Veterinary and Comparative Oncology,
Год журнала:
2024,
Номер
22(4), С. 602 - 612
Опубликована: Сен. 20, 2024
Ataxia
telangiectasia
and
Rad3-related
(ATR)
kinase
is
one
of
the
main
regulators
cell
response
to
DNA
damage
replication
stress.
Effectiveness
ATR
targeting
in
human
cancers
has
been
confirmed
preclinical
studies
inhibitors
are
currently
developed
clinically
oncology.
In
presented
study,
we
tested
anticancer
efficacy
inhibitor
berzosertib
an
vitro
model
canine
haematopoietic
cancers.
Using
MTT
assay
flow
cytometry,
assessed
cytotoxicity
four
established
lymphoma
leukaemia
lines
compared
it
with
its
activity
against
noncancerous
cells.
Further,
estimated
level
apoptosis
berzosertib-treated
cells
via
cytometry
H2AX
phosphorylation
as
a
marker
using
western
blot
technique.
flow-cytometric
analysis,
also
evaluated
potential
synergism
between
chlorambucil
influence
on
cycle
disturbances
induced
by
drug.
The
results
demonstrated
that
berzosertib,
even
without
additional
damaging
agent,
can
be
effective
at
concentrations
were
harmless
for
cells,
although
sensitivity
individual
cancer
varied
greatly.
Cell
death
occurred
through
caspase-dependent
induction
damage.
Berzosertib
acted
synergistically
chlorambucil,
probably
preventing
repair
consequence
S-phase
arrest
abrogation.
conclusion,
inhibition
may
provide
new
therapeutic
option
treatment
lymphomas
leukaemias,
but
further
required
determine
biomarkers
their
susceptibility.
Advanced Science,
Год журнала:
2024,
Номер
unknown
Опубликована: Июль 8, 2024
Targeted
therapy
remains
the
future
of
anti-cancer
drug
development,
owing
to
lack
specificity
current
treatments
which
lead
damage
in
healthy
normal
tissues.
ATR
inhibitors
have
recent
times
demonstrated
promising
clinical
potential,
and
are
currently
being
evaluated
clinic.
However,
despite
considerable
optimism
for
success
these
inhibitors,
reports
associated
tissues
toxicities
remain
a
concern
can
compromise
their
utility.
Here,
ICT10336
is
reported,
newly
developed
hypoxia-responsive
prodrug
inhibitor,
AZD6738,
hypoxia-activated
specifically
releases
AZD6738
only
hypoxic
conditions,
vitro.
This
hypoxia-selective
release
inhibited
activation
(T1989
S428
phosphorylation)
subsequently
abrogated
HIF1a-mediated
adaptation
cancers
cells,
thus
selectively
inducing
cell
death
2D
3D
cancer
models.
Importantly,
tissues,
be
metabolically
stable
less
toxic
cells
than
its
active
parent
agent,
AZD6738.
In
addition,
exhibited
superior
efficient
multicellular
penetration
ability
tumor
models,
eradicated
at
core
compared
summary,
preclinical
data
demonstrate
new
strategy
tumor-targeted
delivery
with
significant
potential
enhancing
therapeutic
index.
Frontiers in Pharmacology,
Год журнала:
2024,
Номер
15
Опубликована: Май 2, 2024
The
therapeutic
effect
of
chemotherapy
and
targeted
therapy
are
known
to
be
limited
by
drug
resistance.
Substantial
evidence
has
shown
that
ATP-binding
cassette
(ABC)
transporters
P-gp
BCRP
significant
contributors
multidrug
resistance
(MDR)
in
cancer
cells.
In
this
study,
we
demonstrated
a
clinical-staged
ATR
inhibitor
ceralasertib
is
susceptible
BCRP-mediated
MDR.
resistant
cells
were
less
sensitive
compared
the
parental
Moreover,
can
reversed
inhibiting
efflux
activity
BCRP.
Interestingly,
was
able
downregulate
level
but
not
BCRP,
suggesting
potential
regulation
between
signaling
expression.
Furthermore,
computational
docking
analysis
predicted
high
affinities
drug-binding
sites
summary,
overexpression
sufficient
confer
ceralasertib,
underscoring
their
role
as
biomarkers
for
efficacy.
DNA and Cell Biology,
Год журнала:
2024,
Номер
43(5), С. 219 - 231
Опубликована: Апрель 18, 2024
Breast
cancer
risk
have
been
discussed
to
be
associated
with
polymorphisms
in
genes
as
well
abnormal
DNA
damage
repair
function.
This
study
aims
assess
the
relationship
between
single
nucleotide
(SNPs)
related
and
female
breast
Chinese
population.
A
case–control
containing
400
patients
healthy
controls
was
conducted.
Genotype
identified
using
sequence
MassARRAY
method
expression
of
estrogen
receptor
(ER),
progesterone
(PR)
human
epidermal
growth
factor
receptor-2
(HER-2)
tumor
tissues
analyzed
by
immunohistochemistry
assay.
