Toward anticancer gold-based compounds targeting PARP-1: A new case study

Article abstract of DOI:10.1039/c6ra11606j

A new gold(iii) complex bearing a 2-((2,2′-bipyridin)-5-yl)-1H-benzimidazol-4-carboxamide ligand has been synthesized and characterized for its biological properties in vitro. In addition to showing promising antiproliferative effects against human cancer cells, the compound potently and selectively inhibits the zinc finger protein PARP-1, with respect to the seleno-enzyme thioredoxin reductase. The results hold promise for the design of novel gold-based anticancer agents disrupting PARP-1 function and to be used in combination therapies.

Full text of DOI:10.1039/c6ra11606j

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Toward anticancer gold-based compounds
targeting PARP-1: a new case study†
Cite this: RSC Adv., 2016, 6, 79147
a
a
b
c
d
a
A. Citta,‡ V. Scalcon,‡ P. Gobel, B. Bertrand, M. Wenzel, A. Folda,
¨
a
b
cd
M. P. Rigobello,* E. Meggers and A. Casini*
Received 4th May 2016
Accepted 20th July 2016
DOI: 10.1039/c6ra11606j
www.rsc.org/advances
0
A
new gold(III) complex bearing
a
2-((2,2 -bipyridin)-5-yl)-1H- the water and glycerol membrane channels termed aquaporins
benzimidazol-4-carboxamide ligand has been synthesized and char- (AQPs) have also been reported to be selectively targeted by
1
5–17
acterized for its biological properties in vitro. In addition to showing certain families of gold(III) complexes,
promising antiproliferative effects against human cancer cells, the used to unravel the roles of AQPs in cancer cell proliferation.
compound potently and selectively inhibits the zinc finger protein In this context, among the most studied and recognized
PARP-1, with respect to the seleno-enzyme thioredoxin reductase. targets for gold compounds, the seleno-enzyme thioredoxin
which could also been
18
19
The results hold promise for the design of novel gold-based anti- reductase (TrxR) has been widely investigated. Human TrxR
cancer agents disrupting PARP-1 function and to be used in combi- contains a cysteine–selenocysteine redox pair at the C-terminal
nation therapies.
active site, and the solvent-accessible selenolate group, arising
from enzymatic reduction, constitutes a likely target for “so”
metal ions such as gold. Thus, a number of mono and dinu-
clear, as well as heteronuclear, gold(I) and gold(III) complexes
Gold compounds have recently gained increasing attention in
the design of new metal-based anticancer therapeutics,
1
–4
have shown good correlation between cytotoxic activity and
including gold(III) complexes with multidentate N-donor or
cyclometalating ligands, gold(III) dithiocarbamates, gold(I)
N-heterocyclic (NHC) carbenes, as well as gold(I) alkynyl
20–29
TrxR inhibition properties.
In addition, mitochondria and
30
the endoplasmic reticulum have been proposed as potential
targets for anticancer gold complexes.
1,5–7
complexes.
Pursuing the search of novel protein targets for anticancer
gold compounds, some of us reported on the inhibitory effects
of different cytotoxic gold-based complexes with phosphine or
bipyridyl ligands, towards the zinc nger (ZF) enzyme poly(-
Concerning the possible mechanisms of action, early work
suggested DNA as the anticancer target for gold complexes.
However, later studies showed that actually the inhibition prop-
erties of different proteins and enzymes by gold compounds play
adenosine diphosphate (ADP)-ribose) polymerase 1 (PARP-
8,9
major roles, whereas interactions with nucleic acids appear to
31,32
1).
Interestingly, Au(III) coordination complexes were among
1
0,11
be markedly less relevant, with a few exceptions.
thiol-containing enzymes such as glutathione reductase (GR),
glutathione-S-transferase, cysteine proteases, protein tyrosine
phosphatases (PTP), and deubiquitinases (DUBs) were shown to
be potently inhibited by gold complexes. Interestingly, recently
For example,
the most efficient in inhibiting PARP-1, at a nM level, followed
by Au(I) compounds.
