Nitric oxide-releasing platinum(iv) prodrug efficiently inhibits proliferation and metastasis of cancer cells

Article abstract of DOI:10.1039/d0cc05422d

A dual-functional Pt(iv) prodrug, Pt-furoxan, can release cytotoxic cisplatin and signaling molecule NO upon cellular internalization. NO modulates the cellular response towards cisplatin, leading to a synergistic anti-proliferation effect and a promising

Full text of DOI:10.1039/d0cc05422d

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DOI: 10.1039/D0CC05422D
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Nitric Oxide-releasing Platinum(IV) Prodrug Efficiently Inhibits
Proliferation and Metastasis of Cancer Cells
Received 00th January 20xx,
Accepted 00th January 20xx
a,b‡
a‡
*a
a
a
a
c
Yi Dai , Yang Zhu , Junjie Cheng , Juan Shen , Hai Huang , Manman Liu , Zhaolin Chen and
*a
Yangzhong Liu
DOI: 10.1039/x0xx00000x
A dual-functional Pt(IV) prodrug, Pt-furoxan, can release cytotoxic instability and inconvenient administration. Therefore, various
cisplatin and signaling molecule NO upon cellular internalization. NO donors have been explored and some of them have been
10
NO modulates the cellular response to cisplatin, leading to used in clinic, such as nitroglycerin, isosorbide nitrate. The
synergistic anti-proliferation effect and promising anti-metastasis combination of NO donors can improve the therapeutic effect
11
effect both in vitro and in vivo.
of many antitumor agents, including platinum-based drugs.
Inspired by these findings, we designed anti-metastasis Pt(IV)
Platinum drugs, such as cisplatin, are widely used in clinic for prodrug by incorporating a furoxan-based NO donor. Furoxan
cancer chemotherapy; they induce apoptosis of tumor cells by is a reducing-responsive agent; it is stable in a range of
10
cross-linking DNA, hence inhibit proliferation of tumors. The temperature and pH conditions; however, it can be activated
combination with other chemotherapeutic agents, such as by reducing agents, such as glutathione (GSH) and cysteine
12
paclitaxel, gemcitabine and vinorelbine, can further enhance (Cys), leading to the release of NO. Therefore, the resulting
1
the drug efficacy of cisplatin. However, recent researches platinum complex, Pt-furoxan is stable during the drug
indicate that chemotherapeutic drugs, including platinum- administration since platinum(IV) complexes are kinetically
2
13
based drugs, could also stimulate metastasis of cancer. Cancer more inertness than platinum(II) complexes. Upon cellular
metastasis is responsible for 90% of cancer related patient internalization, Pt-furoxan can simultaneously release two
3
deaths, especially metastasis of breast cancer. Therefore, active components, cisplatin and NO (Scheme S1), as GSH and
14
exploring the novel platinum drugs with dual-function of anti- ascorbic acid exist high level in cancer cells. The cisplatin
proliferation and anti-metastasis is highly desired. Particularly, inhibits the proliferation of cancer cells, while NO prevents the
Pt(IV) prodrugs offer an opportunity to attach bioactive tumor metastasis.
molecules that could modulate the therapeutic function of
platinum drugs.
The synthesis of Pt-furoxan is described in Figure S1. Briefly,
two intermediates, 3-(hydroxymethyl)-4-phenyl-1,2,5-
4
Nitric oxide (NO) is the first found gaseous signaling oxadiazole 2-oxide and c,c,t-[Pt(NH ) Cl (OCOCH CH COOH) ],
3
2
2
2
2
2
11d, 15
molecule involved in various physiological and pathological were synthesized according to literature.
processes. Although low level of NO (100-500nM) is necessary these two compounds was achieved using N,N'-
for cell proliferation and metastasis, high level of NO (>500 dicyclohexylcarbodiimide (DCC) as dehydrating agent and 4-
The ligation of
5
6
nM) tends to be cytotoxic and induce apoptosis of cancer dimethylaminopyridine (DMAP) as catalyst, which generated
7
8
cells. Therefore, NO could sensitize tumor chemotherapy.
the product Pt-furoxan. These compounds were characterized
1
13
195
Interestingly, NO is also found to effectively inhibit the by H-NMR, C-NMR, Pt-NMR and ESI-MS (Figures S2-S8).
migration and invasion of cancer cells, and interfere with
hetero-adhesion of cancer cells to vascular endothelium.
