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D-Penicillamine targets metastatic melanoma cells with induction of the unfolded protein response (UPR) and Noxa (PMAIP1)-dependent mitochondrial apoptosis.
[cystinuria]
D-Penicillamine
(
3
,
3
-
dimethyl-
D-
cysteine
;
DP
)
is
an
FDA-approved
redox-active
D-
cysteine-derivative
with
antioxidant
,
disulfide-reducing
,
and
metal
chelating
properties
used
therapeutically
for
the
control
of
copper-related
pathology
in
Wilson
's
disease
and
reductive
cystine-solubilization
in
cystinuria
.
Based
on
the
established
sensitivity
of
metastatic
melanoma
cells
to
pharmacological
modulation
of
cellular
oxidative
stress
,
we
tested
feasibility
of
using
DP
for
chemotherapeutic
intervention
targeting
human
A
375
melanoma
cells
in
vitro
and
in
vivo
.
DP
treatment
induced
caspase-dependent
cell
death
in
cultured
human
metastatic
melanoma
cells
(
A
375
,
G
361
)
without
compromising
viability
of
primary
epidermal
melanocytes
,
an
effect
not
observed
with
the
thiol-antioxidants
N-
acetyl-
L-
cysteine
(
NAC
)
and
dithiothreitol
.
Focused
gene
expression
array
analysis
followed
by
immunoblot
detection
revealed
that
DP
rapidly
activates
the
cytotoxic
unfolded
protein
response
(
UPR
;
involving
phospho-
PERK
,
phospho-e
IF
2
α
,
Grp
78
,
CHOP
,
and
Hsp
70
)
and
the
mitochondrial
pathway
of
apoptosis
with
p
53
upregulation
and
modulation
of
Bcl-
2
family
members
(
involving
Noxa
,
Mcl-
1
,
and
Bcl-
2
)
.
DP
(
but
not
NAC
)
induced
oxidative
stress
with
early
impairment
of
glutathione
homeostasis
and
mitochondrial
transmembrane
potential
.
SiRNA-based
antagonism
of
PMAIP
1
expression
blocked
DP-induced
upregulation
of
the
proapoptotic
BH
3
-
only
effector
Noxa
and
prevented
downregulation
of
the
Noxa-antagonist
Mcl-
1
,
rescuing
melanoma
cells
from
DP-induced
apoptosis
.
Intraperitoneal
administration
of
DP
displayed
significant
antimelanoma
activity
in
a
murine
A
375
xenograft
model
.
It
remains
to
be
seen
if
melanoma
cell-directed
induction
of
UPR
and
apoptosis
using
DP
or
improved
DP-derivatives
can
be
harnessed
for
future
chemotherapeutic
intervention
.
Diseases
Validation
Diseases presenting
"an effect not observed with the thiol-antioxidants n-acetyl-l-cysteine"
symptom
cystinuria
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