12
13
It is worth mentioning that PARPs are considered “the
guardian angels” of DNA playing a key role in its repair by
detecting DNA strand breaks and catalyzing poly(ADP-ribosyla-
1
4
33
tion). Therefore, PARP inhibitors can be used in combination
a
Department of Biomedical Sciences, University of Padova, via Ugo Bassi 58/b, 35131 with conventional anticancer agents that act by damaging DNA,
Padova, Italy. E-mail: mariapia.rigobello@unipd.it
such as cytotoxic chemotherapy and radiotherapy, as the PARP
b
Fachbereich Chemie, Philipps-Universit a¨ t Marburg, Hans-Meerwein-Strasse 4, 35043
inhibitors block the DNA-repair mechanisms that cancer cells
Marburg, Germany
34
use to resist destruction.
c
Dept. of Pharmacokinetics, Toxicology and Targeting, Research Institute of Pharmacy,
Concerning the molecular mechanisms of PARP-1 inhibition
by metal complexes, gold ions in either oxidation state 3+ or 1+
University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The
Netherlands
d
School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3A, are able to induce zinc substitution in ZF models, leading to the
31,35,36
UK. E-mail: CasiniA@cardiff.ac.uk
formation of the so-called gold ngers.
Damage of the ZF
†
1
‡
Electronic supplementary information (ESI) available. See DOI:
0.1039/c6ra11606j
domain responsible for DNA recognition leads to PARP-1
inhibition.
Valeria Scalcon and Anna Citta: these authors contributed equally.
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Here, we report on the synthesis of a new gold(III) complex (2)
bearing the bidentate N-donor ligand (1). Notably, the 1H-
benzimidazole-4-carboxamide fragment of 1 has been designed
as PARP-1 inhibitor acting on the catalytic site of the protein,
and not on its ZF DNA binding domain by forming hydrogen
bonds between the carboxamide and Ser904 as well as Gly863
37
within the catalytic site. Ideally, the resulting gold complex
should show enhanced properties as PARP-1 targeted agent
proting of the synergic inhibitory effects of both the Au(III) ions
and the organic ligand. Thus, 1 and 2 were tested for their PARP-
Scheme 1 Synthesis of ligand 1 and of the related Au(III) complex 2.
1
inhibition properties in vitro directly against the puried
enzyme as well as in protein extracts from human cancer cells,
against which the compounds also showed antiproliferative
properties. Gold nger formation was observed by high-
resolution ESI MS upon treatment of the PARP-1 zinc nger
model with 2.
Initially, the stability of the gold(III) complex 2 was evaluated
in PBS buffer (pH 7.4) using UV-visible spectrophotometry. The
compound exhibits an intense transition in the 300–400 nm
range, characteristic of the gold(III) chromophore, that may be
straightforwardly assigned as LMCT bands (Fig. S1, ESI†).
Spectral changes are slowly observed with time that might be
related to the occurrence of partial hydrolysis processes. In any
case, the gold(III) complex is the dominant species in buffered
aqueous solutions aer several hours incubation.
The stability of 2 toward biologically occurring reducing
agent glutathione (GSH) was also evaluated. Results show that
GSH, present at a 2 : 1 molar ratio with respect to 2, does not
markedly affect the evolution of the main LMCT band of the
complex with respect to its normal hydrolysis (Fig. S2†).
However, formation of soluble gold(I) thiolate species as a major
product of gold(III) reduction, cannot be excluded.
Aerwards, the antiproliferative properties of the new gold
complex 2 and ligand 1 were studied by monitoring their ability
to inhibit cell growth using the MTT assay (see Experimental
section). Cytotoxic activity of the compounds was determined
aer exposing for 72 h the human ovarian cancer A2780 cell
line, and its cisplatin resistant variant (A2780cisR), the human
ovarian cancer SKOV3 cell line, as well as the human non-small
cell lung carcinoma A549 line, in comparison to cisplatin and
auranon (AF). The results are summarized in Table 1. The IC50
values of 2 towards all tested cell lines are lower in comparison
to the free ligand 1. This may implicate that the gold(III) center
plays an important role in the still unknown mechanism(s) of
cytotoxic action. The IC50 values towards the cisplatin resistant
A2780cisR cell line is for 1 comparable to cisplatin, but 2 is
markedly more effective. This observation support the idea that
In this context, where multiple protein targets have been
identied for cytotoxic gold compounds, it is absolutely neces-
sary to promptly assess selectivity of new families of complexes
in order to avoid side-effects, and to construct solid and reliable
structure–activity relationships which should orient the design
of targeted chemotherapic agents. Therefore, the activity of the
compounds as TrxR inhibitors was also tested on both puried
enzyme and cell extracts, in comparison to auranon, the gold(I)
38
anti-arthritic drug with cytotoxic properties in vitro, used here
39
as the benchmark inhibitor of TrxR.
To further characterize the mechanisms of anticancer action
of the gold(III) complex 2, the study of its effects on the intra-
cellular redox state was conducted measuring the total and
oxidized glutathione content in cancer cells. Moreover, its
effects on the mitochondrial membrane potential were also
assessed in cancer cells, in comparison to ligand 1. The ob-
tained results allowed evaluating the selectivity of 2 for PARP-1
vs. TrxR, with implications for the design of improved gold-
based targeted agents.
