Scientific Researches On:
Betulinic Acid (Birch Bark Extract)
USA National Center for
Biotechnology Information
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81:
J Agric Food Chem. 2000
Aug;48(8):3437-9.
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Identification of three triterpenoids in almond
hulls.
Takeoka G,
Dao L,
Teranishi R,
Wong R,
Flessa S,
Harden L,
Edwards R.
Western Regional Research Center, Agricultural
Research Service, U.S. Department of Agriculture,
Albany, California 94710, USA. grt@pw.usda.gov
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.
PMID: 10956130 [PubMed - indexed for MEDLINE]
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Mitochondrion as a novel target of anticancer
chemotherapy.
Costantini P,
Jacotot E,
Decaudin D,
Kroemer G.
Centre National de la Recherche Scientifique,
Institut Gustave Roussy, Villejuif, France.
Mitochondrial membrane permeabilization is a
critical event in the process leading to
physiologic or chemotherapy-induced apoptosis
(programmed cell death). This permeabilization
event is, at least in part, under the control of
the permeability transition pore complex (PTPC).
Oncoproteins from the Bcl-2 family and tumor
suppressor proteins from the Bax family interact
with PTPC to inhibit or facilitate membrane
permeabilization, respectively. 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. However,
stabilization of the mitochondrial membrane by
antiapoptotic Bcl-2-like proteins reduces the
cytotoxic potential of most of these drugs.
Targeting of specific PTPC components may overcome
this Bcl-2-mediated apoptosis inhibition. One
strategy involves cross-linking of critical redox-sensitive
thiol groups within the PTPC; another involves the
use of ligands to the mitochondrial benzodiazepine
receptor. Thus, the design of
mitochondrion-targeted cytotoxic drugs may
constitute a novel strategy for overcoming
apoptosis resistance.
Publication Types:
PMID: 10880547 [PubMed - indexed for MEDLINE]
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Pharmacokinetics and tissue distribution of
betulinic acid in CD-1 mice.
Udeani GO,
Zhao GM,
Geun Shin Y,
Cooke BP,
Graham J,
Beecher CW,
Kinghorn AD,
Pezzuto JM.
Department of Pharmacy Practice, College of
Pharmacy, University of Illinois at Chicago,
Chicago, IL 60612, USA. gudeani@uic.edu
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. The
objective of the present study was to determine
the pharmacokinetics of betulinic acid in CD-1
mice. Serum samples were obtained at designed
times after a single 250 or 500 mg/kg
intraperitoneal (IP) dose of betulinic acid.
Tissue samples (skin, heart, liver, spleen,
kidney, lung, brain, colon, caecum, ovary, uterus,
thymus, lymph node, bladder, perirenal fat,
mammary gland and small intestine) were collected
after betulinic acid administration (500 mg/kg).
Betulinic acid was extracted with methylene
chloride and quantitatively analysed by HPLC/MS.
Oleanolic acid and madecassic acid were used as
internal standards. Pharmacokinetic parameters
were calculated using the WinNonlin
pharmacokinetic software package. A
two-compartment, first-order model was selected
for pharmacokinetic modelling. The results showed
that after IP 250 and 500 mg/kg betulinic acid,
the serum concentrations reached peaks at 0.15 and
0.23 h, respectively. The 250 and 500 mg/kg above
betulinic acid IP doses were found to have
elimination half-lives of 11.5 and 11.8 h and
total clearances of 13.6 and 13.5 L/kg/h,
respectively. The pharmacokinetic parameters
observed for IP betulinic acid 500 mg/kg in the
skin of mice were as follows: k(a) (h(-1)) 0.257,
k(10) (h(-1)) 0.234, t(1/2(alpha)) (h) 2.63,
t(1/2(beta)) (h) 20.2, V (L/kg) 0.61, AUC (microg/h/mL)
3504, T(max) (h) 3.90 and C(max) (microg/mL)
300.9. The distribution of betulinic acid in
tissues at 24 h post-IP administration in a
descending order was as follows: perirenal fat,
ovary, spleen, mammary gland, uterus, bladder,
lymph node, liver, small intestine, caecum, lung,
thymus, colon, kidney, skin, heart and brain.