9
Gaseous NO is hardly used in therapeutics due to the
Figure 1. Structures of Pt-furoxan complex, furoxan ligand, oxoplatin and cisplatin.
The NO release from Pt-furoxan in PBS was investigated by
Griess assay in the presence of cysteine (Figure S9-10). In

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more potent than cisplatin to all tumor cells. EnVicewouArrtaicgleinOgnllinye,
15-16
agreement with literatures,
the free furoxan ligand (2)
alone was rather stable and no detectable NO release was two breast cancer cells (MCF-7 and 4T1)DeOxI:h1i0b.i1t0e3d9/sDig0nCiCfi0c5a4n2t2lDy
observed in 72 h. In comparison, 73.8% NO release was higher sensitivity to Pt-furoxan than to cisplatin (15.6 and 19.4
observed from
confirming the thiol-trigged NO release of the furoxan ligand. only marginal cytotoxicity (Figure S13); while the simple
Pt-furoxan yielded 35.0% NO release in the same condition. mixture of did not enhance the cytotoxicity of oxoplatin.
The lower NO release in the Pt complex could be associated The apoptosis induced by platinum complexes was analyzed
with its bulky structure and the less hydrophilicity; this NO using flow cytometry. After treatment of platinum complexes
2 in the presence of cysteine in 72 h (Figure 2A), folds decrease of IC , respectively). The free ligand 2 showed
50
2
1
5
release rate is comparable to the furoxan derivatives.
for 24 h or 48 h, cells were stained with annexin V-FITC and
The NO release from Pt-furoxan in cells was analyzed by propidium iodide (PI). The results showed that Pt-furoxan
fluorescence imaging using a NO probe DAF-FM DA. Weak caused significantly higher apoptosis than cisplatin or
fluorescence was observed in the cells incubated with DAF-FM oxoplatin; while the mixture of free ligand
2 demonstrated
DA, showing the low concentration of intrinsic NO on cells only marginal effect on apoptosis induced by cisplatin or
17
(
Figure 2B). By comparison, the treatment of Pt-furoxan oxoplatin (Figure S14A). Moreover, Pt-furoxan decreased
clearly enhanced the fluorescence in cells, indication the mitochondrial membrane potential ( ψm) more significantly
release of NO from Pt-furoxan in cells (Figure 2B). Pt-furoxan than free ligand , cisplatin, oxoplatin or the mixture of

2
2
itself did not show fluorescence (Figure S11). In addition, flow (Figure S15), indicating that Pt-furoxan induces cell apoptosis
cytometry measurement was applied on the cells treated with while disrupting mitochondrial membrane. In addition, flow
DAF-FM DA. The result confirmed that Pt-furoxan led to more cytometry measurement confirmed that Pt-furoxan S-phase
NO release in cells than oxoplatin or its mixture with free
2
cell cycle arrest was similar to cisplatin, in agreement with the
(Figure 2C). It is worth noting that higher NO release was DNA damage induced cell apoptosis by platinum complexes
observed from Pt-furoxan than from free ligand
2 in cells, (Figure S14B). These data indicate that the enhanced apoptosis
although
2 caused more NO-release in solution based on caused by Pt-furoxan attributed to the high cytotoxicity of the
Greiss assay. This difference is probably due to the different compound.
cellular uptake of two compounds. On the other hand, the
reduction and activation of Pt-furoxan by ascorbic acid was
assessed by DNA platination assay (Figure S12).
A
B
120
100
80
Control
Oxoplatin
Oxoplatin+2
Cisplatin
Cisplatin+2
Pt-furoxan
9000
Oxoplatin
Oxoplatin+2
Cisplatin
Cisplatin+2
Pt-furoxan
*
*
8000
60000
50000
40000
Control
2
Oxoplatin+2
Pt-furoxan
150
100
50
60
A 100
C
Pt-furoxan+L-cys
4
0
0
0
2+L-cys
*
80
60
40
20
0
2
2
PTIO
-
+
-
25
+
-
25
+
-
25
+
-
+
-
+
0
3
0000
0000
Pt (M)
-
25
2.5
Figure 3. (A) Cellular accumulation of platinum complexes. Platinum in HepG2 cells
were measured using ICP-MS after 4 h treatment of 100 μM platinum complexes. (D)
Effects of PTIO on the anti-proliferation of HepG2 cells. After pre-treatment of HepG2
cells with 300 μM of PTIO for 1 h, the cells were treated with 2.5 μM Pt-furoxan or 25
μM other platinum complexes. *p<0.05, **p<0.01, ***p<0.001. Two molar equivalents
of 2 was used alone or in the mixture of all assays.