Results and discussion
A practical synthesis of ligand 1 was developed starting from 4-
0
40
bromo-2,2 -bipyridine through reductive carbonylation
0
41
providing 2,2 -bipyridine-4-carbaldehyde in 96% yield, fol-
42
lowed by condensation with 2,3-diaminobenzamide in 93%
yield. Compound 2 was then synthesized adapting procedures
used for previously reported Au(III) complexes with bidentate N-
donor ligands (Scheme 1) and characterized via different
methods as described in the Experimental section (see ESI†).
43
Table 1 IC50 values of the Au complexes described in this study
against human ovarian carcinoma cell lines SKOV3, cisplatin sensitive
0
Thus, 2-((2,2 -bipyridin)-5-yl)-1H-benzimidazol-4-carboxamide
(A2780) and resistant (A2780cisR) and lung cancer cells (A549)
(50 mg, 0.16 mmol) in suspension in ethanol (0.5 mL) was
compared to cisplatin and auranofin (AF)
reacted with hydrogen tetrachloroaurate (1 eq., 54 mg, 0.16
mmol), also dissolved in ethanol (0.5 mL), in a round-bottom
a
IC50 (mM)

ask equipped with a condenser. The reaction mixture was
Compound
SKOV3
A2780
A2780cisR
A549
reuxed overnight during which time a brown precipitate was
formed. Aer cooling down, the precipitate was collected by
1
2
84.4 ꢀ 7.6
22.7 ꢀ 2.9
1.8 ꢀ 0.4
13.2 ꢀ 3.5
9.70 ꢀ 3.06
4.80 ꢀ 2.35
1.25 ꢀ 0.5
5.2 ꢀ 1.9
33.1 ꢀ 5.9
13.0 ꢀ 2.7
1.5 ꢀ 0.3
35.0 ꢀ 5.9
46.7 ꢀ 17.5
35.0 ꢀ 6.5
2.5 ꢀ 0.7

ltration and washed twice with diethylether (68% yield). The
1
AF
Cisplatin
product was characterized by various techniques including H
and C NMR spectroscopy, mass spectrometry and elemental
analysis (see ESI† for details).
1
3
10.8 ꢀ 2.8
a
Data are the mean ꢀ SD of at least four experiments.
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in general gold(III) complexes do not have the same mechanism corresponding to the N-terminal ZF domain sequence of PARP-1
of action as cisplatin, as discussed in the Introduction. Both 1 was reacted with 2 and the sample was monitored by high-
and 2 are poorly toxic against the A549 cell. The greatest resolution ESI MS as described in the Experimental section.
difference in IC50 value between 1 and 2 is found against the Fig. S3 in the ESI† shows the broadband mass spectrum of the
SKOV3 cell line (2 is ca. 4-fold more potent than 1). Such 2–ZF adduct. In agreement with previously reported studies on
discrepancy in the cytotoxic effects may be due to several other Au(III) complexes, when 2 was incubated with the ZF
2
+
factors, including different transport mechanisms (uptake and domain in a 3 : 1 ratio for 10 min, partial displacement of Zn
efflux) of complex 2 with respect to ligand 1 in the selected from the ZF by gold ions leads already to formation of the so-
cancer cells, which may lead to decreased intracellular accu- called “gold-nger” adduct.
mulation of 1. Finally, AF is certainly the most potent among the
Aerwards, to evaluate if the different cytotoxic effects of 2
tested drugs; however, it is also the most unselective, again were related to differences in intracellular Au accumulation,
demonstrating differences of mechanisms of activity among ICP-MS analysis of cell extracts out of A2780 and SKOV3 cells,
different families of gold compounds.
pre-treated with the gold compound for 24 h, demonstrated that
Compounds 1–2 were then tested against puried PARP-1 the cytotoxicity is somehow proportional to the gold uptake,
31
using an established protocol. As expected, potent PARP-1 and the strongest antiproliferative effects correspond to higher
inhibition was observed with both compounds: 1 has an IC50 values of intracellular gold concentration. In fact, the concen-
6
¼
5.0 ꢀ 2.1 nM, and 2 has IC50 ¼ 6.0 ꢀ 1.3 nM, in the same tration of Au [pmol Au per 10 cells] measured in A2780 and
31
range as previously reported cytotoxic gold(III) complexes.
SKOV3 cells is 1802 ꢀ 209 and 1087 ꢀ 322, respectively.