Copyright 1999 John Wiley & Sons, Ltd.
Publication Types:
PMID: 10870094 [PubMed - indexed for MEDLINE]
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Effects of betulinic acid alone and in
combination with irradiation in human melanoma
cells.
Selzer E,
Pimentel E,
Wacheck V,
Schlegel W,
Pehamberger H,
Jansen B,
Kodym R.
Department of Radiotherapy and Radiobiology,
University Hospital, Vienna, Austria. Edgar.Selzer@AKH-Wien.ac.at
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. In
combination with ionizing radiation the effect of
betulinic acid on growth inhibition was additive
in colony-forming assays. Betulinic acid also
induced apoptosis in human melanoma cells as
demonstrated by Annexin V binding and by the
emergence of cells with apoptotic morphology. The
growth-inhibitory action of betulinic acid was
more pronounced in human melanoma cell lines than
in normal human melanocytes. Notably, despite the
induction of apoptosis, analysis of the expression
of Bcl-2 family members in betulinic-acid-treated
cells revealed that expression of the
anti-apoptotic protein Mcl-1 was induced.
Furthermore, the antiproliferative action of
betulinic acid seemed to be independent of the p53
status. The properties of betulinic acid make it
an interesting candidate, not only as a single
agent but also in combination with radiotherapy.
We conclude that the strictly additive mode of
growth inhibition in combination with irradiation
suggests that the two treatment modalities may
function by inducing different cell death pathways
or by affecting different target cell populations.
Publication Types:
PMID: 10771474 [PubMed - indexed for MEDLINE]
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Determination of betulinic acid in mouse blood,
tumor and tissue homogenates by liquid
chromatography-electrospray mass spectrometry.
Shin YG,
Cho KH,
Chung SM,
Graham J,
Das Gupta TK,
Pezzuto JM.
Program for Collaborative Research in the
Pharmaceutical Sciences, College of Pharmacy,
University of Illinois at Chicago, 60612, USA.
A rapid and sensitive high-performance liquid
chromatography-electrospray MS method has been
developed to determine tissue distribution of
betulinic acid in mice. The method involved
deproteinization of these samples with 2.5 volumes
(v/w) of acetonitrile-ethanol (1:1) and then 5
microl aliquots of the supernatant were injected
onto a C18 reversed-phase column coupled with an
electrospray MS system. The mobile phase employed
isocratic elution with 80% acetonitrile for 10
min; the flow-rate was 0.7 ml/min. The column
effluent was analyzed by selected ion monitoring
for the negative pseudo-molecular ion of betulinic
acid [M-H]- at m/z 455. The limit of detection for
betulinic acid in biological samples by this
method was approximately 1.4 pg and the
coefficients of variation of the assay (intra- and
inter-day) were generally low (below 9.1%). When
athymic mice bearing human melanoma were treated
with betulinic acid (500 mg/kg, i.p.),
distribution was as follows: tumor, 452.2 +/-
261.2 microg/g; liver, 233.9 +/- 80.3 microg/g;
lung, 74.8 +/- 63.7 microg/g; kidney, 95.8 +/-
122.8 microg/g; blood, 1.8 +/- 0.5 microg/ml. No
interference was noted due to endogenous
substances. These methods of analysis should be of
value in future studies related to the development
and characterization of betulinic acid.
PMID: 10517355 [PubMed - indexed for MEDLINE]
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Betulinic acid: a new chemotherapeutic agent in
the treatment of neuroectodermal tumors.
Fulda S,
Jeremias I,
Pietsch T,
Debatin KM.
University Children's Hospital, Ulm, Germany.
We identified betulinic acid (BetA) as a new
cytotoxic agent active against neuroectodermal
tumor cells including neuroblastoma,
medulloblastoma, glioblastoma and Ewing's sarcoma
cells representing the most common solid tumors of
childhood. BetA induced apoptosis independent of
wild-type p53 protein and accumulation of
death-inducing ligand/receptor systems such as
CD95. BetA had a direct effect on mitochondria
resulting 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-XL that
blocked loss of the mitochondrial membrane
potential and cytochrome c release from
mitochondria conferred resistance to BetA at the
level of mitochondrial dysfunction, protease
activation and nuclear fragmentation.
