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AT-101 downregulates BCL2 and MCL1 and potentiates the cytotoxic effects of lenalidomide and dexamethasone in preclinical models of multiple myeloma and Waldenström macroglobulinaemia.
[waldenström macroglobulinemia]
Multiple
myeloma
,
the
second
most
common
haematological
malignancy
in
the
U
.
S
.
,
is
currently
incurable
.
Disruption
of
the
intrinsic
apoptotic
pathway
by
BCL
2
and
MCL
1
upregulation
is
observed
in
>
80
%
of
myeloma
cases
and
is
associated
with
an
aggressive
clinical
course
.
Remarkably
,
there
is
no
approved
drug
with
the
ability
to
target
BCL
2
or
MCL
1
.
Thus
,
we
investigated
the
anti-tumour
effects
of
a
pan-
BCL
2
inhibitor
,
AT-
101
,
which
has
high
binding
specificity
for
BCL
2
and
MCL
1
in
preclinical
models
of
plasma
cell
cancers
(
Multiple
myeloma
and
Waldenström
macroglobulinaemia
)
.
Gene
expression
and
immunoblot
analysis
of
six
plasma
cell
cancer
models
showed
upregulation
of
BCL
2
family
members
.
AT-
101
was
able
to
downregulate
BCL
2
and
MCL
1
in
all
plasma
cell
cancer
models
and
induced
apoptotic
cell
death
in
a
caspase-dependent
manner
by
altering
mitochondrial
membrane
permeability
.
This
cytotoxic
effect
and
BCL
2
downregulation
were
further
potentiated
when
AT-
101
was
combined
with
lenalidomide
/
dexamethasone
(
LDA
)
.
NanoString
nCounter
mRNA
quantification
and
Ingenuity
Pathways
Analysis
revealed
differential
changes
in
the
CCNA
2
,
FRZB
,
FYN
,
IRF
1
,
PTPN
11
genes
in
LDA
-treated
cells
.
In
summary
,
we
describe
for
the
first
time
the
cellular
and
molecular
events
associated
with
the
use
of
AT-
101
in
combination
with
lenalidomide
/
dexamethasone
in
preclinical
models
of
plasma
cell
malignancy
.
Diseases
Validation
Diseases presenting
"the second most common haematological malignancy in the u"
symptom
waldenström macroglobulinemia
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