Scientific Researches On:
Betulinic Acid (Birch Bark Extract)
USA National Center for
Biotechnology Information
21:
J Nat Prod. 2006 Mar;69(3):332-7.
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Cytotoxic constituents from the stem bark of
Dichapetalum gelonioides collected in the
Philippines.
Fang L,
Ito A,
Chai HB,
Mi Q,
Jones WP,
Madulid DR,
Oliveros MB,
Gao Q,
Orjala J,
Farnsworth NR,
Soejarto DD,
Cordell GA,
Swanson SM,
Pezzuto JM,
Kinghorn AD.
Program for Collaborative Research in the
Pharmaceutical Sciences, and the Department of
Medicinal Chemistry and Pharmacognosy, College
of Pharmacy, University of Illinois at Chicago,
60612, USA.
Fractionation of an ethyl acetate-soluble
extract of the stem bark of Dichapetalum
gelonioides, collected in the Philippines, using
the LNCaP (hormone-dependent human prostate)
cell line as a monitor, led to the purification
of three dichapetalin-type triterpenoids [dichapetalins
A (1), I (2), and J (3)], along with two
dolabrane norditerpenoids (6, 7), and the
additional triterpenoids zeylanol (8),
28-hydroxyzeylanol (9), and betulinic acid.
Since compounds 1-3 exhibited promising
selectivity against the SW626 (human ovarian
cancer) cell line, a re-collection of the plant
material was carried out, to obtain more of
these compounds for additional biological
testing. Two further phenylpyranotriterpenoids [dichapetalins
K (4) and L (5)] were isolated from the
re-collected plant material. The structures of
the new compounds 2-5 and 9 were determined on
the basis of spectroscopic data interpretation,
and the relative configuration of 6 was
confirmed using X-ray crystallography. Compounds
4-6 and the methyl ester, 6a, exhibited broad
cytotoxic activity when tested against a panel
of human tumor cell lines. Dichapetalin A (1)
was not active when evaluated in an in vivo
hollow fiber assay in the dose range 1-6 mg/kg.
Publication Types:
PMID: 16562829 [PubMed - indexed for MEDLINE]
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[Biological activity and pharmacological
prospects of lupane terpenoids: I. Natural
lupane derivatives]
[Article in Russian]
Tolstikova TG,
Sorokina IV,
Tolstikov GA,
Tolstikov AG,
Flekhter OB.
The biological activity of natural and
semisynthetic lupane triterpenoids is discussed
in a two-part review. The first part is devoted
to the pharmacological properties of natural
lupane triterpenoids. Betulinic acid has proven
to be the most effective antitumor agent among
more than fifty natural lupanes.
Publication Types:
PMID: 16523720 [PubMed - indexed for MEDLINE]
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Antiproliferative terpenoids from almond
hulls (Prunus dulcis): identification and
structure-activity relationships.
Amico V,
Barresi V,
Condorelli D,
Spatafora C,
Tringali C.
Dipartimento di Scienze Chimiche, Università di
Catania, Viale A. Doria 6, 95125 Catania, Italy.
Bioassay-guided fractionation of the EtOAc crude
extract from Sicilian almond hulls, a waste
material from Prunus dulcis crop, allowed
identification of 10 constituents, isolated as
pure compounds (1-5, 7, and 10) or unseparable
mixtures (5 + 6 and 8 + 9). All compounds were
subjected to spectroscopic analysis and
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl
tetrazolium bromide bioassay on MCF-7 human
breast cancer cells. In addition to the main
components oleanolic (1), ursolic (2), and
betulinic (3) acids, the 2-hydroxy analogues
alphitolic (4), corosolic (5), and maslinic (6)
acids, as well as the related aldehydes, namely,
betulinic (7), oleanolic (8), and ursolic (9),
were identified. From a more polar fraction, the
beta-sitosterol 3-O-glucoside (10) was also
identified. A sample of commercially available
betulin (11) was also included in bioassays as
further support to a structure-activity
relationship study. Betulinic acid showed
antiproliferative activity toward MCF-7 cells
(GI50 = 0.27 microM), higher than the anticancer
drug 5-fluorouracil.
