutical anti-cancer potential of BA.
A comprehensive assessment of the efficacy of BA
against the clinically most important cancer
types is currently lacking. Therefore, we tested
the in vitro sensitivity of broad cell line
panels derived from lung, colorectal, breast,
prostate and cervical cancer, which are the
prevalent cancer types characterized with
highest mortalities in woman and men. Multiple
assays were used in order to allow a reliable
assessment of anti-cancer efficacy of BA. After
48 h of treatment with BA, cell viability as
assessed with MTT and cell death as measured
with propidium iodide exclusion showed clear
differences in sensitivity between cell lines.
However, in all cell lines tested colony
formation was completely halted at remarkably
equal BA concentrations that are likely
attainable in vivo. Our results substantiate the
possible application of BA as a chemotherapeutic
agent for the most prevalent human cancer types.
Publication Types:
PMID: 17169485 [PubMed - indexed for MEDLINE]
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Physical, chemical and pharmacological
characterization of a new oleogel-forming
triterpene extract from the outer bark of birch
(betulae cortex).
Laszczyk M,
Jäger S,
Simon-Haarhaus B,
Scheffler A,
Schempp CM.
Carl Gustav Carus-Institut, Niefern-Oschelbronn,
Germany.
Triterpenes are biologically active secondary
plant substances that display antimicrobial,
hepatoprotective and anti-inflammatory effects.
However, the poor solubility of triterpenes in
both polar and non-polar solvents as well as
expensive purification procedures have prevented
the large-scale isolation of these compounds for
medicinal purposes. Here, we describe a novel
quantitative extraction method of triterpenes
from the outer bark of birch (Betula species) in
which betulin, a lupan triterpene, predominates.
The resulting highly purified triterpene extract
(TE) in the form of a dry powder contains
betulin as the major compound, but also
betulinic acid, lupeol, erythrodiol and
oleanolic acid. We have found that this TE is
able to form an oleogel, thus providing an
opportunity for the topical application of
pharmacologically relevant amounts of
triterpenes. Furthermore, we have investigated
the TE in comparison to its major isolated
compounds in cell culture experiments with human
immortalized keratinocytes and skin cancer
cells. We could demonstrate dose-dependent
cytotoxic and apoptosis-inducing effects of TE
and betulin. These experimental data support the
notion from a previous clinical study that TE
from the outer bark of birch might represent a
new tool for the topical treatment of skin
cancer and skin cancer precursors like actinic
keratoses.
Publication Types:
PMID: 17091432 [PubMed - indexed for MEDLINE]
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Betulinic acid decreases expression of bcl-2
and cyclin D1, inhibits proliferation, migration
and induces apoptosis in cancer cells.
Rzeski W,
Stepulak A,
Szymański M,
Sifringer M,
Kaczor J,
Wejksza K,
Zdzisińska B,
Kandefer-Szerszeń M.
Department of Virology and Immunology, Institute
of Microbiology and Biotechnology, Maria Curie-Skłodowska
University, Akademicka 19, 20-033, Lublin,
Poland. rzeskiw@biotop.umcs.lublin.pl
Betulinic acid (BA) is a pentacyclic triterpene
found in many plant species, among others in the
bark of white birch Betula alba. BA was reported
to display a wide range of biological effects,
including antiviral, antiparasitic,
antibacterial and anti-inflammatory activities,
and in particular to inhibit growth of cancer
cells. The aim of the study was further in vitro
characterization of BA anticancer activity. In
this study, we demonstrated a remarkable
antiproliferative effect of BA in all tested
tumor cell cultures including neuroblastoma,
rabdomyosarcoma-medulloblastoma, glioma,
thyroid, breast, lung and colon carcinoma,
leukemia and multiple myeloma, as well as in
primary cultures isolated from ovarian
carcinoma, cervical carcinoma and glioblastoma
multiforme. Furthermore, we have shown that BA
decreased cancer cell motility and induced
apoptotic cell death. We also observed decrease
of bcl2 and cyclin D1 genes expression, and
increase of bax gene expression after betulinic
acid treatment. These findings demonstrate the
anticancer potential of betulinic acid and
suggest that it may be taken into account as a
supportive agent in the treatment of cancers
with different tissue origin.
PMID: 16964520 [PubMed - indexed for MEDLINE]
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Glycosidation of lupane-type triterpenoids as
potent in vitro cytotoxic agents.
Gauthier C,
Legault J,
Lebrun M,
Dufour P,
Pichette A.
Laboratoire LASEVE, Département des Sciences
Fondamentales, UQAC, Chicoutimi, Québec, Canada
G7H 2B1.
The weak hydrosolubility of betulinic acid (3)
hampers the clinical development of this natural
anticancer agent. In order to circumvent this
problem and to enhance the pharmacological
properties of betulinic acid (3) and the lupane-type
triterpenes lupeol (1), betulin (2), and methyl
betulinate (7), glycosides (beta-D-glucosides,
alpha-L-rhamnosides, and alpha-D-arabinosides)
were synthesized and in vitro tested for
cytotoxicity against three cancerous (A-549,
DLD-1, and B16-F1) and one healthy (WS1) cell
lines. The addition of a sugar moiety at the C-3
or C-28 position of betulin (2) resulted in a
loss of cytotoxicity. In contrast, the
3-O-beta-D-glucosidation of lupeol (1) improved
the activity by 7- to 12-fold (IC50 14-15.0
microM). Moreover, the results showed that
cancer cell lines are 8- to 12-fold more
sensitive to the 3-O-alpha-L-rhamnopyranoside
derivative of betulinic acid (IC50 2.6-3.9
microM, 22) than the healthy cells (IC50 31
microM). Thus, this study indicates that
3-O-glycosides of lupane-type triterpenoids
represent an interesting class of potent in
vitro cytotoxic agents.
Publication Types:
PMID: 16787747 [PubMed - indexed for MEDLINE]
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Activation of apoptosis by derivatives of
betulinic acid in human tumor cells in vitro.
Pokrovskii AG,
Shintyapina AB,
Pronkina NV,
Kozhevnikov VS,
Plyasunova OA,
Shul'ts EE,
Tolstikov GA.
Research Institute of Virology and
Biotechnology, Vektor State Scientific Center of
Virology and Biotechnology, p. Kol'tsovo,
Novosibirsk oblast, 630559 Russia.
PMID: 16776075 [PubMed - indexed for MEDLINE]
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