Scientific Researches On:
Betulinic Acid (Birch Bark Extract)
USA National Center for
Biotechnology Information
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41:
Cancer Res. 2004 Oct
15;64(20):7386-94.
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Apoptosis protease activator protein-1
expression is dispensable for response of human
melanoma cells to distinct proapoptotic agents.
Zanon M,
Piris A,
Bersani I,
Vegetti C,
Molla A,
Scarito A,
Anichini A.
Human Tumor Immunobiology Unit, Department of
Experimental Oncology and Department of Pathology,
Istituto Nazionale per lo Studio e la Cura dei
Tumori, Milan, Italy.
Loss of expression of the apoptosis protease
activator protein-1 (APAF-1) in human melanoma is
thought to promote resistance to programmed cell
death by preventing caspase-9 activation. However,
the role of the APAF-1-dependent pathway in
apoptosis activated by cellular stress and/or DNA
damage has been recently questioned. We
investigated APAF-1 expression in a large panel of
human melanomas and assessed cellular response to
several proapoptotic agents in tumors expressing
or lacking APAF-1 protein. In two melanomas with
wild-type p53 but with differential expression of
APAF-1, treatment with camptothecin, celecoxib, or
an nitric oxide synthase inhibitor (1400W)
significantly modulated expression of 36 of 96
genes in an apoptosis-specific cDNA macroarray,
but APAF-1 mRNA levels were not induced (in
APAF-1(-) cells) nor up-regulated (in APAF-1(+)
cells), a finding confirmed at the protein level.
Treatment with cisplatin, camptothecin, etoposide,
betulinic acid, celecoxib, 1400W, and
staurosporine promoted enzymatic activity not only
of caspases -2, -8, and -3 but also of caspase-9
in both APAF-1(+) and APAF-1(-) tumor cells.
Moreover, drug-induced caspase-9 enzymatic
activity could be not only partially but
significantly reduced by caspase-2, -3, and -8
-specific inhibitors in both APAF-1(+) and
APAF-1(-) tumor cells. In response to 1 to 100
micromol/L of cisplatin, camptothecin, or
celecoxib, APAF-1(+) melanomas (n = 12) did not
show significantly increased levels of apoptosis
compared with APAF-1(-) tumors (n = 7), with the
exception of enhanced apoptosis in response to a
very high dose (100 micromol/L) of etoposide.
These results suggest that the response of human
melanoma cells to different proapoptotic agents
may be independent of their APAF-1 phenotype.
Publication Types:
PMID: 15492260 [PubMed - indexed for MEDLINE]
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From chemoprevention to chemotherapy: common
targets and common goals.
Aggarwal BB,
Takada Y,
Oommen OV.
The University of Texas M.D. Anderson Cancer
Center, Cytokine Research Section, Department of
Experimental Therapeutics, PO Box 143, 1515
Holcombe Boulevard, Houston, Texas 77030, USA.
aggarwal@mdanderson.org
Three decades of research have revealed that
cancer is easier to prevent than to treat and that
consumption of certain fruits and vegetables can
reduce the risk of cancer. Whereas chemotherapy is
designed to destroy cancer after it appears,
chemoprevention involves the abrogation or delay
in the onset of cancer. Regardless of whether a
chemopreventive or chemotherapeutic approach is
taken, cancer is a multifactorial disease that
requires modulation of multiple pathways and
multiple targets. Various molecular targets of
chemoprevention are also relevant to the therapy
of cancer. These targets include the activation of
apoptosis; suppression of growth factor expression
or signalling; downregulation of antiapoptotic
proteins; suppression of
phosphatidylinositol-3'-kinase/Akt, NF-kappaB,
Janus kinase-signal transducer and activator of
transcription and activator protein-1 signalling
pathways; and downregulation of angiogenesis
through inhibition of vascular endothelial growth
factor expression, cyclooxygenase-2, matrix
metalloproteinase-9, urokinase-type plasminogen
activator, adhesion molecules and cyclin D1.
Pharmacologically safe phytochemicals that have
been identified from plants or their variant forms
can modulate these molecular targets. These
phytochemicals include genistein, resveratrol,
dially sulfide, S-ally cysteine, allicin, lycopene,
capsaicin, curcumin, 6-gingerol, ellagic acid,
ursolic acid, betulinic acid, flavopiridol,
silymarin, anethol, catechins and eugenol. Recent
work has shown that these phytochemicals also can
reverse chemoresistance and radioresistance.
Because of their pharmacological safety, these
agents can be used alone to prevent cancer and in
combination with chemotherapy to treat cancer.