Neuroblastoma cells resistant to CD95- or
doxorubicin-triggered apoptosis remained sensitive
to treatment with BetA suggesting that BetA may
bypass some forms of resistance. Moreover, BetA
exhibited potent antitumor activity on primary
tumor cell cultures from all neuroblastoma (4/4),
all medulloblastoma (4/4) and most glioblastoma
patients (20/24) ex vivo. These findings suggest
that BetA may be a promising new agent in the
treatment of neuroectodermal tumors in vivo.
Publication Types:
PMID: 10472570 [PubMed - indexed for MEDLINE]
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Betulinic acid: a new cytotoxic agent against
malignant brain-tumor cells.
Fulda S,
Jeremias I,
Steiner HH,
Pietsch T,
Debatin KM.
University Children's Hospital, Ulm, Germany.
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. Here we report that Bet A was
active against medulloblastoma and glioblastoma
cell lines. In addition, Bet A exerted cytotoxic
activity against primary tumor cells cultured from
patients in 4 of 4 medulloblastoma-tumor samples
tested and in 20 of 24 glioblastoma-tumor samples.
Since a small percentage of primary-glioblastoma-tumor
cells (4/24) did not respond to Bet-A treatment,
resistance to Bet A might occur. Induction of
apoptosis by Bet A involved mitochondrial
perturbations, since inhibition of the
mitochondrial permeability transition by the
mitochondrion-specific inhibitor bongkrekic acid
(BA) reduced Bet-A-induced apoptosis. In addition,
mitochondria undergoing Bet-A-induced permeability
transition triggered DNA fragmentation in isolated
nuclei. Cytochrome c was released from
mitochondria of Bet-A-treated cells, and might be
involved in activation of caspases. Following
treatment with Bet A, caspase-8, caspase-3 and
PARP were proteolytically processed. Inhibition of
caspase cleavage by the broad-range caspase
inhibitor zVAD.fmk strongly reduced Bet-A-induced
apoptosis, indicating that apoptosis was mediated
by activation of caspases. 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.
Publication Types:
PMID: 10399962 [PubMed - indexed for MEDLINE]
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Glucosidation of betulinic acid by
Cunninghamella species.
Chatterjee P,
Pezzuto JM,
Kouzi SA.
Division of Basic Pharmaceutical Sciences, School
of Pharmacy, Northeast Louisiana University,
Monroe, Louisiana 71209, USA.
Microbial transformation of the antimelanoma agent
betulinic acid (1) was studied. Preparative scale
biotransformation with resting-cell suspensions of
Cunninghamella species NRRL 5695 resulted in the
production of a fungal metabolite of 1, which has
been characterized as 28-O-beta-D-glucopyranosyl
3beta-hydroxy-lup-20(29)-en-28-oate (2) based on
spectral and enzymic data. The in vitro
cytotoxicity assay of metabolite 2 revealed no
activity against several human melanoma cell
lines.
Publication Types:
PMID: 10346964 [PubMed - indexed for MEDLINE]
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Betulinic acid-induced apoptosis in glioma
cells: A sequential requirement for new protein
synthesis, formation of reactive oxygen species,
and caspase processing.
Wick W,
Grimmel C,
Wagenknecht B,
Dichgans J,
Weller M.
Laboratory of Molecular Neuro-Oncology, Department
of Neurology, University of Tübingen, School of
Medicine, Tübingen, Germany.
Betulinic acid (BA), a pentacyclic triterpene, is
an experimental cytotoxic agent for malignant
melanoma. Here, we show that BA triggers apoptosis
in five human glioma cell lines. BA-induced
apoptosis requires new protein, but not RNA,
synthesis, is independent of p53, and results in
p21 protein accumulation in the absence of a cell
cycle arrest. BA-induced apoptosis involves the
activation of caspases that cleave poly(ADP
ribose)polymerase. Interactions of death ligand/receptor
pairs of the CD95/CD95 ligand family do not
mediate BA-induced caspase activation. BA enhances
the levels of BAX and BCL-2 proteins but does not
alter the levels of BCL-xS or BCL-xL. Ectopic
expression of BCL-2 prevents BA-induced caspase
activation, DNA fragmentation, and cell death.
