© 2001 American Heart Association, Inc.
Vascular Biology |
Photodynamic Therapy With Motexafin Lutetium Induces Redox-Sensitive Apoptosis of Vascular Cells
From the Cardiovascular Division (Z.C., C.S., C.R., D.I.S.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; Harvard-M.I.T. Division of Health Sciences and Technology (C.R.), Massachusetts Institute of Technology, Cambridge, Mass; and Pharmacyclics, Inc (K.W.W., D.C.A.), Sunnyvale, Calif.
Correspondence to Daniel I. Simon, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Tower 3, Boston, MA 02115. E-mail dsimon{at}rics.bwh.harvard.edu
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Abstract |
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Abstract—Motexafin lutetium is a photosensitizer that accumulates in atherosclerotic plaque and, after activation by far-red light, produces cytotoxic singlet oxygen. The combination of photosensitizer and illumination, known as photodynamic therapy (PDT), has been shown to reduce atheroma formation in animal models and is under clinical investigation. However, the effects of PDT with motexafin lutetium on isolated vascular cells are unknown. This study was designed to characterize the effects of PDT on vascular cell viability and to define the cell-death pathway for this agent. Fluorescence microscopy of RAW macrophages and human vascular smooth muscle cells revealed time-dependent uptake of motexafin lutetium. Illumination of motexafin lutetium–loaded cells with 732-nm light (2 J/cm2) impaired cellular viability and growth (IC50 5 to 20 µmol/L). Depletion of intracellular glutathione potentiated (P=0.035) and the addition of antioxidant N-acetylcysteine attenuated (P=0.002) cell death, suggesting that the intracellular redox state influences motexafin lutetium action. PDT was associated with the loss of mitochondrial membrane potential, mitochondrial release of cytochrome c, and caspase activation. PDT promoted phosphatidylserine externalization and induced apoptotic DNA fragmentation, with the number of apoptotic cells increasing from 7±2% to 34±3% of total cells. Reducing plaque cellularity by the induction of apoptosis may be one mechanism by which PDT reduces plaque burden, possibly modulates plaque vulnerability, and inhibits restenosis in vivo.
Key Words: apoptosis • photodynamic therapy • vascular cells • reactive oxygen species • atherosclerosis
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Introduction |
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More than 1 million percutaneous coronary intervention procedures are performed annually worldwide to relieve the symptoms of coronary artery disease. Restenosis of the treated segment occurs in 32% to 57% of patients undergoing balloon angioplasty within 6 months of the procedure.1 In the United States,
150 000 cases of restenosis occur annually and
account for one fourth of the total percutaneous
coronary intervention procedures performed, at a cost of >$3
billion.2 By providing rigid
scaffolding, endovascular stents reduce restenosis rates in
select lesions.3 However,
in-stent restenosis remains a recognized clinical problem and
can be expected to increase in incidence as stenting increases in
frequency (>80% of procedures) and is applied to small vessels (ie,
<2.7-mm diameter) and long lesions and in patients with diabetes
mellitus.
Radiation therapy with ionizing (ie, ß- and 
-radiation)
and nonionizing (ie, photon) radiation is under active preclinical and
clinical investigation for the prevention and treatment of
restenosis after percutaneous coronary
intervention. Despite consistent and compelling clinical trial
evidence that intracoronary radiation with ß or sources
is capable of effectively treating in-stent
restenosis,4
significant adverse effects (excessive vascular damage producing
pseudoaneurysms,5
total vessel occlusion,5 or
atherosclerosis6 ;
delayed stent thrombosis7 ; and
the possible risk of neoplasm in surrounding tissues) may limit its
widespread application.
The use of nonionizing light energy may provide an alternative to intracoronary radiation. Photoangioplasty (PA) involves the combined use of a photosensitizing agent that accumulates in the target tissue and endovascular illumination to produce cytotoxic singlet oxygen8 9 for the treatment of primary atherosclerosis (ie, regression and plaque stabilization) and for the prevention and treatment of restenosis. PA is capable of inducing cell death with a variety of photosensitizing agents, including porphycene derivatives, chloroaluminum sulfonated phthalocyanine, photofrin II, 5-amino-levulinic acid, and motexafin lutetium.9 10 11 12 13 14 15 However, the relative contributions of apoptosis and necrosis are dependent on the cell line or target tissue, photosensitizing agent, and experimental conditions. PA is an experimental therapy with unproven clinical benefit that is currently under phase I and II clinical investigation.