Publication Types:
PMID: 16448187 [PubMed - indexed for MEDLINE]
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Chemosensitization and radiosensitization of
tumors by plant polyphenols.
Garg AK,
Buchholz TA,
Aggarwal BB.
Department of Radiation Oncology, The University
of Texas M.D. Anderson Cancer Center, Houston,
TX 77030, USA.
The treatment of cancer with chemotherapeutic
agents and radiation has two major problems:
time-dependent development of tumor resistance
to therapy (chemoresistance and radioresistance)
and nonspecific toxicity toward normal cells.
Many plant-derived polyphenols have been studied
intently for their potential chemopreventive
properties and are pharmacologically safe. These
compounds include genistein, curcumin,
resveratrol, silymarin, caffeic acid phenethyl
ester, flavopiridol, emodin, green tea
polyphenols, piperine, oleandrin, ursolic acid,
and betulinic acid. Recent research has
suggested that these plant polyphenols might be
used to sensitize tumor cells to
chemotherapeutic agents and radiation therapy by
inhibiting pathways that lead to treatment
resistance. These agents have also been found to
be protective from therapy-associated
toxicities. How these polyphenols protect normal
cells and sensitize tumor cells to treatment is
discussed in this review. Antioxid. Redox
Signal. 7, 1630-1647.
Publication Types:
PMID: 16356126 [PubMed - indexed for MEDLINE]
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Phospholipid nanosomes.
Castor TP.
Aphios Corporation, 3-E Gill Street, Woburn, MA
01801, USA. tcastor@aphios.com
Phospholipid nanosomes are small, uniform
liposomes manufactured utilizing supercritical
fluid technologies. Supercritical fluids are
first used to solvate phospholipid raw
materials, and then decompressed to form
phospholipid nanosomes that can encapsulate
hydrophilic molecules such as proteins and
nucleic acids. Hydrophobic therapeutics are
co-solvated with phospholipid raw materials in
supercritical fluids that, when decompressed,
form phospholipid nanosomes encapsulating these
drugs in their lipid bilayers. Mathematical
modeling and semi-empirical experiments indicate
that the size and character of phospholipid
nanosomes depend on the several process
parameters and material properties including the
size and design of decompression nozzle, bubble
size, pressure and the rate of decompression,
interfacial forces, charge distribution and the
nature of compound being encapsulated. Examples
are presented for the encapsulation of a protein
and hydrophobic drugs. In vitro and in vivo data
on breast cancer cells and xenografts in nude
mice indicate that paclitaxel nanosomes are less
toxic and much more effective than paclitaxel in
Cremophor EL (Taxol). Camptothecin nanosomes
demonstrate that the normally very
water-insoluble camptothecin can be formulated
in a biocompatible aqueous medium while
retaining in vivo efficacy against lymphoma
xenografts in nude mice. In vitro data for
betulinic acid nanosomes demonstrate enhanced
efficacy against HIV-1 (EC50 of 1.01 microg/ml
versus 6.72 microg/ml for neat betulinic acid).
Phospholipid nanosomes may find utility in the
enhanced delivery of hydrophilic drugs such as
recombinant proteins and nucleic acid as well as
hydrophobic anticancer and anti-HIV drugs.
Publication Types:
PMID: 16305436 [PubMed - indexed for MEDLINE]
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[Antimitochondrial agents: a new class of
anticancer agents]
[Article in French]
André N,
Rome A,
Carré M;
Société Francophone de Recherche en Pédiatrie
(SFRP).
Service d'oncologie pédiatrique, EA3286, hôpital
pour enfants de la Timone, 13005 Marseille,
France. nicolas.andre@mail.ap-hm.fr
Over the last 2 decades, the role of apoptosis
in anticancer agent cytotoxicity has become
clear. Defects in the regulation of apoptosis
(programmed cell death) make important
contributions to the pathogenesis and
progression of most cancers and leukemias.
Apoptosis defects also have a key role in cell
resistance to chemotherapy. Mitochondria play a
central part in cell death in response to
anticancer agents. Most of these agents target
mitochondria via caspases or other regulator
elements of the apoptotic machinery.
