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Organoruthenium Complexes with C^N Ligands are Highly Potent Cytotoxic Agents that Act by a New Mechanism of Action.
DOI: 10.1002/chem.201703581
Communication
& Anticancer
Organoruthenium Complexes with C^N Ligands are Highly Potent
Cytotoxic Agents that Act by a New Mechanism of Action
Vojtech Novohradsky,[a] Jyoti Yellol,[b] Olga Stuchlikova,[a, c] Mar&a Dolores Santana,[b]
Hana Kostrhunova,[a] Gorakh Yellol,[b] Jana Kasparkova,[a, c] Delia Bautista,[d] Jos8 Ruiz,*[b] and
Viktor Brabec*[a]
Abstract: Our study demonstrates that four novel kinetically inert C,N-cyclometalated RuII complexes of the type
[Ru(C^N)(N^N)2][PF6] containing a handle for functionalization on the C^N ligand are very potent cytotoxic agents
against several different human cancer cell lines and are
up to 400-fold more potent than clinically used cisplatin.
In addition, the investigated ruthenium complexes are less
cytotoxic in noncancerous cells, and exhibit higher selectivity for cancer cells than conventional platinum anticancer drugs. The high potency of the investigated ruthenium
compounds can be attributed to several factors, including
enhanced internalization and their capability to change
mitochondrial transmembrane potential in cells. The new
ruthenium complexes also interfere with protein synthesis
with a markedly higher potency than conventional inhibitors of DNA translation. Notably, the latter mechanism has
not been hitherto described for other cytotoxic Ru compounds and cisplatin.
The clinical success of cisplatin and its derivatives, carboplatin,
and oxaliplatin[1] has stimulated the search for alternative transition metal-based drugs that possess anticancer activity.[2]
New metal-based anticancer drugs could widen the spectrum
[a] Dr. V. Novohradsky, O. Stuchlikova, Dr. H. Kostrhunova,
Prof. Dr. J. Kasparkova, Prof. Dr. V. Brabec
Institute of Biophysics, Czech Academy of Sciences
Kralovopolska 135, 61265 Brno (Czech Republic)
E-mail: brabec@ibp.cz
[b] J. Yellol, Dr. M. D. Santana, Dr. G. Yellol, Prof. Dr. J. Ruiz
Departamento de Qu&mica Inorg#nica and
Regional Campus of International Excellence “Campus Mare Nostrum”
Universidad de Murcia and
Biomedical Research Institute of Murcia (IMIB-Arrixaca)
30071 Murcia (Spain)
E-mail: jruiz@um.es
[c] O. Stuchlikova, Prof. Dr. J. Kasparkova
Department of Biophysics, Faculty of Science
Palacky University
17. listopadu 12, 77146 Olomouc (Czech Republic)
[d] Dr. D. Bautista
SAI., Universidad de Murcia
30071 Murcia (Spain)
Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/
chem.201703581.
Chem. Eur. J. 2017, 23, 15294 – 15299
of treatable cancers, reduce toxic side effects, and overcome
platinum resistance. Several studies focusing on the potential
alternatives to platinum-based anticancer drugs have employed ruthenium complexes.[2d, 3] Notably, two anionic RuIII coordination compounds, NAMI-A (imidazolium trans-[tetrachlorido(1H-imidazole)(S-dimethyl
sulfoxide)ruthenate(III)])
and
KP1019 (indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]), have been evaluated in Phase I clinical trials for treating metastatic cancer.
A series of ruthenium(II) complexes that exhibit promising
antitumor activity have been prepared and their biological (antitumor) activity evaluated. In general, antitumor RuII complexes can be divided into two primary families: complexes
that adopt the so-called “piano-stool” conformation and heteroleptic cyclometalated/polypyridyl-type complexes.[4, 5] Organometallic ruthenium(II) complexes of the type [(h6-arene)Ru(en)(Cl)] + account for another class of antitumor ruthenium(II)
complexes. Their DNA binding mode involves combined coordination to guanine residues and noncovalent, hydrophobic interactions, such as intercalation of the arene ligand into DNA
and minor groove binding.[6] Further, a 2-phenylpyridine C^N
ligand has been employed to generate heteroleptic ruthenium(II) complexes, so called RDCs (ruthenium-derived compounds), which represent another class of propitious cytotoxic
and cytostatic agents.[7] These complexes act by an atypical
pathway involving endoplasmatic reticulum stress.
