Coordination Chemistry Reviews 360 (2018) 17–33

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Coordination Chemistry Reviews

journal homepage: www.elsevier.com/locate/ccr

Review

The mechanism of tumour cell death by metal-based anticancer drugs is

not only a matter of DNA interactions
Alberta Bergamo a, Paul J. Dyson b, Gianni Sava a,c,⇑
a
Callerio Foundation Onlus, via A. Fleming 22, 34127 Trieste, Italy
b
Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
c
Department of Life Sciences, University of Trieste, via A. Fleming 22, 34127 Trieste, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Platinum drugs are extensively used in the clinic to treat cancer, often leading to a palliative response
Received 4 July 2017 rather than a cure. While DNA is considered to be the primary target of platinum drugs, there is no clear
Accepted 7 January 2018 relationship between cellular platinum accumulation, DNA platination and Pt-DNA adduct removal, and
herein we describe new mechanistic insights of platinum drugs related to the hallmarks of cancer and
how they interfere with the tumour microenvironment. We then proceed to describe the properties of
Keywords: other metal drugs, including both non-targeted compounds that do not significantly interact with DNA
Platinum drugs
and targeted compounds that interfere more selectively with specific pathways responsible for tumour
Metal-based compounds
Cancer chemotherapy
growth and invasion. Our analysis of the cancer biology and the selected drugs allows us to propose pos-
DNA adducts sible routes for future drug development based on metal scaffolds.
Molecular tumour targets Ó 2018 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
1.1. Mechanism of action of platinum-based drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
1.2. Lessons from testicular cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
1.3. The post, post-genomic paradigms of cancer growth and treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
1.3.1. Recognizing cancer complexity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
1.3.2. Tumour plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
1.3.3. The microenvironment partnership. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
1.3.4. Where to orientate in such complexity?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
1.3.5. Current trends in handling neoplastic diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
2. Re-visiting the concept of treating tumours with cisplatin in the era of the targeted therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
3. Treating tumours or the tumour microenvironment? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
4. Metal-complexes can target the determinants of tumour malignancy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

Abbreviations: 15-LOX-1, 15-lipoxygenase; AIF, apoptosis inducing factor; APC, adenomatous polyposis coli; AKT or PKB, protein kinase B; ATG16L2, autophagy related 16
like 2; AUC, area under the curve; Bad, Bcl-2 associated death promoter; Bcl-2, B-cell lymphoma 2; Bcl-xL, B-cell lymphoma extra large; bFGF, basic FGF; CAF, cancer
associated fibroblast; CASP, caspase; CLNDP, clearance of nedaplatin; CML, chronic myeloid leukemia; COX-2, cycloxygenase 2; CSC, cancer stem cell; CTL, cytotoxic T
lymphocyte; CTLA-4, cytotoxic T-lymphocyte antigen 4; DC, dendritic cells; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; EMT, epithelial mesenchymal
transdifferentiation; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; GLUT, glucose
transporter 1; HH, Hedgehog; HK2, hexokinase 2; LC3, light chain 3; LDH, lactate dehydrogenase; MAPK, mitogen activated protein kinase; Mcl-1, myeloid cell leukemia 1;
MDM4, mouse double minute 4; MDSC, myeloid-derived suppressor cells; MMP-9, matrix metalloproteinase 9; NCP, nucleosome core particle; NDP, Nedaplatin; NK, natural
killer; NSCLC, non-small cell lung cancer; PDGF-C, platelet-derived growth factor C; PDK, pyruvate dehydrogenase kinase; PDH, pyruvate dehydrogenase; PD-L, programmed
death receptor ligand; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog; STAT, signal transducer and activator of transcription; TGF-b, transforming
growth factor beta; TKI, tyrosine kinase inhibitor; TME, tumour microenvironment; TRAIL, tumour necrosis factor-related apoptosis inducing ligand; Treg, regulatory T cells;
TSP-1, thrombospondin-1; UCHL5, ubiquitin C-terminal hydrolase L5; ULK2, unc-51-like kinase; uPA, urokinase-typa plasminogen activator; uPAR, uPA receptor; UPS,
ubiquitinproteasome system; USP14, ubiquitin-specific protease; VEGF-A, vascular endothelial growth factor-A; VDAC, voltage-dependent anoin channels.
⇑ Corresponding author at: Dept. of Life Sciences, University of Trieste, Via A. Fleming 22, 34127 Trieste, Italy.
E-mail addresses: a.bergamo@callerio.org (A. Bergamo), paul.dyson@epfl.ch (P.J. Dyson), gsava@units.it (G. Sava).