We have identified an apoptotic cell-death pathway
promoted by photodynamic therapy (PDT) with motexafin lutetium in
macrophages and smooth muscle cells (SMCs). This
redox-sensitive pathway involves loss of mitochondrial membrane
potential (
m) and the release of
cytochrome c from mitochondria
to the cytosol, thereby triggering caspase activation and initiation of
the apoptotic program.
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Methods |
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Materials
Motexafin lutetium16 formulated in 5% mannitol at a concentration of 2 mmol/L was obtained from Pharmacyclics, Inc. WST-1 cell viability reagent was obtained from Roche Molecular Biochemicals. 5,5',6,6'-Tetrachloro-1,1'3,3'-tetraethylbenzimidazolcarbocyanine iodide (JC-1) and fluorescent probes for staining mitochondria (MitoTracker Green), lysosomes (LysoTracker red), endoplasmic reticulum (rhodamine B, hexyl ester), and the nucleus (Hoechst 33342) were purchased from Molecular Probes. zVAD-fmk was purchased from Enzyme Systems, Inc. Antibody to cytochrome c was from Santa Cruz Biotechnology, Inc. All other reagents were obtained from Sigma Chemical Co.
Cell Lines and Culture Conditions
Murine macrophages (RAW cells, American Type
Culture Collection) and low-passage (passages 2 to 4) human saphenous
vein SMCs were maintained in DMEM supplemented with 10% FBS, 2
mmol/L glutamine, 25 mmol/L HEPES, penicillin, and
streptomycin.
Cellular Motexafin Lutetium Loading and
Illumination
RAW cells and SMCs were grown to confluence, washed
with serum-free medium, and then incubated with motexafin lutetium (0
to 100 µmol/L) or 5% mannitol vehicle diluted in serum-free medium
containing 0.5% BSA in 5% CO2 at 37°C. In
experiments examining the effect of intracellular antioxidants on
viability,
L-buthionine-[S,R]-sulfoximine
(BSO, 10 to 100 µmol/L) or
N-acetylcysteine (NAC, 10
mmol/L) was added 18 hours before illumination or at the time of
addition of exogenous ceramide. After 18 hours, motexafin
lutetium–containing or vehicle-containing media were removed, and
cells were washed with sterile PBS and then illuminated in a darkened
room with a 732-nm diode laser (Diomed) and microlens (Pioneer Optics)
at a fluence rate of 5 mW/cm2 to achieve a
total fluence of 2 J/cm2. After
illumination, PBS was removed, and serum-containing medium was
added.
Fluorescence Microscopy
Motexafin lutetium (10 µmol/L) was added to the
cells and incubated for 2 to 72 hours. Fluorescence uptake
analysis and colocalization studies using specific organelle
probes were performed as previously
described.17
Viability Assays
Cellular viability and growth were assessed by using
a colorimetric assay based on mitochondrial
dehydrogenase cleavage of WST-1 reagent (Roche Molecular Biochemicals)
according to the manufacturer’s protocol. Briefly, RAW
macrophages and SMCs (3x104 cells
per well) seeded in 96- and 24-well tissue culture plates,
respectively, were incubated with motexafin lutetium overnight in 5%
CO2 at 37°C. Ceramide-induced
apoptosis was assessed by incubating cells overnight with the
synthetic compound C2-ceramide (40 µmol/L). Twenty-four hours after
illumination, WST-1 solution was added to cells (1:10 [vol/vol]) and
incubated in 5% CO2 at 37°C for 1 hour. An
aliquot (100 µL) was removed to measure optical density at 450 nm. In
untreated cells, optical density at 450 nm represented
100% viability; color formation of WST-1 added to medium alone
represented 0% viability. Percent viability for the
indicated treatment groups was calculated by fitting a linear
regression line between these values.
Flow Cytometric Analysis of Cell Cycle
Status and Apoptosis
DNA fragmentation was used as an indicator of
apoptosis. Cellular DNA content was quantified by using
propidium iodide (PI) staining of ethanol-fixed RAW cells and flow
cytometry (FACScan, Becton-Dickinson), as previously
described.18
Apoptosis Assessment by Annexin V
Staining
Apoptosis was also assessed by use of annexin
V staining.19 At indicated
times after illumination, cells were washed in PBS and resuspended in
staining solution containing fluorescein annexin V and PI
(Apoptosis Detection Kit, Alexis Biochemicals), according to
the manufacturer’s protocol. In experiments performed to evaluate the
role of caspases in cell death induced by PA with motexafin lutetium,
the broad-spectrum caspase inhibitor zVAD-fmk was added to
the cells 1 hour before illumination. Cells were analyzed by
flow cytometry, and staining was expressed as percent positive
cells.