2
0
10 20 30 40 50 60 70 80 (h) 10000
B
Bright
DAF-FM-DA
Merge
To explore the mechanism of enhanced cytotoxicity of Pt-
furoxan, the cellular accumulation of Pt-furoxan and the effect
of NO release were further investigated. The platinum
accumulation was evaluated by measuring platinum in cells
using ICP-MS after incubation of cells with different platinum
agents for 4 h. The result showed that the accumulation of Pt-
1
00μm
1
00μm
Figure 2. NO release from Pt-furoxan in vitro. (A) Time dependent NO release from Pt- furoxan in cells was significantly higher than that of cisplatin
furoxan (250 μM) and furoxan (500 μM) in the presence or absence of L-cysteine (5
mM) at 37°C. (B) Fluorescence imaging of NO in HepG2 cells. HepG2 cells were co-
incubated with 5 μM of Pt-furoxan for 24 h, stained with DAF-FM-DA probe and
(
Figure 3A), indicating the covalent conjugation of 2 to Pt(IV)
complex in favor of internalization of
2 and oxoplatin by cells.
observed using fluorescence microscope. (C) NO released from Pt-furoxan, furoxan and The high cellular accumulation could be associated with the
its mixture with oxoplatin in HepG2 cells. HepG2 cells were co-incubated with 5 μM of
these platinum complexes (the mole ratio of platinum/2 = 1:2 in mixture, or 10 μM of 2)
prominent cytotoxicity of Pt-furoxan.
To verify the effect of NO release on the cytotoxicity of Pt-
furoxan, cells were pretreated with 300 μM NO scavenger
PTIO for 1 h before drug treatment. The pretreatment of PTIO
for 24 h, stained with DAF-FM-DA probe and measured using flow cytometry. *p<0.05,
*p<0.01.
*
The in vitro cytotoxicity of Pt-furoxan was evaluated using increased cell viability by 35.9% in the Pt-furoxan group,
MTT assay on five human cancer cells (hepatocellular whereas no effect was observed on the viability of cells
carcinoma HepG2, cervical cancer HeLa, lung carcinoma A549, treated with other compounds (Figure 3B). These findings
ovarian cancer A2780 and breast carcinoma MCF-7 cells) and indicate that the NO released from Pt-furoxan indeed
mouse breast cancer 4T1 cells (Table S1). The half maximal
inhibitory concentrations (IC ) indicate that Pt-furoxan is
50
2
| Chem. Commun., 2012, 00, 1-3
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contributes, at least partially, to its enhanced cytotoxicity to clearly indicates the adhesion of 4T1 cells to HUVVEieCwsA,rwtichleiOchnlinise
DOI: 10.1039/D0CC05422D
consistent with the high metastasis of 4T1 cells. The treatment
tumor cells.
Since NO is able to inhibit the motility of cancer cells, the of cisplatin, oxoplatin or the mixture of oxoplatin and
2
anti-metastasis effect of Pt-furoxan was evaluated with marginally reduced the adhesion of 4T1 cells on the plate
wound-healing assay on highly metastatic 4T1 cells. The (Figure 4B, Figure S17A). By comparison, only a few 4T1 cells
photographic imaging showed that the gap on the monolayer were observed on the plate after Pt-furoxan treatment. This
cells gradually recovered with time in 24 h to 48 h, showing result clearly indicates that Pt-furoxan is able to inhibit the IL-
the migration of the cells. Pt-furoxan clearly inhibited the cell 1β-induced adhesion of tumor cells to vascular endothelial
migration, whereas cisplatin, oxoplatin and its mixture with
2
cells, which is consistent with the anti-metastasis effect of Pt-
showed negligible effect (Figure 4A). Moreover, the furoxan.