Publication Types:
PMID: 15461561 [PubMed - indexed for MEDLINE]
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Apoptosis of human carcinoma cells in the
presence of potential anti-cancer drugs: III.
Treatment of Colo-205 and SKBR3 cells with: cis -platin,
Tamoxifen, Melphalan, Betulinic acid, L-PDMP, L-PPMP,
and GD3 ganglioside.
Basu S,
Ma R,
Boyle PJ,
Mikulla B,
Bradley M,
Smith B,
Basu M,
Banerjee S.
Department of Chemistry and Biochemistry,
University of Notre Dame, Notre Dame, IN 46556,
USA. sbasu@nd.edu
Breast cancer is the most common type of cancer,
predominantly among women over 20, whereas colo-rectal
cancer occurs in both men and women over the age
of 50. Chemotherapy of both cancers affect rapidly
growing normal as well as cancer cells. Cancer
cells are non-apoptotic. Seven anti-cancer agents
(cis -platin, Tamoxifen, Melphalan, Betulinic
acid, D-PDMP, L-PPMP, and GD3) have been tested
with human breast (SKBR3) and colon (Colo-205)
carcinoma cells for their apoptotic effect and
found to be positive by several assay systems.
Colo-205 cells were obtained from ATCC, and the
SKBR3 cells were a gift from the Cleveland Clinic.
All of these six agents killed those two cell
lines in a dose-dependent manner. In the early
apoptotic stage (6 h), these cells showed only a
flopping of phosphatidylserine on the outer
lamella of the plasma membranes as evidenced by
the binding of a novel fluorescent dye PSS-380.
After 24 h of the treatment, those apoptotic cells
showed damage of the plasma as well as the nuclear
membrane as evidenced by binding of propidium
iodide to the nuclear DNA. DNA laddering assay
viewed further breakdown of DNA by 1% agarose gel
electrophoresis analysis. It is concluded that
during apoptosis the signaling by Mitochondrial
Signaling Pathway (MSP) is stimulated by some of
these agents. Caspase 3 was activated with the
concomitant appearance of its p17 polypeptide as
viewed by Westernblot analyses. Incorporation of
radioactivity from [U-(14)C]-L-serine in total
sphingolipid mixture was observed between 2 and 4
micromolar concentrations of most of the agents
except ci s-platin. However, apoptosis in
carcinoma cells in the presence of cis -platin is
induced by a caspase 3 activation pathway without
any increase in synthesis of ceramide.
Publication Types:
PMID: 15454695 [PubMed - indexed for MEDLINE]
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Protection of Ewing's sarcoma family tumor (ESFT)
cell line SK-N-MC from betulinic acid induced
apoptosis by alpha-DL-tocopherol.
Raghuvar Gopal DV,
Narkar AA,
Badrinath Y,
Mishra KP,
Joshi DS.
Laboratory Nuclear Medicine Section, Isotope
Group, BARC, C/o Tata Memorial Hospital Annex,
Jerbai Wadia Road, Parel, Mumbai 400012, India.
Betulinic acid (BA) is known to induce apoptosis
in melanoma neuroectodermal and malignant brain
cancer cell lines. Present report describes the
role of antioxidants on the BA-induced toxicity to
human cell line SK-N-MC. Hydrophilic antioxidants
viz., L-ascorbic acid (VitC) and N-acetyl-L-cysteine
(l-NAC) had no protective effect on BA-induced
apoptosis at the maximal concentrations tested.
The lipophilic antioxidant, alpha-DL-tocopherol (VitE)
showed a concentration and a time dependent effect
on the protection of SK-N-MC cells from BA-induced
apoptosis. The apoptotic parameters were analyzed
using FACS analysis of propidium iodide (PI)
stained nuclei, PS externalization using Annexin-V
assay and changes in mitochondrial membrane
potential. Generation of superoxide radical was
monitored by the fluorescent dye hydroethidium
(HE). Cells showed Annexin-V positivity and an
increase in the propidium iodide (PI) uptake in
the early hours of treatment with BA, which was
concomitant with the loss of mitochondrial
membrane potential. Addition of alpha-DL-tocopherol
to the cell cultures 1-h prior to the treatment
with BA abolished all the effects of BA-induced
apoptosis. These observations suggest that BA
initiates events at membrane level leading to
induction of apoptosis. The observed
ineffectiveness of hydrophilic antioxidants and
substantial protection by lipophilic antioxidants
indicate involvement of membrane-associated
damages that form the basis of BA-induced
cytotoxicity.
PMID: 15451550 [PubMed - indexed for MEDLINE]
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Apoptotic activity of betulinic acid
derivatives on murine melanoma B16 cell line.