Earlier reports have shown that benzimidazole is a widely
used pharmacophore,[8] acting either as anti-angiogenic and
antitumor agents[9] or amyloid-b aggregation inhibitors.[10] To
obtain new biologically active transition-metal complexes with
improved ability to kill cancer cells and elucidate the mechanism of action of organometallic complexes with C^N ligands
along with the optimization of the choice of the transitionmetal moiety and C^N ligands, we designed four kinetically
inert ruthenium-based agents of the type [Ru(C^N)(N^N)2][PF6]
(Figure 1). These complexes contain either (i) an in-house benzimidazole C^N ligand (complexes 1 and 2) with an ester
group for further chemical functionalization and a butyl group
for N-substitution chosen initially to adjust lipophilic properties
of the final complex; or (ii) a modified 2-phenylpyridine/1-phenylpyrazole C^N ligand with an aldehyde group (complexes 3
and 4 respectively, Figure 1). Complexes 3 and 4 were prepared also for comparative purposes and for the possibility to
incorporate an additional functionality to further affect their
biological potency. It is important to note that, in this context,
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Table 1. Cytotoxicity (IC50 mean values, mm) for Ru complexes and cisplatin.[a]
MRC-5
1
5.1 : 0.5
A2780
A2780cisR[b]
0.13 : 0.01 0.067 : 0.008
(0.50)
2
2.3 : 0.4 0.13 : 0.02 0.045 : 0.005
(0.35)
3
8.8 : 0.2 0.15 : 0.01 0.14 : 0.02 (0.94)
4
8.8 : 0.1 0.21 : 0.08 0.12 : 0.01 (0.61)
cisplatin 15.2 : 0.5 3.3 : 0.8 18 : 2 (5.28)
HCT-116
MCF-7
0.47 : 0.03 0.25 : 0.07
0.41 : 0.01 0.32 : 0.06
1.02 : 0.04 0.47 : 0.02
0.78 : 0.09 0.72 : 0.03
5.9 : 0.9
9:1
[a] The drug-treatment period was 72 h. The results are expressed as
mean values : SD (standard deviation) for two independent samples,
each made in quadruplicate. [b] Resistance factor, defined as IC50 (resistant, A2780cisR)/IC50 (sensitive, A2780), is given in parentheses.
Figure 1. Ruthenium(II) complexes with C^N ligands investigated in this
work.
a kinetically inert heteroleptic RhIII complex containing two 2phenylpyridine C^N ligands with a CHO group that acts as an
inhibitor of STAT3 and reduces tumor size and angiogenesis in
an in vivo mouse xenograft model was recently reported.[11]
Another goal was to study how the nature of the C^N ligand
affects the various parameters associated with cytotoxicity (cellular accumulation and localization, mitochondrial dysfunction,
cell cycle, protein synthesis, etc.).
Ruthenium complexes were prepared by a synthetic procedure described in the Supporting Information (synthesis and
characterization of ruthenium compounds and Figures S1–S4).
The final compounds were characterized by elemental analysis,
1
H, and 13C NMR spectroscopy, including COSY and HSQC spectroscopy, and UV/Vis absorption spectroscopy; additionally, the
structures of 3 and 4 were unambiguously confirmed by the Xray crystallographic study (for details, see the Supporting Information, synthesis and characterization of ruthenium compounds and Figures S5–S33, Tables S1–S5).
The cytotoxic effects of the investigated Ru compounds
were evaluated against four tumor cell lines, ovarian (A2780),
cisplatin-resistant ovarian (A2780cisR), colon (HCT-116), and
breast (MCF-7) cells. For comparison, the cytotoxic effects of
cisplatin were also determined. The toxicities of the complexes
were also tested against the noncancerous human lung fibroblasts (MRC-5). All Ru complexes were found to be markedly
more cytotoxic than cisplatin, and the IC50 values were in the
submicromolar range (Table 1).
