Betulinic acid is a naturally occurring pentacyclic triterpenoid
which has antiretroviral,
antimalarial,
and anti-inflammatory properties, as well as a more
recently discovered potential as an anticancer agent, by inhibition of topoisomerase.[1]
It is found in the bark
of several species of plants, principally the white
birch (Betula pubescens)[2]
from which it gets its name, but also the ber tree (Ziziphus mauritiana), selfheal (Prunella
vulgaris), the tropical carnivorous plants Triphyophyllum peltatum and Ancistrocladus heyneanus,
Diospyros leucomelas,
a member of the persimmon family, Tetracera
boiviniana, the jambul (Syzygium
formosanum),[3]
flowering quince (Chaenomeles sinensis),[4]
rosemary,[5]
and Pulsatilla
chinensis.
In 1995, betulinic acid was reported as a selective inhibitor
of human melanoma.[7]
Then it was demonstrated to induce apoptosis in
human melanoma in vitro and in vivo in
model systems.[8]
Currently, it is undergoing development with assistance from the Rapid Access
to Intervention Development program of the National Cancer Institute.[2]
Also, betulinic acid was found active against neuroectodermal (neuroblastoma,
medulloblastoma,
Ewing's
sarcoma[9])
and malignant brain tumors,[3][10] ovarian
carcinoma,[3]
in human leukemia
HL-60 cells,[6]
and malignant head and neck squamous cell carcinoma SCC25 and SCC9 cell lines.[11]
In contrast, epithelial tumors, such as breast,
colon,
small cell lung and renal cell carcinomas, as well as T-cell
leukemia cells, were completely unresponsive to treatment with betulinic
acid.
Regarding the mode
of action of betulinic acid, little is known about its antiproliferative
and apoptosis-inducing
mechanisms. In neuroectodermal tumor cells, betulinic acid–induced apoptosis is
accompanied by caspase
activation, mitochondrial membrane alterations and DNA fragmentation.[9][11]
Caspases are produced as inactive proenzymes,
which are proteolytically processed to their active forms. These proteases can
cooperate in proteolytic cascades, in which caspases activate themselves and
each other. The initiation of the caspases cascade may lead to the activation
of endonucleases
such as caspase-activated DNAase (CAD). After activation, CAD contributes to
DNA degradation.[11]
Betulinic acid induces apoptosis by direct effects on mitochondria, leading to
cytochrome-C release, which in turn regulates the "downstream"
caspase activation.[11]
Betulinic acid bypasses resistance to CD95 and doxorubicin-mediated
apoptosis, due to different molecular mechanism of betulinic acid-induced
apoptosis.
The role of p53 in betulinic
acid-induced apoptosis is controversial. Fulda suggested a p53-independent
mechanism of the apoptosis, based on no accumulation of wild-type p53 detected
upon treatment with the betulinic acid, whereas wild-type p53 protein strongly
increased after treatment with doxorubicin.[9]
The suggestion is supported by study of Raisova.[12]
Alternatively,Rieber suggested betulinic acid exerts its inhibitory effect on
human metastatic melanoma partly by increasing p53.[13]
The study also demonstrated
preferential apoptotic effect of betulinic acid on C8161 metastatic melanoma
cells, with greater DNA fragmentation and growth arrest and earlier loss of
viability than their nonmetastatic C8161/neo 6.3 counterpart.[13]
Comparing betulinic acid with other treatment modes, Zuco demonstrated it was
less than 10% as potent as doxorubicin and showed an in vitro
antiproliferative activity against melanoma and nonmelanoma cell lines,
including those resistant to doxorubicin. On the human normal dermatoblast cell
line, betulinic acid was one-half to one-fifth as toxic as doxorubicin.[3]
The ability of betulinic acid to induce two different effects (cytotoxic and cytostatic)
on two clones derived from the same human melanoma metastasis suggests the
development of clones resistant to this agent will be more unlikely, than that
to conventional cytotoxic drugs. Moreover, in spite of the lower potency
compared with doxorubicin, betulinic acid seems to be selective for tumor cells
with minimal toxicity against normal cells.[3]
The effect of betulinic acid on melanoma cell lines is stronger than its
growth-inhibitory effect on primary melanocytes.[14]
A study of a combination of betulinic acid with γ-irradiation showed clearly
additive effects, and indicated they differ in their modes of action.[
A major inconvenience for the future clinical development of betulinic acid
and analogues resides in their poor solubility in aqueous media such as blood
serum and polar solvents used for bioassays. To circumvent this problem of
hydrosolubility and to enhance pharmacological properties, many derivatives
were synthesized and evaluated for cytotoxic activity. One study showed C-20
modifications involve the loss of cytotoxicity. Another study demonstrated the
importance of the presence of the -COOH group, since compounds substituted at
this position, such as lupeol and methyl betulinate, were less active on human
melanoma than betulinic acid. Moreover, some C-28 amino acids and C-3
phthalates derivatives exhibited higher cytotoxic activity against cancer cell
lines with improved selective toxicity and water solubility. Chatterjee et
al. obtained the 28-O-β-D-glucopyranoside of betulinic acid by microbial
transformation with Cunninghamella species, while Baglin et al.
obtained it by organic synthesis. This glucoside did not exhibit any
significant in vitro activity on human melanoma (MEL-2) and human
colorectal adenocarcinoma (HT-29) cell lines, which confirms the importance of
the carboxylic acid function to preserve the cytotoxicity. Recently, Gauthier et
al. synthesized a series of 3-O-glycosides of betulinic acid which
exhibited a strongly potent in vitro anticancer activity against human
cancer cell lines.[15]
A source of soluble and ingestible betulinic acid (and its precursor, betulin) is the chaga
(Inonotus obliquus), a slow-growing medicinal fungus found as a parasite
on birch trees in the coldest regions of the Northern Hemisphere. This mushroom
converts the betulin present in the bark of the birch into a soluble and
ingestible form of betulinic acid. Using a proper extraction protocol
(alcohol/ethanol extraction) will make the compounds available for oral
consumption. The slow-growing nature of the fungus (7-10 years minimum) and
because it cannot be cultivated without losing most of its properties make this
an unreliable source, though.
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