Liu WK,
Ho JC,
Cheung FW,
Liu BP,
Ye WC,
Che CT.
Department of Anatomy, Faculty of Medicine, The
Chinese University of Hong Kong, Shatin, New
Territories, Hong Kong, People's Republic of
China. ken-liu@cuhk.edu.hk
The mitochondrion plays a crucial role in the
process of apoptosis and has thus become one of
the targets for the search for potential
chemotherapeutic agents. Betulinic acid
[3beta-hydroxy-lup-20(19)lupaen-28-carbonic acid],
a lupane-type triterpene which is abundant in many
plant species, has been shown to exert a direct
effect on the mitochondria and subsequent
apoptosis in melanoma cells. Chemical synthesis
and modification of betulinic acid are being
explored to develop more potent derivatives. We
present here the apoptotic activity of several
natural derivatives of betulinic acid which were
isolated from the roots of a Chinese medicinal
herb, Pulsatilla chinensis (Bge) Regel [Ye, W., Ji,
N.N., Zhao, S.X., Liu, J.H., Ye, T., McKervey,
M.A., Stevenson, P., 1996. Triterpenoids from
Pulsatilla chinensis. Phytochemistry 42, 799-802].
Of the five compounds tested,
3-oxo-23-hydroxybetulinic acid was the most
cytotoxic on murine melanoma B16 cells (IC50=22.5
microg/ml), followed by 23-hydroxybetulinic acid
and betulinic acid (IC50=32 and 76 microg/ml,
respectively), with lupeol and betulin exhibiting
the weakest cytotoxicity (IC50> or =100 microg/ml).
Exposure of B16 cells to betulinic acid,
23-hydroxybetulinic acid and
3-oxo-23-hydroxybetulinic acid caused a rapid
increase in reactive oxidative species production
and a concomitant dissipation of mitochondrial
membrane potential in a dose- and time-dependent
manner, which resulted in cell apoptosis, as
demonstrated by fluorescence microscopy, gel
electrophoresis and flow-cytometric analysis. Cell
cycle analysis further demonstrated that both
3-oxo-23-hydroxybetulinic acid and
23-hydroxybetulinic acid dramatically increased
DNA fragmentation at the expense of G1 cells at
doses as low as 12.5 and 25 microg/ml,
respectively, thereby showing their potent
apoptotic properties. Our results showed that
hydroxylation at the C3 position of betulinic acid
is likely to enhance the apoptotic activity of
betulinic acid derivatives (23-hydroxybetulinic
acid and 3-oxo-23-hydroxybetulinic acid) on murine
melanoma B16 cells.
Publication Types:
PMID: 15363977 [PubMed - indexed for MEDLINE]
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Cooperation of betulinic acid and TRAIL to
induce apoptosis in tumor cells.
Fulda S,
Jeremias I,
Debatin KM.
University Children's Hospital, Prittwitzstr. 43,
D-89075 Ulm, Germany. simone.fulda@medizin.uni-ulm.de
We previously reported that the TRAIL (tumor
necrosis factor (TNF)-related apoptosis-inducing
ligand)-induced death signal requires
amplification by mitochondria in certain cell
types, for example, in type II cells. Here, we
provide for the first time evidence that the
natural compound betulinic acid (BetA) cooperated
with TRAIL to induce apoptosis in tumor cells.
Through functional complementation, simultaneous
stimulation of the death receptor pathway by TRAIL
and the mitochondrial pathway by BetA resulted in
complete activation of effector caspases,
apoptosis and inhibition of clonogenic survival.
BetA and TRAIL cooperated to trigger loss of
mitochondrial membrane potential and release of
cytochrome c and Smac from mitochondria. Also,
combination treatment with BetA and TRAIL resulted
in increased cleavage of caspase-8 and Bid
indicating that activation of effector caspases
may feed back in a positive amplification loop.
Importantly, the combination treatment with BetA
and TRAIL cooperated to induce apoptosis in
different tumor cell lines and also in primary
tumor cells, but not in normal human fibroblasts
indicating some tumor specificity. Since most
human cancers represent type II cells, triggering
the mitochondrial pathway by BetA may be a novel
approach to enhance the efficacy of TRAIL-based
therapies, which warrants further investigation.
Publication Types:
PMID: 15361826 [PubMed - indexed for MEDLINE]
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Synthesis of A-seco derivatives of betulinic
acid with cytotoxic activity.
Urban M,
Sarek J,
Klinot J,
Korinkova G,
Hajduch M.
Department of Organic and Nuclear Chemistry,
Faculty of Science, Charles University in Prague,
Hlavova 8, 128 43 Prague 2, Czech Republic.