pretreatment of PTIO restored the cell migration that was
The in vivo antitumor and anti-metastasis activities of Pt-
inhibited by Pt-furoxan (Figure S16), indicating that the NO furoxan were evaluated on 4T1 tumor bearing mice. The
release contributed to the anti-metastasis effect of Pt-furoxan. growth and pulmonary metastasis of breast cancer were
It has been reported that NO could down-regulates MMP, measured. Pt-furoxan and testing compounds were
18
the enzyme promoting metastasis of cancer cells. To administered via intravenous injection. The tumor growth
exploring the mechanism of anti-metastasis of Pt-furoxan, the curves showed that Pt-furoxan exerted higher antitumor effect
activity of MMP2 and MMP9 were analyzed using gelatin than cisplatin; even half Pt dosage of Pt-furoxan inhibited the
zymography. Pt-furoxan significantly inhibited the activity of tumor growth more effectively than cisplatin (Figure 5A). The
MMP 9 and MMP2
mixture with compound
Figure S17B). This observation suggests that inhibition of stain showed that Pt-furoxan caused apoptosis of tumor in a
MMP9 and MMP2 is associated with the anti-metastasis dose-dependent manner (Figure S19). Consistent with the
，
while other platinum complexes and their tumor weight and imaging at the end of the treatment
2
did not alter the function of MMPs confirmed this result (Figure 5B, 5D, and S18). Moreover, H&E
(
function of Pt-furoxan.
tumor inhibition result, even half platinum dosage of Pt-
furoxan induced more intensive apoptosis than cisplatin or the
Control
Oxoplatin Oxoplatin+2
Cisplatin Pt-furoxan
mixture of oxoplatin with furoxan
the high in vivo antitumor potency of Pt-furoxan.
2. These results confirmed
A
0
2
h
1
2
0
8
6
4
2
0
A
PBS
C 25
1
Oxoplatin+2 (2 mg/kg)
Cisplatin (2 mg/kg)
Pt-furoxan (1 mg/kg)
Pt-furoxan (2 mg/kg)
4 h
20
PBS
15
Oxoplatin+2 (2 mg/kg)
Cisplatin (2 mg/kg)
Pt-furoxan (1 mg/kg)
Pt-furoxan (2 mg/kg)
10
5
48 h
0
2
4
6
8
10
12
14
0
2
4
6
8
10
12
14
Time (d)
Time (d)
B Control
2
Oxoplatin
Pt-furoxan
B
1.6
D
PBS
Control
Oxoplatin+2 (2 mg/kg)
Cisplatin (2 mg/kg)
Pt-furoxan (1 mg/kg)
Pt-furoxan (2 mg/kg)
Oxoplatin+2
(2 mg/kg)
1.2
0.8
0.4
0.0
Cisplatin
(
2 mg/kg)
Pt-furoxan
1 mg/kg)
Pt-furoxan
2 mg/kg)
(
Oxoplatin+2
Cisplatin
(
2
00 m
PBS
Oxoplatin+2 (2mg/kg)
Cisplatin (2mg/kg)
Pt-furoxan (1mg/kg)
Pt-furoxan (2mg/kg)
E
Figure 4. In vitro anti-metastasis assay. (A) The effect of platinum complexes on
migration of cancer cells measured using scratch test. 4T1 cells were pre-incubated for
200 m
2
4 h or 48 h with 2 μM platinum complexes. (B) The effect of compounds on adhesion
Figure 5. In vivo antitumor activity and anti-metastasis assays on 4T1 tumor bearing
mice. (A) The relative tumor volume during treatments. (B) The tumor weight in each
group at the end of the experiment. (C) The body weight of mice during the treatments.
(D) The images of tumor at the end of the experiment. X denotes a mouse died during
the treatment. (E) Representative histopathologic examination of the lungs at the end
of the experiment. The metastatic tumors in the lungs are marked with black arrows.
Balb/c mice-bearing 4T1 tumors were injected through the tail vein with PBS, the
mixture of oxoplatin+2 (2 mg Pt/kg body weight, two molar equivalents of 2 was used
in the mixture), cisplatin (2 mg/kg, Pt/body weight) and Pt-furoxan (1 mg/kg or 2 mg/kg,
of 4T1 cells (green) to HUVECs measured using fluorescence microscope. Co-incubation
of Rhodamine 123-labeled 4T1 cells with HUVECs pre-treated with IL-1β (1 ng/ml) in
presence of 5 μM of these platinum complexes for 2 h. Two molar equivalents of 2 was
used alone or in the mixture in all assays.