The
results
revealed
that
ATR
rs13091637
decreased
influenced
ER,
PR
(CT/TT
vs.
CC:
adjusted
odds
ratio
[OR]
=
1.54,
95%
confidence
interval
[CI]:
1.04–2.27,
p
0.032;
CT/TT
OR
1.63,
95%CI:
1.14–2.35,
0.008)
expression.
Stratified
analysis
PALB2
rs16940342
increased
response
menstrual
status
(AG/GG
AA:
1.72,
1.13–2.62,
0.011)
age
menarche
1.03–2.31,
0.037),
whereas
ATM
rs611646
Ku70
rs132793
were
reduced
(GA/AA
GG:
0.50,
0.30–0.95,
0.033).
In
a
summary,
rs16940342,
rs13091637,
rs611646,
risk.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Июнь 14, 2024
Abstract
Background
and
purpose
Interferon
signaling
plays
an
important
role
in
antitumor
immune
responses.
Inhibitors
of
the
DNA
damage
response,
such
as
ATR
inhibitors,
can
increase
interferon
upon
conventional
radiotherapy
with
X-rays.
However,
whether
inhibitors
also
(IFN)
after
high
linear
energy
transfer
(LET)
particle
irradiation
is
not
known.
Materials
methods
Human
glioblastoma
U-251
T98G
cells
were
treated
X-rays,
protons
(linear
(LET):
7
38
keV/μm)
carbon
ions
(LET:
28
73
keV/μm),
without
inhibitor
(VE822)
or
ATM
(AZD1390).
cell
cycle
distribution
assayed
by
immunoblotting
flow
cytometry,
radiosensitivity
clonogenic
survival.
IFN-β
secretion
was
measured
ELISA
STAT1
activation
immunoblotting.
Results
High-LET
caused
stronger
response
compared
to
low-LET
andX-rays
at
similar
radiation
dose.
G2
checkpoint
arrest
abrogated
prolonged
all
types.
The
increased
radiosensitivity,
X-
carbon-ion-irradiation.
inhibition
IFN
both
high-LET
lines.
In
T98G,
enhanced
inhibition.
Notably,
secreted
markedly
more
when
combined
irradiation.
Conclusion
Our
results
show
that
X-,
proton-
Additionally,
induction
strongly
dependent
on
LET
one
tested
Scientific Reports,
Год журнала:
2024,
Номер
14(1)
Опубликована: Авг. 26, 2024
The
ATR
kinase
responds
to
elevated
levels
of
single-stranded
DNA
(ssDNA)
activate
the
G2/M
checkpoint,
regulate
origin
utilization,
preserve
fork
stability,
and
allow
repair
ensure
genome
integrity.
intrinsic
replication
stress
in
cancer
cells
makes
this
pathway
an
attractive
therapeutic
target.
ssDNA
that
drives
signaling
is
sensed
by
ssDNA-binding
protein
A
(RPA),
which
acts
as
a
platform
for
ATRIP
recruitment
subsequent
activation
TopBP1.
We
have
developed
chemical
RPA
inhibitors
(RPAi)
block
RPA-ssDNA
interactions
(RPA-DBi)
protein-protein
(RPA-PPIi);
both
activities
are
required
activation.
Here,
we
biochemically
reconstitute
demonstrate
RPA-DBi
RPA-PPIi
abrogate
ATR-dependent
phosphorylation
target
proteins
with
selectivity
advantages
over
active
site
inhibitors.
post-translational
modifications
(PTMs)
impact
but
do
not
alter
sensitivity
RPAi.
Specifically,
RPA32
TopBP1
stimulate,
while
RPA70
acetylation
does
affect
proteins.
Collectively,
work
reveals
RPAi
mechanism
action
inhibit
can
be
regulated
PTMs
offers
insight
into
anti-cancer
activity
pathway-targeted
therapeutics.
Cancers,
Год журнала:
2024,
Номер
16(23), С. 3941 - 3941
Опубликована: Ноя. 25, 2024
Oncogene-driven
NSCLC
is
usually
treated
with
targeted
therapies
using
tyrosine
kinase
inhibitors
(TKIs)
to
inhibit
oncogene
downstream
signaling
pathways,
affecting
tumor
survival
and
proliferation.
EGFR-
KRAS-mutant
NSCLCs
are
the
most
represented
subtypes,
they
in
clinical
practice
oncogene-targeting
drugs
first
second
line,
respectively.
Unfortunately,
development
of
oncogene-independent
resistant
clones
limits
TKI
efficacy.
Here,
we
used
non-oncogene
addiction
(NOA)
as
an
innovative
therapeutic
strategy
target
other
essential
proteins
that
support
changes
phenotype.
Specifically,
tested,
for
time,
a
combination
inhibitors,
namely
ATR,
involved
DNA
damage
response,
pyruvate
dehydrogenase
kinases
(PDKs),
energy
metabolism.