In this study, the relationships between the
chemical structure and cytotoxic activity of
betulinic acid (1) derivatives were investigated.
Eight lupane derivatives (1-8), one of them new
(6), five diosphenols (9-13), four of them new
(10-13), two new norderivatives (14 and 15), five
seco derivatives (16-20), four of them new (16,
17, 19, and 20), and three new seco-anhydrides
(21-23) were synthesized from 1, and their
activities were compared with the activities of
known compounds. The effects of substitution on
the A-ring and esterification of the carboxyl
group in position 28 on cytotoxicity were of
special interest. Significant cytotoxic activity
against the T-lymphoblastic leukemia cell line CEM
was found in diosphenols 9 and 13 (TCS(50) 4 and 5
micromol/L) and seco-anhydrides 22 and 23 (TCS(50)
7 and 6 micromol/L). All compounds were also
tested on cancer cell lines HT 29, K562, K562 Tax,
and PC-3, and these confirmed activity of
diosphenols 9, 10, and 11 and anhydride 22.
Diosphenols, as the most promising group of
derivatives, were further tested on four more
lines (A 549, DU 145, MCF 7, SK-Mel2).
Publication Types:
PMID: 15270560 [PubMed - indexed for MEDLINE]
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Synthesis and cytotoxic activity of
3-O-acyl/3-hydrazine /2-bromo/20,29-dibromo
betulinic acid derivatives.
Mukherjee R,
Jaggi M,
Siddiqui MJ,
Srivastava SK,
Rajendran P,
Vardhan A,
Burman AC.
Division of Experimental Oncology, Dabur Research
Foundation, 22, Site IV, Sahibabad, Ghaziabad 201
010, UP, India.
A series of 3-O-acyl, 3-hydrazine, 2-bromo, and
20,29-dibromo betulinic acid derivatives (1-27)
have been synthesized and screened for in vitro
cytotoxic activity on human cancer cell lines
MOLT-4, JurkatE6.1, CEM.CM3, BRISTOL8, U937,
DU145, PA-1, A549, and L132. A number of compounds
have shown ED(50)<1 microg/mL against the cancer
cell lines tested and have shown better
cytotoxicity than betulinic acid. Compounds 13,
19, 20, 23, and 27 were the best derivatives and
were selected as lead molecules for further
development. The structure-activity relationship
has been described.
PMID: 15225732 [PubMed - indexed for MEDLINE]
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Isolation and structure of gustastatin from the
Brazilian nut tree Gustavia hexapetala.
Pettit GR,
Zhang Q,
Pinilla V,
Herald DL,
Doubek DL,
Duke JA.
Cancer Research Institute, Department of Chemistry
and Biochemistry, Arizona State University, Tempe,
Arizona 85287-2404, USA. bpettit@asu.edu
A bioassay-guided investigation of Gustavia
hexapetala led to the isolation of a new cancer
cell growth inhibitor designated gustastatin (1)
and four previously known cancer cell growth
inhibitors that included betulinic acid (2). The
structures were assigned on the basis of analyses
of HRMS combined with 1D and 2D NMR data. The
structure of portentol (5) was confirmed by an
X-ray crystal structure determination.
Publication Types:
PMID: 15217278 [PubMed - indexed for MEDLINE]
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Betulinic acid-induced apoptosis in leukemia
cells.
Ehrhardt H,
Fulda S,
Führer M,
Debatin KM,
Jeremias I.
Department of Oncology/Hematology, Dr von
Haunersches Kinderspital, Lindwurmstr 4, München,
Germany.
Betulinic acid (BA), a natural component isolated
from Birch trees, effectively induces apoptosis in
neuroectodermal and epithelial tumor cells and
exerts little toxicity in animal trials. Here, we
show that BA-induced marked apoptosis in 65% of
primary pediatric acute leukemia cells and all
leukemia cell lines tested. When compared for in
vitro efficiency with conventionally used
cytotoxic drugs, BA was more potent than nine out
of 10 standard therapeutics and especially
efficient in tumor relapse. No crossresistances
were found between BA and any cytotoxic drug.
Intracellular apoptosis signaling in leukemia
tumor cells paralleled the pathway found in
neuroectodermal cells involving caspases, but not
death receptors. In isolated mitochondria, BA
induced release of both cytochrome c and Smac.
Taken together, BA potently induces apoptosis in
leukemia cells and should be further evaluated as
a future drug to treat leukemia.
Publication Types:
PMID: 15201849 [PubMed - indexed for MEDLINE]
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Cell death induction by betulinic acid,
ceramide and TRAIL in primary glioblastoma
multiforme cells.
