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Is copper chelation an effective anti-angiogenic strategy for cancer treatment?
[oral submucous fibrosis]
Angiogenesis
and
the
acquisition
of
an
angiogenic
phenotype
is
important
for
cancer
cell
proliferation
.
Copper
in
an
essential
trace
element
that
participates
in
many
enzymatic
complexes
like
the
cytochrome
c
,
superoxide
dismutase
and
lysyl
oxidase
and
it
is
involved
in
processes
,
like
embryogenesis
,
growth
,
angiogenesis
and
carcinogenesis
.
In
particular
,
its
involvement
in
carcinogenesis
was
described
for
the
first
time
in
oral
submucous
fibrosis
,
where
fibroblasts
produce
large
amounts
of
collagen
in
the
presence
of
copper
.
Copper
's
action
in
carcinogenesis
is
two-fold
:
(
1
)
it
participates
in
reactions
with
an
increased
redox
potential
that
result
in
the
production
of
oxidative
products
and
oxidative
stress
.
Through
this
mechanism
,
copper
may
cause
DNA
mutations
in
the
nucleus
and
mitochondria
or
alterations
to
membrane
phospholipids
,
(
2
)
it
participates
in
angiogenesis
even
in
the
absence
of
angiogenic
molecules
,
as
it
was
reported
for
the
first
time
in
rabbit
cornea
models
with
copolymer
pellets
charged
with
PGE
1
.
Copper
chelation
regimens
like
penicillamine
and
tetrathiomolybdate
are
being
described
in
the
literature
as
having
anti-angiogenic
,
anti-fibrotic
and
anti-
inflammatory
actions
.
Animal
models
of
brain
cancer
that
evaluated
the
anti-angiogenic
properties
of
copper
,
have
proven
evidence
of
the
reduction
of
tumor
's
microvascular
supply
,
tumor
volume
and
vascular
permeability
after
plasma
copper
levels
reduction
.
Interestingly
,
plasma
copper
levels
reduction
was
shown
to
suppress
micrometastases
generation
in
mice
models
of
breast
cancer
.
We
hypothesize
that
copper
chelation
therapy
:
increases
oxidative
stress
in
cancer
cells
to
a
level
that
does
not
allow
survival
because
of
the
reduction
of
anti-oxidative
enzymes
production
.
It
may
also
result
in
inhibition
of
angiogenesis
and
of
the
initiation
of
the
angiogenic
switch
,
because
copper
normally
enhances
endothelial
cell
migration
and
proliferation
,
improves
binding
of
growth
factors
to
endothelial
cells
and
enhances
the
expression
of
angiogenic
molecules
.
Copper
chelation
may
also
reduce
extracellular
matrix
degradation
and
cancer
spread
,
through
reduction
of
MMP-
9
production
and
probably
of
other
collagenases
and
may
inhibit
propagation
of
micrometastases
.
However
,
copper
chelation
therapy
may
enhance
angiogenesis
through
reduction
of
thrombospondin-
1
,
that
results
into
an
increase
in
VEGF-VEGFR
2
complexes
and
a
high
level
of
active
MMP-
9
.
These
hypotheses
help
in
understanding
of
the
anti-angiogenic
action
of
copper
chelation
therapies
and
of
the
complex
network
of
interactions
between
copper
and
other
molecules
involved
in
angiogenesis
.
It
may
also
stimulate
further
research
regarding
differences
in
copper
metabolism
,
the
effects
of
anti-copper
regimens
on
organs
,
the
development
of
resistance
,
and
their
possible
angiogenic
action
through
thrombospondin
expression
reduction
.
Diseases
Validation
Diseases presenting
"of the initiation of the angiogenic switch"
symptom
oral submucous fibrosis
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