Measurement of m
by Flow Cytometry
m was measured by
incubating macrophages (106/mL) with
10 µg/mL JC-1 in culture medium at 37°C for 10 minutes in the dark,
as previously described.20
Samples were treated in parallel with the 50 µmol/L carbonyl
cyanide m-chlorophenylhydrazone
(mClCCP), added 15 minutes before JC-1, to depolarize
m as a positive control. The percentage of
cells with JC-1 aggregates and monomers was calculated by quadrant
statistical analysis of FL1 and FL2, respectively.
Quadrant boundaries were set with reference to a parallel sample
stained in the presence of mClCCP.
Cytochrome
c Release
Release of cytochrome
c from mitochondria was
assessed as previously
described.21 Samples (30 µg
protein per lane) were subjected to 15% SDS-PAGE under reducing
conditions and then blotted onto nitrocellulose. Cytochrome
c was detected with a
polyclonal antibody from Santa Cruz Biotechnology, and tubulin was
detected with a monoclonal antibody from Sigma.
Statistical Analysis
All data are presented as the mean±SD.
Groups were compared by the nonpaired
t test. A value of
P<0.05 was considered
significant.
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Results |
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Cellular Accumulation and Subcellular Localization of Motexafin Lutetium
We assessed the accumulation and subcellular localization of motexafin lutetium by using fluorescence microscopy. The signature fluorescence emission band of motexafin lutetium is centered at 750 nm and was used to monitor real-time biolocalization within RAW macrophages and human SMCs. A time-dependent increase in intracellular motexafin lutetium fluorescence was seen in both cell types. The temporal uptake of macrophages is shown in online Figure
I (please see
www.ahajournals.org).
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Subcellular localization of motexafin lutetium in
macrophages and SMCs was determined by using organelle-specific
fluorescent probes. Online Figure
I illustrates typical
localization patterns for SMCs after incubation with motexafin lutetium
for 24 hours. Colocalization of motexafin lutetium within intracellular
organelles was determined by using interferometric Fourier
spectroscopy. Fluorescence spectra were acquired, with
fluorescence emission profiles obtained at every pixel.
Intracellular biolocalization showed overlay of the photosensitizer
(750 nm) with the emission maxima of the organelle fluorophore for
lysosomes (600 nm), endoplasmic reticulum (586 nm), and
mitochondria (532 nm); see online Figure I. Motexafin lutetium was
mainly localized within the lysosomes and endoplasmic reticulum
and, to a lesser extent, within the mitochondria.
Effect of Motexafin Lutetium on Cellular
Viability and Growth
Illumination of motexafin lutetium–loaded cells with
732-nm light, delivered at a fluence rate of 5
mW/cm2 to achieve a total fluence of 2
J/cm2, resulted in significant morphological
changes in macrophages and SMCs (online Figure II; see
www.ahajournals.org) and impaired macrophage viability and
growth (IC50 20 µmol/L), reducing viability
by up to 90% at 100 µmol/L
(Figure 1). PDT also reduced human SMC viability
(IC50 5 µmol/L); see online Figure III
(www.ahajournals.org). Induction of cell death required the combination
of motexafin lutetium and light, inasmuch as neither drug nor light
alone had significant effects on cellular
viability.
Intracellular Redox State Influences Effect of
Motexafin Lutetium on Cellular Viability
Because atherosclerosis is associated
with enhanced oxidative stress and the depletion of intracellular
antioxidants,22 23
we explored the effect of altering the intracellular redox state on
PDT-induced cell death by depleting intracellular glutathione stores
with the use of BSO. BSO is a specific inhibitor of
-glutamyl cysteine synthetase, and treatment of cells with this
agent results in glutathione
depletion.24 BSO potentiated
the effect of motexafin lutetium on macrophage viability
(IC50 1 µmol/L,
Figure 1). BSO alone had no effect on macrophage
viability. Moreover, treatment of the cells with the antioxidant NAC
significantly reduced cell death induced by PDT
(Figure 1, insert). We compared the effects of BSO and NAC in
a non-PDT apoptotic pathway. Ceramide may act as a second
messenger in signaling for apoptosis induced by tumor necrosis
factor-
and Fas.25 In
contrast to PDT, macrophage apoptosis induced by
exogenous C2-ceramide was largely unaffected by treatment with BSO or
NAC (online Figure IV; see www.ahajournals.org). Taken together, these
observations suggest that apoptosis initiated by PDT is redox
sensitive and that distinct signaling cascades may be operative in PDT
compared with certain non-PDT pathways.