Jeremias I,
Steiner HH,
Benner A,
Debatin KM,
Herold-Mende C.
Dr. von Haunersches Kinderspital, Munich, Germany.
I.Jeremias@lrz.uni-muenchen.de
BACKGROUND: Glioblastoma multiforme (WHO Grade IV,
GBM) is the most malignant brain tumour with a
mean survival time of less than one year.
Betulinic acid, ceramide and TRAIL (TNF-related
apoptosis inducing ligand) represent novel
therapeutic agents for potential use in GBM.
METHOD: Primary GBM cells of 21 patients with
macroscopically complete tumour resection were
tested in vitro for cell death induction by
betulinic acid, ceramide, TRAIL and established
therapeutics (BCNU, cisplatin, doxorubicin,
vincristin and gamma-irradiation). FINDINGS: At
peak plasma concentrations (PPC), Betulinic acid,
ceramide and TRAIL induced cell death in primary
GBM cells at higher rates than established
cytotoxic drugs. Specific cell death > or =75% was
observed in 43% (9/21), 38% (8/21), and 19% (4/21)
for betulinic acid, ceramide, and TRAIL
respectively, while this was only found in 5%
(1/21) of gamma-irradiated and cisplatin-treated
cells, and in none of the GBM cultures, where BCNU
or vincristin were applied in PPC. CONCLUSION: Due
to a markedly improved cell death of GBM cells as
compared with established therapeutics, Betulinic
acid, ceramide and TRAIL might represent potent
substances for future treatment of GBM.
Publication Types:
PMID: 15197616 [PubMed - indexed for MEDLINE]
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Betulinic acid augments the inhibitory effects
of vincristine on growth and lung metastasis of
B16F10 melanoma cells in mice.
Sawada N,
Kataoka K,
Kondo K,
Arimochi H,
Fujino H,
Takahashi Y,
Miyoshi T,
Kuwahara T,
Monden Y,
Ohnishi Y.
Department of Oncological and Regenerative
Surgery, School of Medicine, The University of
Tokushima, Tokushima 770-8503, Japan.
We examined the antitumour effect of a combination
of betulinic acid (BA) and vincristine (VCR) on
murine melanoma B16F10 cells in vitro and in vivo.
Betulinic acid, a pentacyclic triterpene, showed a
synergistic cytotoxic effect on melanoma cells by
combinational use of VCR. Betulinic acid and VCR
induced cell cycle arrest at different points (BA
at G1 phase and VCR at G2/M phase) and caused
apoptosis in B16F10 melanoma cells. In the in vivo
study, VCR inhibited metastasis of tumour cells to
the lung. The addition of BA to VCR augmented
suppression of the experimental lung metastasis of
melanoma cells in C57BL/6 mice. The number of lung
nodules of more than 1 mm in diameter in mice
treated with BA and VCR was less than that in mice
treated with VCR alone. These results suggest that
BA is an effective supplement for enhancing the
chemotherapeutic effect on malignant melanoma.
PMID: 15083202 [PubMed - indexed for MEDLINE]
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Betulinic acid: a promising anticancer
candidate.
Eiznhamer DA,
Xu ZQ.
Advanced Life Sciences, 1440 Davey Road,
Woodridge, IL 60517, USA.
Betulinic acid is a naturally occurring
pentacyclic triterpenoid which has demonstrated
selective cytotoxicity against a number of
specific tumor types, a variety of infectious
agents such as HIV, malaria and bacteria, and the
inflammatory process in general. Biological
activity was first demonstrated in melanoma cell
lines and was confirmed in mice bearing human
melanoma xenografts. These in vivo studies also
established a favorable safety margin for
betulinic acid, as systemic side effects were not
observed at any dose. Recently, considerable in
vitro evidence has demonstrated that betulinic
acid is effective against small- and
non-small-cell lung, ovarian, cervical, and head
and neck carcinomas. Published data suggest that
betulinic acid induces apoptosis in sensitive
cells in a p53- and CD95-independent fashion.
While the precise molecular target and mechanism
of action remain elusive and are the focus of a
number of ongoing research programs, accumulated
experimental evidence indicates that betulinic
acid functions through a mitochondrial-mediated
pathway. Supplemental reports suggest that the
generation of reactive oxygen species, inhibition
of topoisomerase I, activation of the MAP kinase
cascade, inhibition of angiogenesis, and
modulation of pro-growth transcriptional
activators and aminopeptidase N activity may play
a role in betulinic acid-induced apoptosis. These
potential mechanisms of action may enable
betulinic acid to be effective in cells resistant
to other chemotherapeutic agents. Arguments
supporting the role of this agent in the treatment
of cancers and other infectious conditions will be
reviewed.