Nevertheless, some anticancer agents, already in
clinical use (paclitaxel, vinblastine,
lonidamine, etoposide, arsenic trioxide) or in
pre-clinical development (betulinic acid, MT21),
directly target and permeabilize mitochondria.
The acknowledgement of mitochondria as a new
target for anticancer agents provides a new way
to bypass cancer cell chemoresistance.
Publication Types:
PMID: 16298120 [PubMed - indexed for MEDLINE]
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Aminopeptidase-N/CD13 (EC 3.4.11.2)
inhibitors: chemistry, biological evaluations,
and therapeutic prospects.
Bauvois B,
Dauzonne D.
Unité INSERM 507, Hôpital Necker, Université
René Descartes Paris V, Bâtiment Lavoisier, 161
rue de Sèvres, 75015 Paris, France.
Aminopeptidase N (APN)/CD13 (EC 3.4.11.2) is a
transmembrane protease present in a wide variety
of human tissues and cell types (endothelial,
epithelial, fibroblast, leukocyte). APN/CD13
expression is dysregulated in inflammatory
diseases and in cancers (solid and hematologic
tumors). APN/CD13 serves as a receptor for
coronaviruses. Natural and synthetic inhibitors
of APN activity have been characterized. These
inhibitors have revealed that APN is able to
modulate bioactive peptide responses (pain
management, vasopressin release) and to
influence immune functions and major biological
events (cell proliferation, secretion, invasion,
angiogenesis). Therefore, inhibition of APN/CD13
may lead to the development of anti-cancer and
anti-inflammatory drugs. This review provides an
update on the biological and pharmacological
profiles of known natural and synthetic APN
inhibitors. Current status on their potential
use as therapeutic agents is discussed with
regard to toxicity and specificity.
Publication Types:
PMID: 16216010 [PubMed - indexed for MEDLINE]
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Betulinic acid induces apoptosis in skin
cancer cells and differentiation in normal human
keratinocytes.
Galgon T,
Wohlrab W,
Dräger B.
Faculty of Pharmacy, Institute of Pharmaceutical
Biology and Pharmacology,
Martin-Luther-University Halle-Wittenberg, Halle/Saale,
Germany.
Betulinic acid (BA), a pentacyclic triterpene of
plant origin, induces cell death in melanoma
cells and other malignant cells of
neuroectodermal origin. Little is known about
additional biological effects in normal target
cells. We show, in this study, that BA induces
differentiation as well as cell death in normal
human keratinocytes (NHK). Cytotoxicity profiles
of BA are compared among normal human
keratinocytes, HaCaT cells, IGR1 melanoma cells
and normal melanocytes. As expected, BA is toxic
to all cell types, normal and malignant, but
varies in its cytotoxic potency and in the
extent of induction of apoptotic vs. necrotic
cell death in the four different skin cell
types. Apoptosis is proved by annexin V and
Apo2.7 binding and by DNA fragmentation.
Induction of differentiation-associated antigens
in keratinocytes--filaggrin and involucrin--is
demonstrated, together with specific
morphological changes in treated cell cultures.
BA, apart from its cytotoxic activities in
cellular systems, is capable of inducing
differentiation of NHK into corneocytes without
immediately provoking apoptotic cell death.
Publication Types:
PMID: 16176281 [PubMed - indexed for MEDLINE]
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Signalling responses linked to betulinic
acid-induced apoptosis are antagonized by MEK
inhibitor U0126 in adherent or 3D spheroid
melanoma irrespective of p53 status.
Rieber M,
Rieber MS.
IVIC, Tumor Cell Biology Laboratory, Apartado
21827, Caracas 1020 A, Venezuela. mrieber@ivic.ve
MEK1/2 inhibitors like U0126 can potentiate or
antagonize the antitumor activity of cytotoxic
agents such as cisplatin, paclitaxel or
vinblastine, depending on the drug or the target
cells. We now investigated whether U0126,
differentially regulates melanoma signaling in
response to UV radiation or betulinic acid, a
drug lethal against melanoma. This report shows
that U0126 inhibits early response (ERK) kinase
activation and cyclin A expression in wt p53
C8161 melanoma exposed to either UV radiation or
betulinic acid. However, U0126 does not protect
from UV damage, but counteracts betulinic
acid-mediated apoptosis in the same cells.