Furthermore, BA induces the formation of reactive
oxygen species that are essential for BA-triggered
cell death. The generation of reactive oxygen
species is blocked by BCL-2 and requires new
protein synthesis but is unaffected by caspase
inhibitors, suggesting that BA toxicity
sequentially involves new protein synthesis,
formation of reactive oxygen species, and
activation of crm-A-insensitive caspases.
PMID: 10336521 [PubMed - indexed for MEDLINE]
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Preparation of amino acid conjugates of
betulinic acid with activity against human
melanoma.
Jeong HJ,
Chai HB,
Park SY,
Kim DS.
Department of Medicinal Chemistry and
Pharmacognosy, College of Pharmacy, University of
Illinois at Chicago, 60612, USA.
Betulinic acid has been coupled with a series of
amino acids at C-28 carboxylic acid position 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.
A number of amino acid conjugates of betulinic
acid showed improved water solubility as well as
selective cytotoxicity. This investigation
demonstrates that amino acid conjugates of
betulinic acid can produce potentially important
derivatives, which may be developed as antitumor
agents.
Publication Types:
PMID: 10328313 [PubMed - indexed for MEDLINE]
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Synthesis of betulinic acid derivatives with
activity against human melanoma.
Kim DS,
Pezzuto JM,
Pisha E.
Department of Medicinal Chemistry and
Pharmacognosy (m/c 833), College of Pharmacy,
University of Illinois at Chicago 60612-7231, USA.
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.
Publication Types:
PMID: 9873420 [PubMed - indexed for MEDLINE]
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Comment on:
Correspondence re: S. Fulda et al., Betulinic
acid triggers CD95 (Apo1/Fas)- and p53-independent
apoptosis via activation of caspases in
neuroectodermal tumors. Cancer Res., 57:
4956-4964, 1997.
Rieber M,
Rieber MS.
Publication Types:
PMID: 9865749 [PubMed - indexed for MEDLINE]
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Activation of mitochondria and release of
mitochondrial apoptogenic factors by betulinic
acid.
Fulda S,
Scaffidi C,
Susin SA,
Krammer PH,
Kroemer G,
Peter ME,
Debatin KM.
University Children's Hospital, Prittwitzstrasse
43, D-89075 Ulm, Germany.
Different classes of anticancer drugs may trigger
apoptosis by acting on different subcellular
targets and by activating distinct signaling
pathways. Here, we report that betulinic acid (BetA)
is a prototype cytotoxic agent that triggers
apoptosis by a direct effect on mitochondria. In
isolated mitochondria, BetA directly induces loss
of transmembrane potential independent of a
benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl
ketone-inhibitable caspase. This is inhibited by
bongkrekic acid, an agent that stabilizes the
permeability transition pore complex. Mitochondria
undergoing BetA-induced permeability transition
mediate cleavage of caspase-8 (FLICE/MACH/Mch5)
and caspase-3 (CPP32/Yama) in a cell-free system.
Soluble factors such as cytochrome c or
apoptosis-inducing factor released from BetA-treated
mitochondria are sufficient for cleavage of
caspases and nuclear fragmentation. Addition of
cytochrome c to cytosolic extracts results in
cleavage of caspase-3, but not of caspase-8.
However, supernatants of mitochondria, which have
undergone permeability transition, and partially
purified apoptosis-inducing factor activate both
caspase-8 and caspase-3 in cytosolic extracts and
suffice to activate recombinant caspase-8. These
findings show that induction of mitochondrial
permeability transition alone is sufficient to
trigger the full apoptosis program and that some
cytotoxic drugs such as BetA may induce apoptosis
via a direct effect on mitochondria.
Publication Types:
PMID: 9852046 [PubMed - indexed for MEDLINE]
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Preparation and cytotoxic effect of ceanothic
acid derivatives.
Lee SS,
Chen WC,
Huang CF,
Su Y.
School of Pharmacy, College of Medicine, National
Taiwan University, Taipei, Taiwan, Republic of
China. shoeilee@ha.mc.ntu.edu.tw
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.