Aerwards, PARP-1 activity was evaluated on cell extracts Nevertheless, in spite the reduced accumulation of 2 in SKOV3
from A2780, A2780cisR and SKOV3 cells. Thus, incubation of cells, the inhibition of PARP-1 activity is more pronounced than
protein cell extracts with the compounds for 24 h at room in the case of A2780 cells (Fig. 1).
temperature was followed by PARP-1 activity determination.
Fig. 1 shows the residual PARP-1 activity in protein extracts vitro inhibition of puried rat TrxR by the two compounds was
treated with the complexes at a xed concentration (10 mM). studied using established protocols as described in the Exper-
Since TrxR is also a potential target for gold complexes, in
Attractively, both compounds can induce PARP-1 inhibition imental section. The results are summarized in Table 2 and
to a similar extent in A2780 and A2780cisR cell lines, while Fig. S4.† Complex 2 inhibits cytosolic thioredoxin reductases
a marked difference could be detected in the case of SKOV3 (TrxR1) in the same range as auranon (IC50 ¼ 14.32 ꢀ 1.62 nM
cells, where 2 is able to inhibit PARP-1 until ca. 10% of its vs. IC50 ¼ 6.88 ꢀ 1.25 nM, respectively). Conversely, ligand 1 is
residual activity. Instead, 1 is practically ineffective on these completely ineffective, as expected since it is deprived of the
cells, in line with the scarce anticancer effects observed above. Au(III) centre able to bind the selenol groups (Fig. S1, ESI†).
Furthermore, PARP-1 activity was evaluated on protein Further studies demonstrated that 2 is also able to inhibit the
extracts obtained from SKOV3 cells pre-treated with non- TrxR closely related, but selenium-free, enzyme glutathione
cytotoxic doses of each compound for 48 hours. Aerwards, reductase (GR) with IC50 ¼ 0.40 ꢀ 0.06 mM, about 28-fold less
the protein extracts were collected and analyzed for PARP-1 efficiently than in the case of TrxR (Table 2).
activity. Preliminary results indicate that only the gold
complex 2 (20 mM) was able to induce ca. 70% reduction of ties was evaluated in cell lysates. For this purpose, SKOV3 cells
PARP-1 activity, while ligand 1 was poorly effective. where the two compounds showed markedly different cytotoxic
Aerwards, the effect of compounds on TrxR and GR activi-
In order to assess formation of adducts between the gold effects, were pre-treated for 48 h with 20 and 40 mM of 1 and 2,
complex and the zinc nger domain of PARP-1, a peptide model respectively. The obtained results show that 1 does not affect
enzymes activities, while 2, causes ca. 50% TrxR inhibition and
a slight decrease of GR activity at 40 mM (Fig. 2). In addition,
similar experiments were conducted in the A2780 cells, and the
obtained results showed no statistically signicant inhibition of
TrxR at the tested compounds' concentrations (Fig. S5†).
Notably, these latter results further corroborate the hypothesis of
alternative pharmacological targets for the reported compounds.
Table 2 IC50 values of the inhibition of TrxR1 and GR on the isolated
enzymes
IC50 (nM)
Fig. 1 PARP-1 activity levels in human ovarian cancer cellular extracts. Complexes
PARP-1 activity was measured in homogenates (50 mg of protein)
TrxR1
GR
treated with the compounds (10 mM) over 24 h at room temperature.
Data are the mean ꢀ SD of at least three experiments each performed
in triplicate.
1
2
AF
>100
>10 000
400 ꢀ 60
>10 000
14.32 ꢀ 1.62
6.88 ꢀ 1.25
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derivatives were shown to alter mitochondrial parameters, such
as causing a drop of the mitochondrial membrane potential
46
(MMP).
MMP evaluation was conducted monitoring the uorescence
of tetramethylrhodamine methyl esters (TMRM) according to
established protocols (see Experimental for details). Thus, it
was possible to determine if the complexes are able to induce
m
a quick drop in mitochondrial membrane potential (Dj ),
47
detectable as a decline in the uorescence intensity of TMRM.
Therefore, MMP of SKOV3 cells treated for 18 h with
compounds 1 and 2 was measured by cytouorometric analysis
in comparison to auranon (AF) and CCCP (Fig. 3). Cells were
incubated with 25 nM TMRM for 20 min and then analyzed by

ow cytometry utilizing an argon laser at 585 nm, as described
in the Experimental section.
From the obtained results it has been possible to determine
that, at variance with AF and the classical uncoupling agent
CCCP (carbonyl cyanide m-chlorophenyl hydrazone), both
complexes 1 and 2 do not affect the MMP values with respect to
the controls, as it has instead been reported for gold(III)
porphyrins and dithiocarbamato complexes.