Publication Types:
PMID: 15057642 [PubMed - indexed for MEDLINE]
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Phenolic compounds obtained from stems of
Couepia ulei with the potential to induce quinone
reductase.
Jang DS,
Park EJ,
Kang YH,
Vigo JS,
Graham JG,
Cabieses F,
Fong HH,
Pezzuto JM,
Kinghorn AD.
Program for Collaborative Research in the
Pharmaceutical Sciences and Department of
Medicinal Chemistry and Pharmacognosy, College of
Pharmacy, University of Illinois at Chicago,
Chicago, IL 60612, USA.
Activity-guided fractionation of the EtOAc-soluble
extract of the stems of Couepia ulei, using a
bioassay based on the induction of quinone
reductase (QR) in cultured Hepa 1c1c7 mouse
hepatoma cells led to the isolation of two active
compounds, a new natural product,
erythro-2,3-bis(4-hydroxy-3-methoxyphenyl)-3-ethoxypropan-1-ol
(1), and a known compound, evofolin-B (2), along
with five inactive compounds all of known
structure, viz., betulinic acid, oleanolic acid,
pomolic acid, (+/-)-syringaresinol, and ursolic
acid. These isolates were identified by analysis
of physical and spectral data. Compounds 1 and 2
exhibited QR inducing activity, with observed CD
(concentration required to double induction)
values of 16.7 and 16.4 microM, respectively.
Publication Types:
PMID: 15022717 [PubMed - indexed for MEDLINE]
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Apoptosis-modulating agents in combination with
radiotherapy-current status and outlook.
Belka C,
Jendrossek V,
Pruschy M,
Vink S,
Verheij M,
Budach W.
Department of Radiation Oncology, Experimental
Radiation Oncology, University of Tübingen, Hoppe
Seyler Strasse 3, D-72076 Tübingen, Germany. belka@uni-tuebingen.de
PURPOSE: To increase the therapeutic efficacy of
ionizing radiation or to reduce radiation-mediated
side effects, diverse research centers for
translational radiation oncology have headed for a
specific modulation of defined cellular death
pathways. In this regard, several signaling
systems have proved to be of high potential value.
RESULTS: It has previously been shown that
apoptotic pathways induced by ionizing radiation
are distinct from death pathways triggered by
death ligands such as tumor necrosis
factor-related apoptosis-inducing ligand (TRAIL).
The combination of both radiation and TRAIL was
highly efficient in vitro and in preclinical mouse
models. However, several aspects of normal tissue
toxicity have not been solved, and no Phase I data
are available yet. A second approach tested in a
Phase I trial is based on the observation that
synthetic phospholipid derivatives (alkyllysophospholipids
and alkylphosphocholines) strongly enhance
apoptotic effects by modulating the balance among
the mitogenic, anti-apoptotic MAPK,
phosphatidylinositol 3'-kinase (PI3K)/Akt, and the
pro-apoptotic SAPK/JNK signaling pathways.
Furthermore, others have provided evidence that
inhibition of anti-apoptotic signals generated by
mitogenic stimuli may increase radiation
responses. In this context, controversial data are
available regarding the influence of a
pharmacologic abrogation of MEK1, Erk1/2 signaling
on apoptotic sensitivity but no Phase I trials of
MEK inhibitors either alone or in combination with
radiation have yet been published. However,
inhibition of the PI3K/Akt survival pathway using
compounds such as the protein kinase C (PKC)
inhibitor PKC412 has been shown to induce
apoptosis or to increase the apoptotic sensitivity
of tumor cells. Therefore, these drugs may be used
alone or in combination with radiation to increase
tumor control; however, Phase I data are lacking.
Several other drugs, including cyclooxygenase-2
inhibitors, betulinic acid, and proteasome
inhibitors, have been shown to interact with
apoptotic signal transduction. Again, most of the
drugs have not been tested in combination with
radiation in vivo or-in the case of
cyclooxygenase-2 inhibitors-exert pleiotropic
effects. CONCLUSION: Although the examples do not
reflect all available strategies, it is clear that
several promising approaches targeting defined
cell death pathways have been developed and
entered into clinical trials. The use of synthetic
phospholipid derivatives in a Phase I trial is an
important example, proving that basic research in
radiation biology finally guides the development
of new treatment strategies. This, and other
approaches, will hopefully increase tumor control
rates and reduce side effects in the future.