https://doi.org/10.1016/j.ccr.2018.01.009
0010-8545/Ó 2018 Elsevier B.V. All rights reserved.
18 A. Bergamo et al. / Coordination Chemistry Reviews 360 (2018) 17–33

4.1. Sustaining proliferative signalling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

4.2. Resisting cell death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
4.3. Inducing angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
4.4. Activating invasion and metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
4.5. Genome instability and mutation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
4.6. Reprogramming energy metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
4.7. Evading immune destruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
5. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

1. Introduction 1.1. Mechanism of action of platinum-based drugs

New metal-based anticancer compounds are systematically
benchmarked against cisplatin, with respect to its chemical proper-
ties, biological activity and therapeutic applications. Occasionally
the other registered analogues of cisplatin (Fig. 1) are also used to
benchmark new putative metal-based anticancer drugs. Conse-
quently, the approaches used to transfer metal-based compounds
from the laboratory to the clinic, to add to the arsenal of chemother-
apeutics used to control cancer growth, has been ‘conditioned’ by
attempts to obtain compounds with similar therapeutic profiles
to cisplatin, but without the drawbacks of cisplatin. Therefore,
approaches to overcome the toxicity of cisplatin and/or tumour
resistance to cisplatin-containing chemotherapies dominate the
field. This strategy had successfully produced two further drugs
approved world-wide (carboplatin and oxaliplatin) and three other
analogues approved by China, Japan and South Korea (lobaplatin,
nedaplatin and heptaplatin, respectively) (Fig. 1 and Table 1) [1].
The introduction of new platinum-based derivatives into clini-
cal studies has significantly slowed down and, in the last two dec-
ades, only very few analogues were selected, none of which
successfully completed the clinical trials and were proposed to
the FDA or EMA for approval [1–4]. Since it is highly questionable
whether cisplatin would make it into the clinic today, we should,
perhaps, not be surprized that new metal-based drugs with pro-
files similar to cisplatin fail to gain clinical approval. An under-
standing of the reasons for this failure should help to identify
other approaches that may turn out to be more effective.
The principle mode of action of cisplatin and its analogues is
believed to be due to binding to DNA in cancer cells with the cor-
responding negative consequences for cell survival (Fig. 2) [5,6].
Considerable progress has also been made in unravelling other
mechanistic details, for example, understanding how platinated
DNA regions are repaired (see below), which can lead to drug resis-
tance. However, only a small fraction of cisplatin binds to DNA and
the details surrounding the fate of the majority of the drug has yet
to be fully elucidated, i.e. the full mechanism of action of cisplatin
and the other platinum-based drugs remains largely unknown.
A rather simple molecule such as cisplatin is unable to distin-
guish between different cancer cells and the way cisplatin binds
to cellular DNA is presumably independent of the type of cell. Stud-
ies on DNA repair mechanisms may explain resistance phenomena
of certain cancer cells to cisplatin, but it is often difficult to attri-
bute these repair mechanisms to different types of cancer cell
[7,8]. Overall, the way in which cisplatin binds to DNA and the
known resistance mechanisms do not adequately explain why,
even with a very responsive tumour such as testicular cancer, there
are individuals who are completely cured, independent of the stage
of their disease, and others where treatment is only partially suc-
cessful or even completely ineffective [9]. The hypothesis that
the main mechanism of action of cisplatin is based on its ability
to form adducts with the cellular DNA, which cause distortions
that are not recognized by DNA repair mechanisms, has led to a
large number of cisplatin-derivatives that failed to progress

Fig. 1. Structures of the main platinum drugs approved for cancer therapy. In black those approved for use world-wide; in blue those approved in specific countries
(Lobaplatin-China, Nedaplatin-Japan, Heptaplatin-Korea). Carboplatin represents the prototype of 2nd generation and oxaliplatin is the representative of the 3rd generation
of the clinically approved platinum drugs. The arrows trace the ancestry of the second and third generation derivatives of cisplatin.
 A. Bergamo et al. / Coordination Chemistry Reviews 360 (2018) 17–33 19

Table 1
Main characteristics of the clinically approved platinum drugs (from S. Dilruba and G.V. Kalayda, 2013 [1]).