Finally, since overexpression of PARP in cancer cells has
been linked to drug resistance and PARP-1 inhibition has been
shown to sensitize tumor cells to chemotherapeutic agents
including platinum compounds, we decided to evaluate the
cytotoxic effect of cisplatin administered in combination with
different concentrations of 2. Initial data were obtained for 72 h
co-administration of cisplatin (7.5 mM) and 2 at different
concentrations (10–20–30 mM) in SKOV3 cells (see Experimental
for details). In Table S1 (ESI†) a comparison of the predicted
survival rates (dened as the expected cell viability if the
combined activities of the compounds are additive) and the
experimentally determined values (the observed viabilities) is
reported. Unfortunately, the observed survival rates for the
Fig. 2 Effect of the compounds 1 and 2 on thioredoxin reductase and
glutathione reductase activities in cell lysates. SKOV3 cells were
treated for 48 h with 20 and 40 mM of 1 and 2, respectively. * ¼ p < 0.01.
Overall, the obtained results on both PARP-1 and TrxR
activities, indicate that the cytotoxic gold complex 2 may oper-
ate via inhibition of PARP-1, whereas TrxR is only moderately
affected. Concerning the observed differences in PARP-1 inhi-
bition by 1 and 2, it may be suggested that the ligand is not so
selective for binding to PARP-1 as the gold complex 2, once in
the presence of other intracellular components. Nevertheless,
in terms of the overall cytotoxic potency, differences in the
uptake mechanisms and cellular accumulation between the two
compounds should also be taken into account.
The glutathione redox pair (GSH/GSSG) is another funda-
mental component of the cell redox regulation in cisplatin
44
resistant cells. Therefore, our study continued with the anal-
ysis of total glutathione content (reduced + oxidized) and of the
GSH/GSSG ratio in SKOV3, aer treatment with the two
compounds for 48 h in comparison to AF. The obtained results
are shown in Fig. S6 in the ESI† available. It can be observed
that for all tested compounds no statistically signicant varia-
tion of the total GSH content, as well as of the GSH/GSSG ratio
occur, again made exception for 2, which causes a slight
increase of GSSG content at 40 mM, in accordance with the
compound's above-mentioned inhibition effect of glutathione
reductase. This behavior suggests that GSH does not particu-
larly inuence the cytotoxic potency of the gold complex, as for
cisplatin in the case of certain resistant cancer cells.
Mitochondrial membrane potential (MMP), a consequence
of the electrochemical proton gradient maintained for the
purpose of ATP synthesis, is an important indicator of func-
Fig.
3 Percentage of cells with a low and high mitochondrial
membrane potential. Mitochondrial membrane potential of SKOV3
cells treated for 18 h with compounds 1 and 2 was measured by
tional mitochondria. Previously reported studies showed that a cytofluorometric analysis. Cells were incubated with 25 nM TMRM
for 20 min and then analyzed by flow cytometry utilizing an argon laser
gold(III) complexes are able to determine the decrease of MMP
depending on the ligands. As an example, gold(III) porphyrin 1a
at 585 nm. Bars represent mean percentages ꢀ S.D. (n ¼ 3) of SKOV3
cells whose mitochondria maintained a high (gray) or low (dark gray)
induced apoptosis by mitochondrial death pathways related to
TMRM fluorescence, that correspond to their mitochondrial
membrane potential.
45
reactive oxygen species. Similarly, gold(III)-dithiocarbamato
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combinations of 2 with cisplatin are similar to those predicted
on the basis of an additive effect, ruling out the synergism.
Further studies will be necessary to investigate possible synergic
effects in different cancer cell types and to validate the possi-
bility of using 2 in combination therapy.
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We have reported here on the potent PARP-1 inhibition prop-
erties of a new cytotoxic gold(III) complex with a bidentate N-
donor ligand. A series of biological and biochemical assays
has shown that the compound targets preferentially PARP-1
with respect to the seleno-enzyme thioredoxin reductase, and
in doing so it is more effective than the free ligand. The absence
of effects of the gold(III) compound on both MMP and intra-
8 A. de Almeida, B. L. Oliveira, J. D. G. Correia, G. Soveral and
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targeted anticancer metallodrugs.
P. Richard, P. Le Gendre, E. Warmerdam, M. H. de Jager,
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1
2
Acknowledgements
Authors thank EU COST Actions CM1105 for funding and for
providing opportunities for discussion; M. P. R. acknowledges
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1805/9-1).
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2
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