Publication Types:
PMID: 14751526 [PubMed - indexed for MEDLINE]
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Immunomodulatory activity of betulinic acid by
producing pro-inflammatory cytokines and
activation of macrophages.
Yun Y,
Han S,
Park E,
Yim D,
Lee S,
Lee CK,
Cho K,
Kim K.
Department of Pharmacy, Sahmyook University, 26-21
Gongreung-2 Dong, Seoul 139-742, Korea.
Betulinic acid (BA), a pentacyclic triterpene
isolated from Lycopus lucidus, has been reported
to be a selective inducer of apoptosis in various
human cancer and shown anti-inflammatory and
immunomodulatory properties. We postulated that BA
modulates the immunomodulatory properties at least
two groups of protein mediators of inflammation,
interleukin-1beta (IL-1beta) and the tumor
necrosis factor-alpha (TNF-alpha) on the basis of
the critical role of the monocytes and tissue
macrophages in inflammatory and immune responses.
TNF-alpha and IL-1beta were produced by BA in a
dose dependent manner at concentration of 0.625
and 10 microg/mL. The production of NO associated
with iNOS was inhibited when treated with LPS at
the concentration of 2.5 to 20 microg/mL of BA
whereas COX-2 expression was decreased at 2.5 to
20 microg/mL. These modulations of inflammatory
mediators were examined in LPS-stimulated RAW
264.7 cells and peritoneal macrophages. The
morphology of macrophage was also examined and
enhanced surface CD 40 molecule was expressed when
treated BA at 0.625 to approximately 5 microg/mL
with or without LPS. Furthermore, BA (20 microg/mL)
enhanced apoptosis by producing DNA ladder in the
RAW 264.7 cells. Our results indicated that BA
induced activation of macrophage and
pro-inflammatory cytokines. This may provide a
molecular basis for the ability of BA to mediate
macrophage, suppress inflammation, and modulate
the immune response.
Publication Types:
PMID: 14723345 [PubMed - indexed for MEDLINE]
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New lupane derived compounds with pro-apoptotic
activity in cancer cells: synthesis and
structure-activity relationships.
Sarek J,
Klinot J,
Dzubák P,
Klinotová E,
Nosková V,
Krecek V,
Korínková G,
Thomson JO,
Janost'áková A,
Wang S,
Parsons S,
Fischer PM,
Zhelev NZ,
Hajdúch M.
Department of Organic and Nuclear Chemistry,
Charles University in Prague, Hlavova 8, 128 43
Prague 2, Czech Republic.
Cellular screening of various synthetic
triterpenoid compounds formally derived from
lupane has identified a number of analogues as
potential anticancer drug candidates. Here we
describe the synthesis and structure-activity
relationships of betulin and betulinic acid
derivatives containing an E-ring modified with
different oxygen functions. Thus compounds
containing the lup-18-en-21-one,
lup-18-ene-21,22-dione, 18,19-secolupane, and the
highly oxygenated 18,19-secolupane systems, as
well as des-E-lupane derivatives, were prepared
from the readily available natural pentacyclic
triterpene betulin using oxidative procedures.
These compounds were named betulinines. We
demonstrate that only selected compounds,
particularly those containing a lupane
E-ring-derived unsaturated ketone or diketone
function, possessed in vitro cytotoxic activity
against tumor cell lines, suggesting a
structure-activity relationship.
Publication Types:
PMID: 14640549 [PubMed - indexed for MEDLINE]
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Chemistry, biological activity, and
chemotherapeutic potential of betulinic acid for
the prevention and treatment of cancer and HIV
infection.
Cichewicz RH,
Kouzi SA.
Department of Chemistry and Biochemistry,
University of California, Santa Cruz, California
95064, USA.
3beta-Hydroxy-lup-20(29)-en-28-oic acid (betulinic
acid) is a pentacyclic lupane-type triterpene that
is widely distributed throughout the plant
kingdom. A variety of biological activities have
been ascribed to betulinic acid including
anti-inflammatory and in vitro antimalarial
effects. However, betulinic acid is most highly
regarded for its anti-HIV-1 activity and specific
cytotoxicity against a variety of tumor cell
lines. Interest in developing even more potent
anti-HIV agents based on betulinic acid has led to
the discovery of a host of highly active
derivatives exhibiting greater potencies and
better therapeutic indices than some current
clinical anti-HIV agents. While its mechanism of
action has not been fully determined, it has been
shown that some betulinic acid analogs disrupt
viral fusion to the cell in a post-binding step
through interaction with the viral glycoprotein
gp41 whereas others disrupt assembly and budding
of the HIV-1 virus. With regard to its anticancer
properties, betulinic acid was previously reported
to exhibit selective cytotoxicity against several
melanoma-derived cell lines. However, more recent
work has demonstrated that betulinic acid is
cytotoxic against other non-melanoma (neuroectodermal
and malignant brain tumor) human tumor varieties.