Adhesion of tumor cells to vascular endothelial cells is an
important step for tumor invasion and metastasis. To verify
the effect of Pt-furoxan on adhesion of tumor cells, a
fluorescence-based assay was conducted on human umbilical Pt/body weight), (n = 5). PBS was used as a control. Mice were treated every-other-day
6
times. Error bars denote standard deviations.
vein endothelial cells (HUVECs). HUVECs seeded on plate were
pretreated with IL-1β and then co-cultured with 4T1 cells that
stained with Rhodamine 123. After co-incubation for 1 h, the
The platinum accumulation in tumor was measured using
free 4T1 cells were washed out and the cells adhered to ICP-MS. The treatment with Pt-furoxan at a dosage of 2 mg
HUVECs were counted under a fluorescence microscope. The Pt/kg (10.26 μmol Pt/kg) resulted in 1.94 μg Pt/g tumor, which
observation of Rhodamine-stained 4T1 cells on the plate is 2.9-fold higher in comparison to the treatment of cisplatin
This journal is © The Royal Society of Chemistry 20xx
Chem. Commun., 2013, 00, 1-3 | 3
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0.66 μg Pt/g tumor) in the same Pt dosage (Figure S20). While
ChemComm
(
Notes and references
1
View Article Online
DOI: 10.1039/D0CC05422D
(a) T. C. Johnstone, K. Suntharalingam, S. J. Lippard, Chem.
the high drug accumulation is consistent with the higher in
vivo antitumor effect of Pt-furoxan, the half dosage of Pt-
furoxan (1.0 mg Pt/kg) led to a similar drug accumulation (0.68
μg Pt/g tumor) relative to cisplatin in a dosage of 2 mg Pt/kg,
even though the low dosage of Pt-furoxan demonstrated high
antitumor effect than cisplatin. This result reveals that, in
addition to drug accumulation in tumor, the function of
platinum agents, such as NO releasing of Pt-furoxan in this
study, contributes significantly to the antitumor efficacy.
The systemic toxicity of Pt-furoxan was monitored with
body weight during the treatment. Pt-furoxan did not alter the
growth of mice in both dosages, suggesting the low toxicity of
the drug (Figure 5C). By comparison, cisplatin clearly
decreased the body weight of mice, and even one mouse died
during the treatment of cisplatin. Moreover, to analyze the
toxicity of these platinum complexes to major organs, heart,
liver, spleen, lung and kidney of mice from drug experimental
groups were collected and stained with H&E. Cisplatin clearly
caused kidney damage, whereas no obvious damage was
observed with the treatment of Pt-furoxan or other platinum
agents (Figure S21).
The anti-metastasis effect of Pt-furoxan was also analyzed in
vivo on the 4T1 breast tumor bearing mice model. After 14-day
treatment of these platinum complexes, lung tissues were
stained with H&E dying to analyze the pulmonary migration of
cancer cells. The results showed that Pt-furoxan detectably
inhibited the metastasis of cancer cells to lungs (Figure 5E), in
agreement with the in vitro results of anti-metastasis assay.
In summary, a novel NO-releasing Pt(IV) complex, Pt-furoxan
was designed and synthesized in this work. Pt-furoxan can
release cisplatin and NO in cells. While cisplatin causes the
apoptosis of tumor cells, the NO released in cells modulates
cell response and enhanced the potency of cisplatin. Therefore,
Pt-furoxan exhibits synergistic effect on the inhibition of tumor
growth. In vitro and in vivo experiments indicate that Pt-
furoxan is more potent than cisplatin. Meanwhile, Pt-furoxan
possesses lower systemic toxicity than cisplatin. Moreover, Pt-
furoxan effectively inhibits the migration of cancer cells in vitro
and tumor metastasis in mice model. Further investigations
indicate that Pt-furoxan can suppress the activity of MMP9 and
MMP2, two key steps of tumor metastasis. In addition, Pt-
furoxan efficiently inhibits the adhesion of tumor cells to
vascular endothelial cells. These findings indicate that Pt-
furoxan possesses dual function of anti-proliferation and anti-
metastasis, and exhibits lower systemic toxicity in vivo.
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here are no conflicts to declare
4
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Graphic Abstract
Nitric Oxide-releasing Platinum(IV) Prodrug Efficiently Inhibits the Proliferation and Metastasis of Cancer Cells
Pt
H3N NH3
Apoptosis
Cl
Cl
Pt
H3N
NH3
Metastasis
c
GS
H
Metastasis-related
proteins
Pt-furoxan
Nitric oxide
5
Pt-furoxan, a nitric oxide-releasing platinum(IV) prodrug exhibits dual function by releasing cytotoxic cisplatin to induce
cell apoptosis, and a signaling molecule NO to inhibit tumor metastasis.
This journal is © The Royal Society of Chemistry [year]
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