Protection from the latter drug by joint
treatment with U0126 was also evident in wt p53
MelJuso melanoma and mutant p53 WM164 melanoma.
The latter cells were the most responsive to
betulinic acid, showing a selective decline in
the cdk4 protein, without a comparable change in
other key cell cycle proteins like cdc2, cdk2,
cdk7 or cyclin A, prior to apoptosis-associated
PARP fragmentation. Laser scanning cytometry
also showed that betulinic acid induced a
significant increase in chromatin condensation
in WM164 melanoma irrespective of whether they
were in adherent form or as multicellular
spheroids. All these betulinic acid-induced
changes were counteracted by U0126. Our data
show for the first time that (a) cdk4 protein is
an early target of betulinic acid-induced
apoptosis and (b) unrestricted ERK signaling
favours betulinic acid-induced apoptosis, but
this is counteracted by U0126, partly through
counteracting chromatin condensation and
restoring Akt activation decreased by betulinic
acid treatment. (c) 2005 Wiley-Liss, Inc.
Publication Types:
PMID: 16152620 [PubMed - indexed for MEDLINE]
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Combination of betulinic acid with cisplatin--different
cytotoxic effects in two head and neck cancer
cell lines.
Eder-Czembirek C,
Czembirek C,
Erovic BM,
Selzer E,
Turhani D,
Vormittag L,
Thurnher D.
Department of Otorhinolaryngology, Head and Neck
Surgery, Medical University of Vienna,
Waehringer Guertel 18-20, A-1090 Vienna,
Austria.
Betulinic acid (BetA), a new experimental
cytotoxic compound that is active against human
melanoma cells and neuroectodermal tumor cells,
has recently been shown to be also effective
against head and neck squamous carcinoma cells (HNSCC).
In this study we investigated BetA in
combination with cisplatin in squamous cell
carcinoma cell lines of the tongue. SCC25 and
SCC9 were treated with BetA and/or cisplatin.
Cells were counted with an automated analyzing
system. Caspase activation was determined using
the M30 Cyto-Death ELISA, expression of the
anti-apoptotic protein Mcl-1 by Western blot
analysis. Visualization of apoptotic cells was
achieved by immunohistochemistry. Synergistic
cytotoxic effect and the induction of apoptosis
under combined treatment was observed in SCC25
cells only after 24 or 48 h, whereas treatment
of SCC25 cells for 72 h with BetA and cisplatin
showed antagonism or subadditive effects. In
SCC9 cells, antagonism occurred over an increase
of dose and time during treatment. Furthermore,
we could not demonstrate a significant
alteration in the expression of the
anti-apoptotic protein, Mcl-1. Our in vitro data
demonstrate that BetA seems to be an unlikely
candidate for combination with cisplatin in the
treatment of head and neck cancer.
Publication Types:
PMID: 16077972 [PubMed - indexed for MEDLINE]
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Transient activation of EGFR/AKT cell
survival pathway and expression of survivin
contribute to reduced sensitivity of human
melanoma cells to betulinic acid.
Qiu L,
Wang Q,
Di W,
Jiang Q,
Schefeller E,
Derby S,
Wanebo H,
Yan B,
Wan Y.
Department of OB/GYN, Renji Hospital, Shanghai
Second Medical University, P.R. China.
Betulinic acid (BA), a pentacyclic triterpene
first identified less than a decade ago, has
served as a melanoma-specific cytotoxic agent,
and yet its specificity is being challenged.
Recently, we found that human melanoma cells
exhibited less sensitivity to betulinic acid
than human skin keratinocytes. This study was
designed to investigate the cell signaling
pathway leading human melanoma cells to
increased resistance to betulinic acid
treatment. In vitro experiments using cultured
human melanoma cells indicated that betulinic
acid transiently induced survivin expression.