Drug Main characteristics Target tumours

Cisplatin The most clinically used platinum drug; included in many combination regimens
comprising biological/biotechnological drugs.
Carboplatin Same as cisplatin, perhaps less toxic and suitable for more aggressive high-dose
chemotherapy.
Oxaliplatin Bulkiness and lipophilicity are believed responsible for differential processing of
platinum-DNA adducts.
Nedaplatin Recommended therapeutic dose 80–100 mg/m2; PK profile similar to that of
carboplatin. Ishibashi’s formula to predict the correct individual dose: Dose NDP
= AUC
CLNDP, where CLNDP = 0.0738
creatinine clearance + 4.47. Limited
use in Japan. (Shimada et al., 2013, [181])
Lobaplatin Structurally very similar to oxaliplatin; standard dose: 35 mg/m2. Limited use in
China.
Heptaplatin Active in cisplatin resistant tumours. Limited use in the Republic of Korea.
Various cancers, among which ovarian, testicular, bladder, colorectal,
lung and head and neck cancers
Same as cisplatin but with limited efficacy against testicular germ-
cell cancers, squamous cell carcinoma of the head and neck and
bladder cancer
Mainly colorectal cancers but under clinical trials for pancreatic,
gastric, breast and non-small cell lung cancers.
Non-small and small cell lung cancer, esophageal cancer, uterine
cervical cancer, head and neck cancer, or urothelial cancer
CML, small cell lung cancer, breast cancer
Gastric cancer

AUC: area under the curve; CLNDP: clearance of NDP; CML = chronic myeloid leukemia; NDP: Nedaplatin.

