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Combination of SNX-2112 with 5-FU exhibits antagonistic effect in esophageal cancer cells.
[esophageal squamous cell carcinoma]
The
low
efficacy
of
single
-drug
chemotherapy
forms
the
basis
for
combination
therapy
in
esophageal
squamous
cell
carcinoma
.
SNX-
2112
,
a
selective
heat
shock
protein
90
(
Hsp
90
)
inhibitor
,
was
recently
reported
as
being
effective
in
combination
with
cisplatin
and
paclitaxel
.
In
this
study
,
we
investigated
the
effect
of
SNX-
2112
in
combination
with
5
-
fluorouracil
(
5
-
FU
)
,
another
first
-line
anticancer
drug
,
in
esophageal
cancer
.
Unexpectedly
,
tetrazolium
assay
revealed
that
the
combination
of
SNX-
2112
with
5
-
FU
exhibited
antagonistic
effect
.
Flow
cytometry
revealed
that
the
SNX-
2112
and
5
-
FU
combination
greatly
decreased
the
number
of
G
2
/
M
cells
compared
to
SNX-
2112
-
only
treatment
in
Eca‑
109
cells
.
This
effect
might
be
related
to
the
altered
mRNA
level
of
cyclin-related
genes
including
cyclin
D
1
,
Chk
2
and
Cdk
4
.
Further
,
5
-
FU
attenuated
SNX-
2112
-
induced
apoptosis
by
decreasing
poly
(
ADP-ribose
)
polymerase
(
PARP
)
cleavage
and
inactivating
caspase-
3
,
-
8
and
-
9
.
Additionally
,
5
-
FU
suppressed
the
SNX-
2112
-
induced
decrease
of
mitochondrial
membrane
potential
.
Moreover
,
5
-
FU
partly
recovered
Hsp
90
client
proteins
,
including
Akt
,
p
-
Akt
,
inhibitor
of
κB
kinase
(
IKK
)
α
,
extracellular
signal-regulated
kinase
(
ERK
)
1
/
2
,
and
glycogen
synthase
kinase
(
GSK
)
-
3
β
,
which
SNX-
2112
had
downregulated
.
Taken
together
,
this
is
the
first
report
that
the
combination
of
SNX-
2112
with
5
-
FU
exhibited
antagonistic
effect
in
esophageal
cancer
cells
by
affecting
growth
inhibition
,
cell
cycle
,
apoptosis
,
and
Hsp
90
client
proteins
,
suggesting
that
care
is
required
in
the
clinical
application
of
combined
SNX-
2112
and
5
-
FU
.
Diseases
Validation
Diseases presenting
"squamous cell carcinoma"
symptom
carcinoma of the gallbladder
child syndrome
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
esophageal adenocarcinoma
esophageal carcinoma
esophageal squamous cell carcinoma
junctional epidermolysis bullosa
kallmann syndrome
kindler syndrome
liposarcoma
monosomy 21
oculocutaneous albinism
oral submucous fibrosis
papillon-lefèvre syndrome
This symptom has already been validated