The expression of survivin started 30 min post-betulinic
acid treatment, peaked at 2 h, remained elevated
for 8 h and returned to basal level within 24 h.
Similarly, epithelial growth factor (EGF)
treatment induced expression of survivin in a
time-dependent manner. Since epithelial growth
factor receptor (EGFR) activation leads to the
activation of cell signaling components that are
important to cell survival, we next examined
whether BA-induced survivin expression is
mediated by the EGFR pathway. The results showed
that BA induced EGFR tyrosine phosphorylation in
a time-dependent manner. Further, BA strongly
induced AKT phosphorylation in a similar
pattern. AKT activation started 15 min
post-treatment, peaked at approximately 1 h,
remained elevated for 4 h and returned to basal
level within 8 h. BA also induced ERK activation
and, in contrast, weakly induced JNK and p38
activation. Pretreatment of EGFR inhibitor
PD153035 blocked BA-induced EGFR phosphorylation,
ERK and AKT activation, and survivin expression.
Results of the MTT dye assay showed that a
combination of PD153035 and BA enhanced melanoma
cell death. Collectively, we conclude that
betulinic acid transiently activated the EGFR/AKT
cell survival pathway and induced survivin
expression, contributing to less sensitivity in
human melanoma cells. The data suggest that a
combination of the EGFR inhibitor and betulinic
acid may be a better clinical option to treat
human melanoma.
Publication Types:
PMID: 16077934 [PubMed - indexed for MEDLINE]
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Lupane triterpenoids from Maytenus species.
Núñez MJ,
Reyes CP,
Jiménez IA,
Moujir L,
Bazzocchi IL.
Instituto Universitario de Bio-Orgánica Antonio
González, Universidad de La Laguna, and
Instituto Canario de Investigación del Cáncer,
Avenida Astrofísico Francisco Sánchez 2, 38206
La Laguna, Tenerife, Spain.
Five new lupane triterpenes (1-5), in addition
to 24 known ones, were isolated from Maytenus
cuzcoina and M. chiapensis. Their structures
were elucidated on the basis of spectroscopic
analysis, including homonuclear and
heteronuclear correlation NMR (COSY, ROESY, HSQC,
and HMBC) experiments. The compounds were
assayed for antimicrobial and cytotoxic
activities, with 3-epi-betulinic acid and
28,30-dihydroxy-3-oxolup-20(29)-ene showing
moderate cytotoxicity.
Publication Types:
PMID: 16038541 [PubMed - indexed for MEDLINE]
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Betulinic acid as new activator of NF-kappaB:
molecular mechanisms and implications for cancer
therapy.
Kasperczyk H,
La Ferla-Brühl K,
Westhoff MA,
Behrend L,
Zwacka RM,
Debatin KM,
Fulda S.
Department of Hematology, Oncology, University
Children's Hospital, Prittwitzstr. 43, Ulm
D-89075, Germany.
Recent evidence demonstrates that the anticancer
activity of betulinic acid (BetA) can be
markedly increased by combination protocols, for
example with chemotherapy, ionizing radiation or
TRAIL. Since nuclear factor-kappaB (NF-kappaB),
a key regulator of stress-induced
transcriptional activation, has been implicated
in mediating apoptosis resistance, we
investigated the role of NF-kappaB in BetA-induced
apoptosis. Here, we provide for the first time
evidence that BetA activates NF-kappaB in a
variety of tumor cell lines. NF-kappaB
DNA-binding complexes induced by BetA consisted
of p50 and p65 subunits. Nuclear translocation
of p65 was also confirmed by immunofluorescence
microscopy. BetA-induced NF-kappaB activation
involved increased IKK activity and
phosphorylation of IkappaB-alpha at serine 32/36
followed by degradation of IkappaB-alpha.
Reporter assays revealed that NF-kappaB
activated by BetA is transcriptionally active.