Interestingly, all investigated Ru complexes were markedly
more toxic (125- to 390-fold) than cisplatin in cisplatin resistant
A2780cisR cells and (13- to 29-fold) in MCF-7 (inherently resistant to cisplatin). Furthermore, the resistance factor [defined as
the ratio of IC50 values in resistant (A2780cisR) and cisplatinsensitive parent cells (A2780)] was 0.35–0.94 for Ru complexes,
whereas it was markedly higher for cisplatin (5.28) (Table 1 and
Table S6 in the Supporting information). This suggests that the
mechanism underlying the biological action of the investigated
Ru complexes is different from that of cisplatin and its direct
derivatives, allowing the investigated Ru complexes to successChem. Eur. J. 2017, 23, 15294 – 15299
www.chemeurj.org
fully overcome the resistance mechanisms operating in the
case of cisplatin. Importantly, the IC50 values found for the investigated Ru complexes in cancer cells tested in our study
were 6–76-fold lower than those for non-carcinoma cells MRC5, whereas the IC50 values found for cisplatin under identical
conditions in cancer cells were only 0.8–4.6-fold lower than
those found for non-carcinoma cells MRC-5 (Table S7 in the
Supporting information). Thus, these results confirm a higher
selectivity of the investigated Ru compounds for cancer cells
compared with cisplatin.
One of the most important factors for the biological activity
of metal-based drugs is the intracellular accumulation and the
way the complexes are transported into the intracellular
space.[12] The key factor relevant for cell uptake and anticancer
activity of some metallodrugs is the hydrophobicity of complexes.[13] The total cellular accumulation of the investigated
Ru complexes and cisplatin in A2780 and HCT-116 cell lines
was studied (see the Supporting Information, biological evaluation–details and Tables S8, S9). The results summarized in
Table S8 indicate that the levels of ruthenium associated with
the cells after exposure to 1–4 of both cell lines were 23- to
66-fold higher than the level of Pt if both cell lines were treated with cisplatin. As also shown in Table S8, the cellular accumulation is a function of hydrophobicity of the metal complex,
which suggests that these complexes are mostly dependent
on a passive diffusion uptake mechanism. The extent of cellular accumulation also correlates with the cytotoxicity of the
complexes. As presented in Table 1 and Table S8 in the Supporting information, 1 and 2 with the highest level of cellular
accumulation are the most hydrophobic and also exhibit the
best cytotoxic effects. An interesting summary of these results
is that the presence of C^N ligands in the Ru complexes ensures hydrophobicity, thereby significantly facilitating the association of these compounds with cells, and enhancing the cytotoxicity of this class of Ru complexes. This is in agreement
with a similar observation previously found by Chao et al. for
related ruthenium heteroleptic polypyridyl-type complexes.[11]
Cellular accumulation studies were also performed to investigate the localization of the investigated Ru complexes and
cisplatin in A2780 cells treated with these complexes (see Supporting Information). The results (Table S9 in the Supporting In-
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formation) indicate that the largest amounts of
ruthenium from 1–4 become trapped in the cell
membrane(s), probably due to their lipophilicity. An
appreciable amount is also detected in cytosol.
Minor amounts of Ru from complexes 1–4 were
found in the cytoskeleton and nucleus. Thus, the results demonstrating cellular accumulation of ruthenium suggest that nuclear macromolecules including
DNA are not a likely target for cytotoxic effects of
this class of Ru complexes.