Publication Types:
PMID: 9834149 [PubMed - indexed for MEDLINE]
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Molecular ordering of apoptosis induced by
anticancer drugs in neuroblastoma cells.
Fulda S,
Susin SA,
Kroemer G,
Debatin KM.
University Children's Hospital, Ulm, Germany.
Apoptosis mediated by anticancer drugs may involve
activation of death-inducing ligand/receptor
systems such as CD95 (APO-1/Fas), cleavage of
caspases, and perturbance of mitochondrial
functions. 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. After Doxo treatment, enhanced
CD95/CD95-L expression and caspase-8 activation
were not blocked by Bcl-2 or Bcl-X(L) and were
found in cells with a mitochondrial transmembrane
potential (delta psi(m)) that was still normal
(delta psi(m)high cells). In marked contrast,
after Bet A treatment, caspase-8 activation
occurred in a Bcl-2- or Bcl-X(L)-inhibitable
fashion and was confined to cells that had lost
their delta psi(m) (delta psi(m)low cells).
Mitochondria from cells treated with either Doxo
or Bet A induced cleavage of both caspase-8 and
caspase-3 in cytosolic extracts. Thus, caspase-8
activation may occur upstream or downstream of
mitochondria, depending on the
apoptosis-initiating stimulus. In contrast to
caspase-8, cleavage of caspase-3 or
poly(ADP-ribose)polymerase was always restricted
to delta psi(m)low cells, downstream of the Bcl-2-
or Bcl-X(L)-controlled checkpoint of apoptosis.
Cytochrome c, released from mitochondria
undergoing permeability transition, activated
caspase-3 but not caspase-8 in a cell-free system.
However, both caspases were activated by
apoptosis-inducing factor, indicating that the
mechanism of caspase-8 activation differed from
that of caspase-3 activation. Taken together, our
findings demonstrate that perturbance of
mitochondrial function constitutes a central
coordinating event in drug-induced cell death.
Publication Types:
PMID: 9766678 [PubMed - indexed for MEDLINE]
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Induction of p53 without increase in p21WAF1 in
betulinic acid-mediated cell death is preferential
for human metastatic melanoma.
Rieber M,
Strasberg Rieber M.
IVIC, Tumor Cell Biology Laboratory, Caracas,
Venezuela. mrieber@pasteur.ivic.ve
Because betulinic acid was recently described as a
melanoma-specific inducer of apoptosis, we
investigated whether this agent was comparably
effective against metastatic tumors and those in
which metastatic ability and 92-kD gelatinase
activity had been decreased by introduction of a
normal chromosome 6. Human metastatic C8161
melanoma cells showed greater DNA fragmentation
and growth arrest and earlier loss of viability in
response to betulinic acid than their non-metastatic
C8161/neo 6.3 counterpart. These effects involved
induction of p53 without activation of p21WAF1 and
were synergized by bromodeoxyuridine in metastatic
Mel Juso, with no comparable responses in non-metastatic
Mel Juso/neo 6 cells. Our data suggest that
betulinic acid exerts its inhibitory effect partly
by increasing p53 without a comparable effect on
p21WAF1.
Publication Types:
PMID: 9628583 [PubMed - indexed for MEDLINE]
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Betulinic acid induces apoptosis in human
neuroblastoma cell lines.
Schmidt ML,
Kuzmanoff KL,
Ling-Indeck L,
Pezzuto JM.
Department of Pediatrics, College of Medicine,
University of Illinois at Chicago 60612-7324, USA.
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. This model will be
utilised to investigate the role of
apoptosis-related genes in neuroblastoma
proliferation and to determine the therapeutic
efficacy of BA in neuroblastoma in vivo.
PMID: 9516843 [PubMed - indexed for MEDLINE]
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Comment in:
Betulinic acid triggers CD95 (APO-1/Fas)- and
p53-independent apoptosis via activation of
caspases in neuroectodermal tumors.
Fulda S,
Friesen C,
Los M,
Scaffidi C,
Mier W,
Benedict M,
Nuñez G,
Krammer PH,
Peter ME,
Debatin KM.
Division of Hematology/Oncology, University
Children's Hospital, German Cancer Research
Center, Heidelberg.