Interestingly, inhibition of BetA-induced NF-kappaB
activation by different chemical inhibitors (proteasome
inhibitor, antioxidant, IKK inhibitor)
attenuated BetA-induced apoptosis. Importantly,
specific NF-kappaB inhibition by transient or
stable expression of IkappaB-alpha
super-repressor inhibited BetA-induced apoptosis
in SH-EP neuroblastoma cells, while transient
expression of IkappaB-alpha super-repressor had
no influence on BetA-induced apoptosis in two
other cell lines. Thus, our findings that
activation of NF-kappaB by BetA promotes BetA-induced
apoptosis in a cell type-specific fashion
indicate that NF-kappaB inhibitors in
combination with BetA would have no therapeutic
benefit or could even be contraproductive in
certain tumors, which has important implications
for the design of BetA-based combination
protocols.
Publication Types:
PMID: 16007147 [PubMed - indexed for MEDLINE]
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[Synthesis and antitumor activity of
cyclopropane derivatives of betulinic and
betulonic acids]
[Article in Russian]
Symon AV,
Veselova NN,
Kaplun AP,
Vlasenkova NK,
Fedorova GA,
Liutik AI,
Gerasimova GK,
Shvrts VI.
New cyclopropane derivatives of betulin were
synthesized by attachment of dichlorocarbenes or
dibromocarbenes to the double bond of betulin
diacetate, followed by the deprotection of
hydroxyl groups. The betulin cyclopropane
derivative was obtained from
20,29-dihydro-20,29-dichloromethylenebetulin by
treatment with lithium in tert-butanol. These
compounds were converted into the corresponding
derivatives of betulonic acid by oxidation with
chromium trioxide. The reduction of oxo group
with sodium borohydride led to the corresponding
derivatives of betulinic acid.
20,29-Dihydro-20,29-dichloromethylenebetulinic
acid proved to be the most cytotoxic toward
human melanoma of the Colo 38 and Bro lines and
human ovarian carcinoma of the CaOv line (IC50
10 microM).
20,29-Dihydro-20,29-dibromomethylenebetulinic
acid inhibited the growth of the Bro melanoma
cell line and the CaOv carcinoma cell line
practically by 50% at a concentration of 10
microM. The other derivatives of betulinic and
betulonic acids were active toward all of the
three cancer cell lines at concentrations higher
than 10 microM. The English version of the
paper: Russian Journal of Bioorganic Chemistry,
2005, vol. 31, no. 3; see also http://www.maik.ru.
Publication Types:
PMID: 16004391 [PubMed - indexed for MEDLINE]
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Betulinic acid, a natural cytotoxic agent,
fails to trigger apoptosis in human Burkitt's
lymphoma-derived B-cell lines.
Karpova MB,
Sanmun D,
Henter JI,
Smirnov AF,
Fadeel B.
Childhood Cancer Research Unit, Department of
Woman and Child Health, Karolinska University
Hospital, Stockholm, Sweden.
Betulinic acid (BA), a pentacyclic triterpene of
natural origin, effectively induces apoptosis in
neuroectodermal tumors and was recently shown to
be a potent trigger of cell death in human
leukemia-derived cell lines. To explore the
potential of BA in the treatment of hematologic
malignancies, we tested a panel of 10 Burkitt's
lymphoma (BL)-derived B-cell lines for
sensitivity to BA. The human Jurkat T leukemia
cell line was included as a positive control.
Our studies show that BA exerts cytotoxic
effects in some of the BL cell lines tested,
including DG75, a chemoresistant BL cell line.
However, cell death was caspase-independent, as
evidenced by a lack of protection by zVAD-fmk, a
pancaspase inhibitor, and displayed signs of
necrosis. Furthermore, BA-induced caspase
activation was seen to a minor extent in only 1
of the 10 BL cell lines tested (Ramos, a
p53-deficient cell line), but was readily
detected in Jurkat cells. Together, these
studies indicate that resistance to BA-induced
apoptosis is a common feature of BL-derived cell
lines. Copyright 2005 Wiley-Liss, Inc.
Publication Types:
PMID: 16003746 [PubMed - indexed for MEDLINE]
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Erratum in:
- J Pharmacol
Exp Ther. 2005 Oct;315(1):475.