In contrast, it has been proposed that in the case
of several metallodrugs, DNA damage plays a key
role in the mechanism of their antitumor action. To
determine whether DNA is a pharmacological target
for the investigated Ru complexes, the sensitivity of
DNA repair (NER)-deficient cells towards these complexes and cisplatin was tested and compared to
that of isogenic DNA repair-proficient cells.[14] The
Figure 2. A) Fluorescence images of A2780 cells untreated or treated with equitoxic condetails of this approach and the detailed results are
centrations (IC50, 72 h) of cisplatin, 1–4 for 18 h which were stained with the mitochondescribed in the Supporting Information (biological
dria-selective dye TMRE for changes in mitochondrial membrane potential and then anaevaluation–details). The results (Table S10 in the Suplyzed by confocal laser-scanning microscope. Top row: fluorescence channel, bottom
porting Information) indicate that in contrast to cisrow: bright field. Scale bars represent 25 mm. Images are the representatives from three
independent experiments. B) Quantification of mitochondrial dysfunction. Single-cell
platin, there is no significant difference in cell-killing
analysis was performed by using ImageJ software and results are expressed as the mean
of wild type cells and cells deficient in DNA repair
fluorescence intensity per cell; error bars are the standard deviations calculated from at
by the investigated Ru complexes. These data clearly
least one hundred single cells analyzed out from three independent experiments.
show that, in contrast to cisplatin, DNA-repair status
does not significantly affect the effectiveness of Ru
complexes, suggesting that reparable DNA damage is not the
sents a downstream effect related to the cell death (apoptosis)
major factor contributing to the cytotoxic activity of the Ru
(Figure S34 in the Supporting information) primarily induced
complexes.
by the effect on another cellular site(s).
There is a large body of evidence indicating that antitumor
The perturbations in mitochondrial function associated with
Ru complexes may be effective as mitochondria-targeting antireduced mitochondrial membrane potential may result in the
cancer drugs.[15] We determined changes in the mitochondrial
oxidative stress related to increased generation of reactive
transmembrane potential (Dym) in A2780 cells induced by the
oxygen species (ROS). Intracellular ROS were quantified to deinvestigated Ru compounds and cisplatin (for comparative purtermine the oxidative stress in A2780 cells after the treatment
with 1, 3, or cisplatin as described in the Supporting Informaposes) by a TMRE staining assay (tetramethylrhodamide
methyl ester). TMRE is a lipophilic but slightly cationic fluorestion. Treatment of A2780 cells with 1 and 3 resulted in a concent dye that is preferentially sequestered by active mitochoncentration-dependent increase in the production of ROS (Figure S35 in the Supporting Information). In contrast, the effect
dria. Inactive mitochondria are characterized by reduced membrane potential and consequently do not sequester TMRE.[16]
of cisplatin on ROS production in treated cells was insignificant. This observation suggests that the investigated Ru comThe depletion of Dym was then monitored by a confocal microscope, as described in the Experimental section in the Supplexes can cause disruption of mitochondrial function and associate production of reactive oxygen species (ROS).
porting Information. The results (Figure 2) showed that in the
It has been shown[16, 17] that impedance-based monitoring of
TMRE assay, the signals observed by confocal microscopy (fluorescence channel) were not significantly changed from the
cellular responses to biologically active small molecule comA2780 cells treated for 18 h with cisplatin (Figure 2 A, image 6
pounds produces TCRPs (time-dependent cell response proand Figure 2 B). In contrast, if the A2780 cells were treated
files), which can be predictive of the mechanism of action of
under the same conditions, the signals were strongly attenuatsmall molecules. The TCRPs of cisplatin and Ru complexes 1–4
ed in the case of the investigated Ru complexes (Figure 2 A,
are displayed in Figures 3 A–E.
images 1–4 and Figure 2 B).
Significant differences in the effects of the investigated Ru
Thus, complexes 1–4 caused a significant decrease in the micomplexes and cisplatin can be observed. The effect of cisplatochondrial transmembrane potential in comparison with nontin (Figure 3 E) is characterized by a slight initial increase in the
treated control cells (Figure 2), which is a hallmark of mitocell index in comparison with the control, followed by a conchondria dysfunction. However, it has to be noted that on the
centration-dependent decrease in the cell index below control
basis of these results, it cannot be definitely decided whether
levels, reflecting cytotoxic responses; cisplatin at the concenthe mitochondria are the primary target for these complexes
tration corresponding to IC90 fails to kill adherent cells comor whether the mitochondrial membrane depolarization reprepletely even at the longest times of their growth. The TCRP of
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(Figures S36, S37 and Table S11 in the Supporting Information)
show the cell-cycle arrest primarily in the G1 phase if the
A2780 cells were treated with 1 or 3. For comparative purposes, cell cycle analysis was also performed with the A2780 cells
treated with cisplatin. Cisplatin caused cell-cycle arrest mainly
in the S and G2 phases, which is consistent with previous reports.[18] The effect on cellular distribution into the particular
cell cycle phases was manifested in a concentration-dependent
manner and is elevated with increasing concentrations of Ru
complexes (Figure S37 in the Supporting Information). Thus,
the ability of the investigated Ru complexes to block the cell
cycle primarily in the G1 phase is consistent with the conclusion drawn from the analysis of TCRP profiles (Figure 3).