Betulinic acid appears to function by means of
inducing apoptosis in cells irrespective of their
p53 status. Because of its selective cytotoxicity
against tumor cells and favorable therapeutic
index, even at doses up to 500 mg/kg body weight,
betulinic acid is a very promising new
chemotherapeutic agent for the treatment of HIV
infection and cancer. Copyright 2003 Wiley
Periodicals, Inc.
Publication Types:
PMID: 14595673 [PubMed - indexed for MEDLINE]
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Betulinic acid suppresses carcinogen-induced
NF-kappa B activation through inhibition of I
kappa B alpha kinase and p65 phosphorylation:
abrogation of cyclooxygenase-2 and matrix
metalloprotease-9.
Takada Y,
Aggarwal BB.
Cytokine Research Laboratory, Department of
Bioimmunotherapy, University of Texas M. D.
Anderson Cancer Center, Houston, TX 77030, USA.
Betulinic acid (BA), a pentacyclic triterpene
isolated from the bark of the white birch tree,
has been reported to be a selective inducer of
apoptosis in tumor cells. It also exhibits
anti-inflammatory and immunomodulatory properties.
How BA mediates these effects is not known.
Because of the critical role of the transcription
factor NF-kappaB in growth modulatory,
inflammatory, and immune responses, we postulated
that BA modulates the activity of this factor. In
this study we investigated the effect of BA on NF-kappaB
and NF-kappaB-regulated gene expression activated
by a variety of inflammatory and carcinogenic
agents. BA suppressed NF-kappaB activation induced
by TNF, PMA, cigarette smoke, okadaic acid, IL-1,
and H(2)O(2). The suppression of NF-kappaB
activation was not cell-type specific. BA
suppressed the activation of IkappaBalpha kinase,
thus abrogating the phosphorylation and
degradation of IkappaBalpha. We found that BA
inhibited NF-kappaB activated by TNFR 1, TNFR-associated
death domain, TNFR-associated factor 2, NF-kappaB-inducing
kinase, and IkappaBalpha kinase. Treatment of
cells with this triterpinoid also suppressed NF-kappaB-dependent
reporter gene expression and the production of NF-kappaB-regulated
gene products such as cyclooxygenase-2 and matrix
metaloproteinase-9 induced by inflammatory
stimuli. Furthermore, BA enhanced TNF-induced
apoptosis. Overall, our results indicated that BA
inhibits activation of NF-kappaB and NF-kappaB-regulated
gene expression induced by carcinogens and
inflammatory stimuli. This may provide a molecular
basis for the ability of BA to mediate apoptosis,
suppress inflammation, and modulate the immune
response.
PMID: 12960358 [PubMed - indexed for MEDLINE]
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Betulinic acid: a new cytotoxic compound
against malignant head and neck cancer cells.
Thurnher D,
Turhani D,
Pelzmann M,
Wannemacher B,
Knerer B,
Formanek M,
Wacheck V,
Selzer E.
Department of Otorhinolaryngology, Head and Neck
Surgery, University Hospital Vienna, Währinger
Gürtel 18-20, A-1090 Vienna, Austria.
dietmar.thrunher@univie.ac.at
BACKGROUND: A new compound, betulinic acid, has
been found to be cytotoxic against a variety of
tumor cells originating from the neural crest. Its
efficacy against head and neck squamous cellular
carcinoma cell lines has so far not been tested.
METHODS: Cell numbers were assayed by automated
counting; caspase activation and programmed cell
death were determined using an antibody specific
for an apoptosis-associated epitope in epithelial
cells. The expression pattern of Bcl-2 family
members was assessed by Western blotting. RESULTS:
In two HNSCC cell lines betulinic acid induced
apoptosis, which was characterized by a
dose-dependent reduction in cell numbers,
emergence of apoptotic cells, and an increase in
caspase activity. Western blot analysis of the
expression of various Bcl-2 family members in
betulinic acid-treated cells showed, surprisingly,
a suppression of the expression of the
proapoptotic protein Bax but no changes in Mcl-1
or Bcl-2 expression. CONCLUSION: These data
clearly demonstrate for the first time that
betulinic acid has apoptotic activity against
HNSCC cells. Copyright 2003 Wiley Periodicals,
Inc. Head Neck 25: 732-740, 2003
PMID: 12953308 [PubMed - indexed for MEDLINE]
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