Resistance of human astrocytoma cells to
apoptosis induced by mitochondria-damaging
agents: possible implications for anticancer
therapy.
Ceruti S,
Mazzola A,
Abbracchio MP.
Department of Pharmacological Sciences, Via
Balzaretti 9, University of Milan, 20133 Milan,
Italy.
The success of anticancer chemotherapy is often
hampered by resistance to apoptosis, which may
depend on defects in intracellular cell death
pathways. Characterizing the alterations of
these pathways is a prerequisite for developing
alternative and effective antitumoral
strategies. Here, we investigated the
susceptibility of a human astrocytoma cell line,
ADF, to apoptotic cell death induced by
mitochondria-damaging agents. Neither the
anticancer agent betulinic acid nor the "mitochondriotropic"
poisons 2-deoxy-d-ribose and potassium cyanide
induced apoptosis of these cells, despite
induction of highly significant mitochondrial
depolarization, eventually resulting in necrotic
death. Resistance to apoptosis was not due to
presence of the multidrug resistance pump or to
impaired expression of caspase-8, caspase-9, or
"executioner" caspase-3. Cloning of caspase-9
revealed the presence of full-length
caspase-9alpha and a short variant
(caspase-9beta), which, in other tumors, acts as
a dominant negative of the long isoform. All
analyzed clones showed a point mutation in the
prodomain region that is known to interact with
mitochondria-released factors. Thus, in these
human astrocytoma cells, mitochondria-damaging
agents induce a regulated form of
mitochondrial-dependent necrotic cell death (oncosis).
Resistance to apoptosis is due to an intrinsic
defect of caspase-9, leading to inhibition of
enzyme activation and/or impaired interaction
with proteins released from depolarized
mitochondria. These results may have
implications for developing strategies aimed at
overcoming tumor resistance to chemotherapy.
Publication Types:
PMID: 15879006 [PubMed - indexed for MEDLINE]
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Synthesis of phthalates of betulinic acid and
betulin with cytotoxic activity.
Kvasnica M,
Sarek J,
Klinotova E,
Dzubak P,
Hajduch M.
Department of Organic and Nuclear Chemistry,
Faculty of Science, Charles University in
Prague, Hlavova 8, 128 43 Prague 2, Czech
Republic.
Synthesis of 3beta-O-phthalic esters from
betulinic acid and its esters and synthesis of
phthalic esters from betulin and its
monoacetates using classical acylation procedure
with phthalic anhydride. The evaluation of
cytotoxicity of the prepared compounds was using
numbers of tumor cell lines in MTT test. It was
discovered that hemiphthalic esters had better
cytotoxicity than starting compounds as
betulinic acid or quite inactive betulin.
Publication Types:
PMID: 15848757 [PubMed - indexed for MEDLINE]
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Sensitization for anticancer drug-induced
apoptosis by betulinic Acid.
Fulda S,
Debatin KM.
University Children's Hospital, Prittwitzstrasse
43, Ulm 89075, Germany. simone.fulda@medizin.uni-ulm.de
We previously described that betulinic acid (BetA),
a naturally occurring pentacyclic triterpenoid,
induces apoptosis in tumor cells through the
mitochondrial pathway. Here, for the first time,
we provide evidence that BetA cooperated with
anticancer drugs to induce apoptosis and to
inhibit clonogenic survival of tumor cells.
Combined treatment with BetA and anticancer
drugs acted in concert to induce loss of
mitochondrial membrane potential and the release
of cytochrome c and Smac from mitochondria,
resulting in activation of caspases and
apoptosis. Overexpression of Bcl-2, which
blocked mitochondrial perturbations, also
inhibited the cooperative effect of BetA and
anticancer drugs, indicating that cooperative
interaction involved the mitochondrial pathway.
Notably, cooperation of BetA and anticancer
drugs was found for various cytotoxic compounds
with different modes of action (e.g.,
doxorubicin, cisplatin, Taxol, VP16, or
actino-mycin D). Importantly, BetA and
anticancer drugs cooperated to induce apoptosis
in different tumor cell lines, including p53
mutant cells, and also in primary tumor cells,
but not in human fibroblasts indicating some
tumor specificity. These findings indicate that
using BetA as sensitizer in chemotherapy-based
combination regimens may be a novel strategy to
enhance the efficacy of anticancer therapy,
which warrants further investigation.
