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.
Neuro-Oncology Advances,
Год журнала:
2023,
Номер
6(1)
Опубликована: Дек. 19, 2023
Abstract
Background
The
most
prevalent
cancer
treatments
cause
cell
death
through
DNA
damage.
However,
damage
response
(DDR)
repair
pathways,
initiated
by
tumor
cells,
can
withstand
the
effects
of
anticancer
drugs,
providing
justification
for
combining
DDR
inhibitors
with
DNA-damaging
treatments.
Methods
Cell
viability
assays
were
performed
CellTiter-Glo
assay.
was
evaluated
using
Western
blotting
analysis.
RNA-seq
and
single-cell
level
expression
used
to
identify
signatures.
In
vivo,
studies
conducted
in
mice
determine
effect
ATris
on
TMZ
sensitization.
Results
We
found
a
subpopulation
glioma
sphere-forming
cells
(GSCs)
substantial
synergism
temozolomide
(TMZ)
panel
3
clinical-grade
ataxia-telangiectasia-
Rad3-related
kinase
(ATRis),
(elimusertib,
berzosertib,
ceralasertib).
Interestingly,
synergistic
lines
had
O6-methylguanine-DNA
methyltransferase
(MGMT)
promoter
methylation,
indicating
that
ATRi
mainly
benefits
tumors
no
MGMT
repair.
Further,
activated
ATR-checkpoint
1
(Chk1)
axis
an
MGMT-dependent
way.
caused
ATR-dependent
Chk1
phosphorylation
double-strand
breaks
as
shown
increased
γH2AX.
Increased
decreased
observed
upon
addition
ATRis
MGMT-methylated
(MGMT-)
GSCs.
also
improved
sensitivity
mouse
survival
combination
treatment.
Conclusions
This
research
provides
rationale
selectively
targeting
combination.
Overall,
we
believe
methylation
status
GBM
could
serve
robust
biomarker
patient
selection
combined
TMZ.
Research Square (Research Square),
Год журнала:
2024,
Номер
unknown
Опубликована: Июль 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
towards
ensuring
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,
termed
RPA-DBi,
protein-protein
RPA-PPIi;
both
activities
are
required
activation.
Here,
we
employ
biochemically
reconstituted
demonstrate
RPA-DBi
RPA-PPIi
abrogate
ATR-dependent
phosphorylation
downstream
target
proteins.
post-translational
modifications
(PTMs)
impact
but
do
not
alter
sensitivity
RPAi.
Specifically,
RPA32
TopBP1
stimulate,
while
RPA70
acetylation
has
no
effect
on
Collectively,
work
reveals
RPAi
mechanism
action
inhibit
can
be
regulated
PTMs
offers
insight
into
anti-cancer
activity
targeted
therapeutics.
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.