Motexafin Lutetium–Induced Apoptotic
Cell Death in Macrophages and SMCs
The mechanism of cell death induced by PDT with
motexafin lutetium was examined by using annexin V staining of
macrophages and SMCs. Annexin V binds membrane-associated
phosphatidylserine (PS), which is located in the
inner phospholipid bilayer but is externalized rapidly to the cell
surface (ie, outer lipid bilayer) in the apoptotic process.
Because translocation/exposure of PS also occurs during necrosis,
annexin V–FITC is used in conjunction with PI to distinguish
apoptotic (annexin V–FITC positive, PI negative) from necrotic
cells (annexin V–FITC positive, PI positive). PDT increased the number
of apoptotic macrophages 4.2±1.2-fold (mean±SD, n=4;
Figure 2) and the number of apoptotic SMCs
4.0±1.9-fold (n=3). The percentage of necrotic cells did not increase
from baseline after PDT
(Figure 2).
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Induction of apoptosis was also confirmed by
staining the cells with PI and analyzing DNA content by flow cytometry.
PDT with motexafin lutetium induced apoptotic DNA
fragmentation, with the number of apoptotic cells increasing
from 7±2% to 34±3% of total cells
(Figure 3).
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Mitochondrial Membrane Depolarization and
Cytochrome c Release Is
Associated With Motexafin Lutetium Action
The very short lifetime of singlet oxygen generated by
PDT and our observation that motexafin lutetium accumulates in the
mitochondria led us to consider the possibility that cytotoxicity to
mitochondria was likely an upstream event in motexafin lutetium action.
m is necessary for the supply of energy by
the mitochondrion, and loss of m is
associated with cells undergoing apoptosis. To investigate
whether PDT with motexafin lutetium resulted in a loss of
m, macrophages were incubated with
the potential sensitive fluorescent probe JC-1, which undergoes
a molecular aggregation and shift in fluorescence from green to
red-orange at high membrane potentials. Loss of
m results in a decrease in red-orange
fluorescence, as visualized in online Figure V (see
www.ahajournals.org), by incubating macrophages with the mClCCP
as a positive control (83% depolarized cells). PDT with motexafin
lutetium resulted in a time-dependent loss of
m (20% depolarized cells at 30 minutes,
47% at 60 minutes).
Cytochrome c, a
component of the mitochondrial electron-transfer chain that is
present in the intermembrane space, is released into the cytosol
during the early phases of
apoptosis.26
Therefore, we assayed the accumulation of mitochondrial cytochrome
c into the cytosol after PDT by
Western blot analysis of cytosolic extracts prepared under
conditions that keep mitochondria intact. As shown in
Figure 4, cytosol from untreated macrophages or
macrophages loaded with motexafin lutetium, but not
illuminated, contained no cytochrome
c. In contrast, cytochrome
c accumulated in the cytosol of
macrophages after PDT with motexafin lutetium.
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In many apoptotic systems, release of cytochrome
c into the cytosol results in
the activation of the executioner caspases of apoptosis. To
determine whether caspase activation is needed for the
apoptotic program after PDT with motexafin lutetium, the effect
of the broad-spectrum caspase inhibitor zVAD-fmk on PS
externalization was examined. zVAD-fmk reduced dose-dependently
the percentage of apoptotic macrophages, as determined
by annexin V staining after PDT with motexafin lutetium, from 49% to
23% (25 µmol/L zVAD-fmk) and 11% (50 µmol/L zVAD-fmk)
(Figure 2).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
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In the present study, we have identified a cell-death pathway induced by PDT with motexafin lutetium in vascular cells. This redox-sensitive pathway involves the loss of
m, release of cytochrome
c from mitochondria to the
cytosol, and activation of caspases that trigger apoptosis.
This mode of cell death may be central to the proposed clinical use of
PDT to prevent and treat restenosis or as a primary
atherosclerotic plaque–ablating therapy, allowing for vascular cell
dropout without promoting an inflammatory response. Several groups have reported that PDT can induce cell death with a variety of photosensitizing agents, including porphycene derivatives, chloroaluminum sulfonated phthalocyanine, photofrin II, and 5-amino-levulinic acid.10 11 12 13 14 15 However, the relative contributions of apoptosis and necrosis are dependent on the cell line, photosensitizing agent, and/or experimental conditions. We demonstrated that singlet oxygen–generating motexafin lutetium induced apoptotic cell death, that glutathione depletion potentiated cell death, and that the antioxidant NAC attenuated cell death. Taken together, these findings suggest that PDT with motexafin lutetium induced apoptosis in a redox-sensitive manner. There is mounting evidence that many agents that induce apoptosis act either as oxidants or stimulators of cellular oxidative metabolism.27 28 29 30 Reactive oxygen species (ROS) serve as important signal transduction molecules in apoptosis induced by UV light,31 ionizing radiation,32 anthracyclines,33 and arsenic.18 Scavenging ROS, either by antioxidants34 or overexpression of phospholipid hydroperoxide glutathione peroxidase,35 suppress apoptosis, providing additional evidence that ROS act as signaling intermediates in programmed cell death.