Publication Types:
PMID: 15802021 [PubMed - indexed for MEDLINE]
PMCID: PMC1501129
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Betulinic acid induces apoptosis in human
chronic myelogenous leukemia (CML) cell line
K-562 without altering the levels of Bcr-Abl.
Raghuvar Gopal DV,
Narkar AA,
Badrinath Y,
Mishra KP,
Joshi DS.
Laboratory Nuclear Medicine Section, Isotope
Group, BARC, C/o Tata Memorial Hospital Annexe,
Jerbai Wadia Road, Parel, Mumbai 400012, India.
Betulinic acid (BA), a plant derived
triterpenoid, isolated from various sources
shows cytotoxicity in cell lines of melanoma,
neuroectodermal and malignant brain tumors.
Chronic myelogenous leukemia (CML) is
characterized by Philadelphia chromosome (Bcr-Abl),
a molecular abnormality leading to the intrinsic
tyrosine kinase activity that provides growth
and survival advantage to the cells. Present
study describes the cytotoxicity of BA on human
CML cell line K-562, positive for Bcr-Abl. The
decrease in the viability of K-562 cells treated
with BA at different concentrations and time
intervals was assessed using MTT assay. Cell
death induced by BA was determined to be
apoptotic as measured by FACS analysis of PI
stained nuclei, PS externalization by Annexin-V
fluorescence and characteristic DNA
fragmentation. DiOC6(3) fluorescent probe
determined alterations in the mitochondrial
membrane potential (MMP). RT-PCR confirmed the
expression levels of Bcr-Abl in controls and
K-562 cells treated with BA. The rapid loss of
MMP of K-562 cells upon treatment with BA shows
the direct activation of apoptosis at the level
of mitochondria, overcoming the resistance of
the high levels of expression of Bcr-Abl.
PMID: 15649617 [PubMed - indexed for MEDLINE]
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Apoptosis inducing activity of viscin, a
lipophilic extract from Viscum album L.
Urech K,
Scher JM,
Hostanska K,
Becker H.
Verein für Krebsforschung, Institute Hiscia,
Kirschweg 9, CH-4144 Arlesheim, Switzerland.
urech@hiscia.ch
Detection of antiproliferative activity and
bioactivity-guided fractionation of viscin, a
lipophilic extract from Viscum album L., led to
the isolation of betulinic acid, oleanolic acid
and ursolic acid as active components. Viscin,
betulinic acid, oleanolic acid and ursolic acid
inhibited growth and induced apoptotic cell
death in Molt4, K562 and U937 leukaemia cells.
The growth inhibitory effect of viscin was more
pronounced in Molt4 and U937 cells (IC50
(concentration that inhibited cell proliferation
by 50%): 118 +/- 24 and 138 +/- 24 microg mL(-1))
than in K562 cells (IC50: 252 +/- 37 microg mL(-1)).
Oleanolic acid was the least effective in all
cell lines (7.5-45.5% inhibition at 10 microg mL(-1))
and ursolic acid the most active in Molt4 and
U937 cells (81.8 and 97.8% inhibition,
respectively, at 5 microg mL(-1)). A
dose-dependent loss of membrane phospholipid
asymmetry associated with apoptosis was induced
in all cell lines as shown in flow cytometry by
the externalization of phosphatidylserine and
morphological changes in cell size and
granularity. There were differences in
individual cell lines' response towards the
apoptosis-inducing effect of viscin, betulinic
acid, oleanolic acid and ursolic acid. The
triterpenoids beta-amyrin, beta-amyrinacetate,
lupeol, lupeolacetate, beta-sitosterol and
stigmasterol, and the fatty acids oleic acid,
linoleic acid, palmitic acid and stearic acid
were also present in the lipophilic extract.
PMID: 15638998 [PubMed - indexed for MEDLINE]
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