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Triacetin-based acetate supplementation as a chemotherapeutic adjuvant therapy in glioma.
[canavan disease]
Cancer
is
associated
with
epigenetic
(
i
.
e
.
,
histone
hypoacetylation
)
and
metabolic
(
i
.
e
.
,
aerobic
glycolysis
)
alterations
.
Levels
of
N-
acetyl-
L-
aspartate
(
NAA
)
,
the
primary
storage
form
of
acetate
in
the
brain
,
and
aspartoacylase
(
ASPA
)
,
the
enzyme
responsible
for
NAA
catalysis
to
generate
acetate
,
are
reduced
in
glioma
;
yet
,
few
studies
have
investigated
acetate
as
a
potential
therapeutic
agent
.
This
preclinical
study
sought
to
test
the
efficacy
of
the
food
additive
Triacetin
(
glyceryl
triacetate
,
GTA
)
as
a
novel
therapy
to
increase
acetate
bioavailability
in
glioma
cells
.
The
growth
-inhibitory
effects
of
GTA
,
compared
to
the
histone
deacetylase
inhibitor
Vorinostat
(
SAHA
)
,
were
assessed
in
established
human
glioma
cell
lines
(
HOG
and
Hs
683
oligodendroglioma
,
U
87
and
U
251
glioblastoma
)
and
primary
tumor
-derived
glioma
stem-like
cells
(
GSCs
)
,
relative
to
an
oligodendrocyte
progenitor
line
(
Oli
-
Neu
)
,
normal
astrocytes
,
and
neural
stem
cells
(
NSCs
)
in
vitro
.
GTA
was
also
tested
as
a
chemotherapeutic
adjuvant
with
temozolomide
(
TMZ
)
in
orthotopically
grafted
GSCs
.
GTA-induced
cytostatic
growth
arrest
in
vitro
comparable
to
Vorinostat
,
but
,
unlike
Vorinostat
,
GTA
did
not
alter
astrocyte
growth
and
promoted
NSC
expansion
.
GTA
alone
increased
survival
of
mice
engrafted
with
glioblastoma
GSCs
and
potentiated
TMZ
to
extend
survival
longer
than
TMZ
alone
.
GTA
was
most
effective
on
GSCs
with
a
mesenchymal
cell
phenotype
.
Given
that
GTA
has
been
chronically
administered
safely
to
infants
with
Canavan
disease
,
a
leukodystrophy
due
to
ASPA
mutation
,
GTA-mediated
acetate
supplementation
may
provide
a
novel
,
safe
chemotherapeutic
adjuvant
to
reduce
the
growth
of
glioma
tumors
,
most
notably
the
more
rapidly
proliferating
,
glycolytic
and
hypoacetylated
mesenchymal
glioma
tumors
.
Diseases
Validation
Diseases presenting
"investigated acetate as a potential therapeutic agent"
symptom
canavan disease
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