Mitochondria play a central role in programmed cell
death.36 Mitochondrial
respiration generates a major physiological source
of ROS, and activators of apoptosis (eg, caspase-2,
caspase-9, cytochrome c, and
apoptosis-inducing factor) reside in mitochondria.
Mitochondria-derived ROS may signal apoptosis by modifying
membrane proteins, such as a large-conductance channel known as
permeability transition pore, to modulate
m37
or by activating downstream targets such as stress-activated
protein kinase cascades.38
Mitochondria also contain proteins that regulate apoptosis,
such as Bcl-2, Bcl-xL, Bax, and Bad, which can prevent or accelerate
programmed cell death. In the present study, we have shown that PDT
with motexafin lutetium results in the loss of
m, release of cytochrome c from
mitochondria to the cytosol, and activation of caspases that trigger
apoptosis. The precise mechanism by which PDT with motexafin
lutetium is linked to these mitochondrial events remains to be
determined and is the focus of ongoing studies.
The influence of redox state on apoptosis may have
important implications for the clinical use of motexafin lutetium.
Motexafin lutetium and other photosensitizers accumulate in
atherosclerotic vessels more than in normal vessels, probably secondary
to photosensitizer binding to
lipoproteins.39 40 41 42
Atherosclerotic vessels are associated with oxidative
stress22 43 and
with the depletion of key intracellular antioxidants such as
glutathione.23 In the
present study, treatment of macrophages with the
glutathione-depleting agent
BSO24 potentiated the effect
of motexafin lutetium on macrophage viability 20-fold.
Therefore, enhanced susceptibility of oxidatively stressed tissues may
provide an additional mechanism by which the actions of motexafin
lutetium may be relatively selective for atherosclerotic compared with
normal vessels.
It is important to note that the vascular effects of PDT are not limited to apoptosis but extend to other important biological processes, including SMC migration, proliferation, and extracellular matrix production.9 PDT has been shown to modulate cytokine release or activation44 and growth factor responses45 that promote vascular growth. Numerous studies reporting the effectiveness of PDT in inhibiting neointimal hyperplasia after experimental angioplasty13 46 47 48 49 attest to the importance of these nonapoptotic effects of PDT, given prior observations that neointimal SMCs may be more resistant to apoptosis than medial SMCs secondary to neointimal upregulation of antiapoptotic genes.38
Study Limitations
Although we have demonstrated that
mitochondria-dependent apoptosis is a mode of cell death after
light treatment of motexafin lutetium–loaded cells, the significance
of motexafin lutetium accumulation and singlet oxygen generation within
lysosomes and endoplasmic reticulum is unknown. ROS have been
implicated in the translocation of Bax and Bad from the cytosol to the
mitochondria, where these factors form heterodimers with Bcl-2 and
induce cytochrome c
release.50 The experimental
conditions for cellular motexafin lutetium exposure and illumination in
the present in vitro study have been designed intentionally to
mimic the clinical PA procedure under phase I and II investigations
with respect to drug and light doses. Nonetheless, we cannot rule out
alternative cell-death pathways (ie, necrosis) in vivo that are due to
complex issues relating to drug distribution/localization, light
delivery, and tissue penetration. A blood field is not expected to
attenuate the tissue ablative capacity and clinical efficacy of PA with
motexafin lutetium because it is activated by blood- and
tissue-penetrating far-red (732 nm)
light.9
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Conclusions |
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We have identified a redox-sensitive apoptotic cell-death pathway promoted by PA with motexafin lutetium in vascular cells. PA is an experimental therapy with unproven clinical benefit. Further studies clarifying the mechanisms of PA action will help to guide photosensitizer and light treatment–delivery protocols to optimize clinical efficacy.
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Acknowledgments |
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This work was supported in part by grants from the National Institutes of Health (HL-57506 and DK-55656 to D.I.S. and HL-03104 to C.R.) and by unrestricted research grants from Pharmacyclics, Inc, to D.I.S. and C.R. D.I.S. and C.R. serve as scientific consultants to Pharmacyclics, Inc. The authors would like to thank Dr Wai-Fung Cheong for expert assistance in the endovascular illumination protocol.
Received January 3, 2001; accepted January 18, 2001.
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