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Targeting survival and cell trafficking in multiple myeloma and Waldenstrom macroglobulinemia using pan-class I PI3K inhibitor, buparlisib.
[waldenström macroglobulinemia]
The
phosphatidylinositol-
3
kinase
(
PI
3
K
)
pathway
is
activated
in
multiple
myeloma
(
MM
)
and
Waldenstrom
Macroglobulenima
(
WM
)
,
and
plays
a
crucial
role
in
tumor
progression
and
drug
resistance
.
In
this
study
,
we
characterized
the
role
of
pan-class
I
PI
3
K
inhibition
on
cell
trafficking
and
survival
of
MM
and
WM
cells
.
We
tested
the
effect
of
pan-class
I
PI
3
K
inhibition
by
siRNA
silencing
or
pharmacologic
inhibition
with
buparlisib
on
MM
cell
survival
,
apoptosis
and
cell
cycle
in
vitro
and
tumor
growth
and
mobilization
of
MM
cells
in
vivo
.
We
then
evaluated
buparlisib-dependent
mechanisms
of
induced
MM
cell
mobilization
.
Moreover
,
the
effect
of
buparlisib
on
cell
survival
,
apoptosis
,
and
adhesion
of
WM
cells
to
bone
marrow
stromal
cells
(
BMSCs
)
has
been
evaluated
.
We
showed
that
buparlisib
induced
toxicity
in
MM
cells
,
supported
by
induction
of
apoptosis
and
cell
cycle
arrest
.
Buparlisib
was
also
found
to
reduce
tumor
progression
in
vivo
.
Importantly
,
buparlisib
enhanced
MM
cell
mobilization
in
vivo
which
was
driven
by
decreased
adhesion
of
MM
cells
to
BMSCs
and
increased
chemotaxis
via
up-regulation
of
CXCR
4
expression
.
Similar
to
its
effects
on
MM
cells
,
buparlisib
also
induced
cell
survival
and
apoptosis
,
and
decreased
adhesion
in
WM
cells
.
These
data
highlight
the
critical
contribution
of
class
I
PI
3
K
signaling
to
the
regulation
of
survival
and
cell
dissemination
in
B-
cell
malignancies
.
Am
.
J
.
Hematol
.
89
:
1030
-
1036
,
2014
.
©
2014
Wiley
Periodicals
,
Inc
.
Diseases
Validation
Diseases presenting
"tumor growth"
symptom
adrenal incidentaloma
carcinoma of the gallbladder
cholangiocarcinoma
cowden syndrome
cystinuria
esophageal adenocarcinoma
esophageal carcinoma
esophageal squamous cell carcinoma
hodgkin lymphoma, classical
liposarcoma
lymphangioleiomyomatosis
primary effusion lymphoma
severe combined immunodeficiency
von hippel-lindau disease
waldenström macroglobulinemia
wiskott-aldrich syndrome
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