Betulinic acid (BA), a melanoma-specific cytotoxic
agent, induced apoptosis in neuroectodermal
tumors, such as neuroblastoma, medulloblastoma,
and Ewing's sarcoma, representing the most common
solid tumors of childhood. BA triggered an
apoptosis pathway different from the one
previously identified for standard
chemotherapeutic drugs. BA-induced apoptosis was
independent of CD95-ligand/receptor interaction
and accumulation of wild-type p53 protein, but it
critically depended on activation of caspases
(interleukin 1beta-converting enzyme/Ced-3-like
proteases). FLICE/MACH (caspase-8), considered to
be an upstream protease in the caspase cascade,
and the downstream caspase CPP32/YAMA/Apopain
(caspase-3) were activated, resulting in cleavage
of the prototype substrate of caspases PARP. The
broad-spectrum peptide inhibitor
benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone,
which blocked cleavage of FLICE and PARP, also
completely abrogated BA-triggered apoptosis.
Cleavage of caspases was preceded by disturbance
of mitochondrial membrane potential and by
generation of reactive oxygen species.
Overexpression of Bcl-2 and Bcl-XL conferred
resistance to BA at the level of mitochondrial
dysfunction, protease activation, and nuclear
fragmentation. This suggested that mitochondrial
alterations were involved in BA-induced activation
of caspases. Furthermore, Bax and Bcl-xs, two
death-promoting proteins of the Bcl-2 family, were
up-regulated following BA treatment. Most
importantly, neuroblastoma cells resistant to
CD95- and doxorubicin-mediated apoptosis were
sensitive to treatment with BA, suggesting that BA
may bypass some forms of drug resistance. Because
BA exhibited significant antitumor activity on
patients' derived neuroblastoma cells ex vivo, BA
may be a promising new agent for the treatment of
neuroectodermal tumors in vivo.
Publication Types:
PMID: 9354463 [PubMed - indexed for MEDLINE]
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Enhanced cytotoxicity of some triterpenes
toward leukemia L1210 cells cultured in low pH
media: possibility of a new mode of cell killing.
Noda Y,
Kaiya T,
Kohda K,
Kawazoe Y.
Faculty of Pharmaceutical Sciences, Nagoya City
University, Japan.
Several triterpenes were tested for cytotoxicity
by our contrived primary screening method using
resting or dormant leukemia L1210 cells after 3 d-preculture
without medium change. Some triterpenes were found
to be more cytotoxic toward the 3 d-precultured
resting cells than toward the growing cells in a
fresh medium. These triterpenes are distinguished
by highly selective cytotoxicity toward the
starved resting cells unlike common anticancer
agents. The highest selectivity was shown by
betulinic acid, the ratio of its IC50 values
toward the growing versus resting cells amounting
to 175. It is suggested that this selective
cytotoxicity is attributable to low pH (< or =
6.8) of the medium. It is noteworthy that
betulinic acid is not cytotoxic at all in media of
ordinary pH (> or = 7.0) even after a 48-h
exposure. 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.
Publication Types:
PMID: 9353895 [PubMed - indexed for MEDLINE]
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Discovery of betulinic acid as a selective
inhibitor of human melanoma that functions by
induction of apoptosis.
Pisha E,
Chai H,
Lee IS,
Chagwedera TE,
Farnsworth NR,
Cordell GA,
Beecher CW,
Fong HH,
Kinghorn AD,
Brown DM, et al.
Department of Medicinal Chemistry and
Pharmacognosy, College of Pharmacy, University of
Illinois at Chicago 60612, USA.
As a result of bioassay-guided fractionation,
betulinic acid, a pentacyclic triterpene, was
identified as a melanoma-specific cytotoxic agent.
In follow-up studies conducted with athymic mice
carrying human melanomas, tumour growth was
completely inhibited without toxicity. As judged
by a variety of cellular responses, antitumour
activity was mediated by the induction of
apoptosis. Betulinic acid is inexpensive and
available in abundant supply from common natural
sources, notably the bark of white birch trees.
The compound is currently undergoing preclinical
development for the treatment or prevention of
malignant melanoma.
Publication Types:
PMID: 7489361 [PubMed - indexed for MEDLINE]
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