The impedance-based TCRP obtained for the investigated
Ru complexes (Figure 3) revealed that these TCRPs can be interpreted to mean that a possible mechanism of action of Ru
complexes may involve inhibition of protein translation. In
order to verify the inhibition effect of Ru complexes on protein
synthesis in living cells, the incorporation of [35S] methionine
([35S]-Met) was detected as a measure of translation activity of
the cells in the presence of Ru complexes). In these experiments, we intentionally used low concentrations of 1 or 3 and
short incubation times (0.5 and 1 h) to secure cell viability so
as to mainly detect the upstream effects of the Ru complexes.
A2780 cells were incubated with [35S]-Met for 2 h to allow for
their incorporation into newly synthesized proteins. Ruthenium
complexes significantly decreased protein synthesis (Figure 4).
To verify that the observed effect of Ru complexes on protein synthesis is specific, we evaluated how they affect both
Figure 3. Interaction of 1 (A), 2 (B), 3 (C), 4 (D), and cisplatin (E) with A2780
cells monitored by a real-time cell analyzer (RTCA). For 1: IC30 = 0.08 mm,
IC50 = 0.13 mm, IC90 = 0.4 mm; for 2: IC30 = 0.08 mm, IC50 = 0.12 mm,
IC90 = 0.40 mm; for 3: IC30 = 0.1 mm, IC50 = 0.15 mm, IC90 = 0.6 mm; for
4: IC30 = 0.1 mm, IC50 = 0.20 mm, IC90 = 0.60 mm; for cisplatin: IC30 = 1.0 mm,
IC50 = 3.0 mm, IC90 = 8.0 mm. F: A comparison of RTCA profiles found for 1, 2,
3, 4, and cisplatin in their equimolar concentrations (1.5 mm). The vertical
lines indicate the start of treatment after allowing the cells to grow and
adhere to microelectrodes for 24 h. Cell indices were normalized to account
for differences in cell counts that exist across the wells prior to treatment.
Incubations were performed in quadruplicate with 10 000 cells per well
using inhibitory drug concentrations determined for 72 h of incubation in
colorimetric cell viability assay.
cisplatin (Figure 3 E) coclustered with the TCRPs of DNA-damaging compounds interfering with DNA synthesis and replication and transcription, which are also known to induce cellcycle arrest in S or G2/M phases followed by the induction of
cell death.[16, 17] In contrast, treatment with IC50, IC90, or equimolar (1.5 mm) concentrations of the investigated Ru complexes
(Figures 3 A–D) resulted in an immediate, more pronounced
decrease in the cell index and complete killing of adherent
cells at the longest times of cell growth. Thorough examination of the profile obtained for the investigated Ru complexes
(Figure 3 A–D) revealed that their TCRPs can be coclustered
with subclusters containing TCRPs for compounds inhibiting
protein translation and inducing cell-cycle arrest principally in
G1, S, or G1/S phases, followed by initiation of cell death.[17]
This conclusion was further supported by the results of cell
cycle analysis by flow cytometry. The results of this analysis
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Figure 4. Effect of Ru complexes on translation and transcription in A 2780
cells as measure of incorporation of 35S-methionone or 3H-uridine, respectively. The radioactivities of control, untreated cells were taken as 100 %.
A) Cells were treated with 1, 3, Actinomycin D, and cycloheximide at indicated concentrations for 1 h. B) Cells were treated with 1 (0.4 mm), 3 (0.4 mm),
and cycloheximide (500 mm) for indicated time intervals. C) Cells were treated with 1 (0.8 mm), 3 (0.8 mm), Actinomycin D (40 mm), cycloheximide
(500 mm) for 1 h.
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translation and transcription by metabolic labeling. Transcriptional activity was monitored by incubation with [3H]uridine
for 2 h. Actinomycin D (ActD) and cycloheximide served as
controls as well-known transcription and translation inhibitors,
respectively. As expected, cycloheximide strongly inhibited
translation but only affected transcription at high doses,
whereas ActD concomitantly blocked both transcription and
translation (Figure 4) since protein synthesis requires a supply
of mRNA. Similarly to cycloheximide, both 1 and 3 inhibited
protein synthesis without a significant impact on transcription.
Our results also show that these Ru complexes are capable of
inhibiting translation at concentrations approximately three
orders of magnitude lower than conventional cycloheximide, a
well-known specific inhibitor of protein synthesis in eukaryotic
cells.[19]
The results of this experiment show that the inhibition of
protein synthesis takes place at a translational but not a transcriptional level (Figure 4). The membrane fraction obtained
after cell fractionation (Table S9 in the Supporting Information)
contained whole cellular membranes including the cellular organelles membranes with their membrane proteins (but excluding the nuclear membrane and nuclear membrane proteins) [see the protocols for use of FractionPREP cell fractionation kit from BioVision (Mountain View, CA)]. Hence, the prevailing accumulation of Ru from the investigated Ru complexes
in the membrane fraction is not in contradistinction with the
assumption that the investigated Ru complexes inhibit protein
synthesis by interactions with ribosomes or tRNA at endoplasmatic reticulum, where translation takes place.
Collectively, the ruthenium complexes tested in the present
work are significantly more potent than clinically used cisplatin
and its derivatives in cancer cells, and their therapeutic index
is at least 10 times higher than that found for clinically used
cisplatin. The data presented in this work also demonstrate
that the investigated ruthenium complexes differ significantly
from the previously reported cytotoxic ruthenium-based compounds and cisplatin in their mechanism of action. They interfere with protein synthesis, which is a mechanism hitherto not
described for other cytotoxic ruthenium-based compounds
and cisplatin. On the other hand, it was shown very recently[20]
that in contrast to the presumed DNA-damage-response mechanism of antitumor action of clinically used platinum drug oxaliplatin, oxaliplatin in fact kills cells by inducing ribosome biogenesis stress. Thus, oxaliplatin, unlike cisplatin, was shown to
markedly perturb the global translation machinery, thereby disturbing the synthesis of the entire set of proteins, similar to
that reported in this communication for the investigated Ru
complexes.
Further, importantly, the cycloruthenated complexes examined in the present work inhibit protein synthesis with a markedly higher potency than the conventional inhibitors. The
unique mechanism of action together with their high selectivity to the cancer over the normal cells predestines these complexes and their derivatives for further biological testing as
potent anticancer drugs.
Last but not least here we demonstrate that the investigated
Ru complexes cause mitochondrial dysfunction involving ROS
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production as well. Thus, it cannot be excluded that the investigated Ru complexes exhibit a dual effect in killing cancer
cells causing primarily inhibition of proteosynthesis and in a
lesser extent disruption of mitochondrial function simultaneously.
Acknowledgements
VN, OS, HK, JK and VB were supported by the Czech Science
Foundation (Grants 17-05302S). The research of OS was also
supported by Palacky University in Olomouc (IGAPrF2017 017).
The work of JY, MDS, GY, DB and JR was supported by the
Spanish Ministry of Economy and Competitiveness and FEDER
funds (Project CTQ2015-64319-R). The authors also thank to
the members of the COST Actions CM1105 and CM1406 and
MetDrugs network (CTQ2015-70371-REDT) for stimulating discussions.
Conflict of interest
The authors declare no conflict of interest.
Keywords: anticancer agents · cell growth · mitochondrial
disfunction · protein synthesis · ruthenium
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Manuscript received: August 1, 2017
Accepted manuscript online: September 18, 2017
Version of record online: October 13, 2017
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