However, palliation should not be confused with cure, and corre-

Fig. 2. Schematic representation of the mechanism of cytotoxicity induced by
platinum-based drugs. The drug enters the cell, undergoes activation (aquation)
and then binds to guanine N-atoms in DNA forming inter- and intra-strand
crosslinks that lead to cell death.
beyond pre-clinical studies or were subsequently abandoned dur-
ing clinical studies.
The DNA targeting mechanism has conditioned the preclinical
development of drugs based on other transition metals. The over-
whelming majority of new metal compounds proposed for the
treatment of tumours are evaluated for their cytotoxic effects
against a few cell lines to see if they are as active as cisplatin. This
approach ignores the biological target of the drug since it is usually
assumed that the active drug component interacts with DNA to
produce lesions responsible for the cell death [10–12]. Mechanistic
studies therefore tend to be centred on how the compound
releases or is transformed into the active species that subsequently
binds to the DNA bases and on the speciation of the compound in
biological fluids [13–16].
1.2. Lessons from testicular cancer
Of all cancers, testicular cancer is the most responsive to plat-
inum therapies, in which the chemotherapy is curative in a large
proportion of the treated subjects even when started in advanced
stages of tumour growth [9,17]. The activity of platinum drugs on
testicular cancer has not been reproduced in any other cancer types
even if the chemotherapy regimens with platinum agents are used
with success in the palliative treatment of many other tumours.
sponds to prolongation of the time to the exitus compared to the
natural history of the tumour. Nevertheless, the addition of plat-
inum compounds to chemotherapy regimens is useful for overall
survival in, for example, ovarian, lung, colorectal and breast cancers
and, in general, head-and-neck cancers, although in these cancers
cures are rarely obtained [see for example: [18–20]].
The natural question arising from this difference between tes-
ticular and other cancers is, therefore, what is the molecular basis
for this difference, which makes the latter group less responsive to
platinum drugs? And, if these differences are known, can they be
used to design new metal-based structures (of platinum or other
metals) capable of curing these cancers?
However, before answering these questions, it should be noted
that testicular cancer is not a unique type of tumour and there are
at least five types of tumours with different histologies and differ-
ent molecular pathways referred to as testicular cancer. Testicular
cancers can be roughly divided into seminomatous and non-
seminomatous tumours, and there are further sub-categories
within each of these two groups [21]. If differences between testic-
ular cancers can explain why some are cured whereas others are
not, then it should be possible to define the molecular pathways
that are activated by cisplatin-induced damage leading to the acti-
vation of cell death processes. An in vitro study exploring the sen-
sitivity of testicular tumours to cisplatin led to the conclusion that
‘‘. . .there seems to be no clear relationship between cisplatin-induced
apoptosis and (a) growth characteristics, (b) cellular Pt accumulation,
(c) DNA platination, (d) Pt-DNA adduct removal, (e) p53 status, (f)
intrinsic Bcl-2 and Bax expression and (g) cisplatin-induced modula-
tion of the Bcl-2/Bax ratio.” (Fig. 3) [22]. Despite this analysis, many
attempts to design more effective platinum-based drugs have been
based on obtaining compounds which lead to (a) higher amounts
of DNA platination, (b) higher resistance to the removal of Pt-
DNA adducts and (c) higher levels of cellular platinum
accumulation.
Extending the analysis concerning testicular cancer to other
cancer types should be taken with caution. Recent studies have
unravelled some aspects of the complexity of the sensitivity of tes-
ticular cancer to platinum drugs and, as mentioned above, the
expression of p53, Bcl-2 and Bax were not particularly relevant
for the induction of apoptosis by cisplatin [22]. In another
in vitro study of different testicular cancer cell lines it was con-
cluded that ‘‘. . .wild-type TP53 and the low levels of p53 in complex
with the p53 negative feed-back regulator MDM2 contribute to cis-
platin sensitivity.” and that ‘‘. . .the high levels of the pluripotency reg-
ulator Oct4 . . . the high levels of miR-17/106b seed family and pro-
apoptotic Noxa and the low levels of cytoplasmic p21 (WAF1/Cip1)
20 A. Bergamo et al. / Coordination Chemistry Reviews 360 (2018) 17–33
Fig. 3. Cytotoxicity of platinum drugs and characteristics of the pathways activated in treated testicular cancer cells [9,17,22].
appear to be causative for the exquisite sensitivity to cisplatin-based
therapy of testicular cancer.” (Fig. 3) [9,17].
In other words, it is not possible to expect the efficacy of cis-
platin of tumours that do not show the same characteristics of
the responsive tumours, because only the cells of these tumours
have the possibility to activate the corrected pathways necessary
to induce cell death. Therefore, it is not possible to overcome the
resistance of tumours to cisplatin with new derivatives endowed
with a higher capacity than cisplatin to penetrate the tumour cell,
of producing Pt-DNA adducts, and being less susceptible to the
mechanisms that remove these adducts. Instead, it is necessary
to identify the characteristics of the pathways that regulate
tumour cell survival in order to design metal-based drugs that
induce the changes required to induce cell death.
1.3. The post, post-genomic paradigms of cancer growth and treatment
In recent years powerful new research tools and refined exper-
imental models have become available, and critical regulatory
genes were identified changing the anatomical, histological, cellu-
lar and molecular genetic landscape of cancer. This wealth of new
information has shaped a new history and geography of tumours
superseding the reductive view that tumours are merely masses
of abnormally proliferating cancer cells.
1.3.1. Recognizing cancer complexity
Today we have a clearer view of cancer complexity. Tumours
are considered as real tissues, which are dependent on multiple
distinct cell types. The participation of cancer and host cells in het-
erotypic interactions result in their constant and dynamic co-
evolution, changing their characteristics with time. This implies
that studying and understanding the characteristics of tumours
should not be separated from considering the microenvironment,
which is both a cause and a consequence of tumorigenesis. The
main trait underlying tumour complexity is the tremendous
heterogeneity of neoplastic diseases. Heterogeneity concerns the
genetics, the epigenetics, the proteomics and the biochemistry of
the tumour, and is manifest at intra-tumoural, inter-metastatic,
intra-metastatic and inter-patient levels. From a genetic stance,
cells located at distant sites within a tumour mass show more dif-
ferences than neighbouring cells [23]. Such intra-tumour hetero-
geneity is relevant to tumour progression, since it provides the
basis for inter-metastatic heterogeneity among different meta-
static lesions of the same patient, each originating from a founder
cell, or small group of cells, with a very different mutation kit, and
likely originating from different and distinct primary tumour areas
[23]. This situation has important implications regarding
chemotherapeutic sensitivity and responses. In addition, the off-
spring of the founder cell(s), as they continue to divide, can acquire
new and different mutations generating heterogeneity among the
cells of an individual metastasis, affecting the response to systemic
therapies and providing the seeds for drug resistance. Somatic
mutations within tumours further underpin the heterogeneity
among tumours of different patients, and account for the unique
clinical course of each patient typically observed in clinical prac-
tice. However, patient outcome is also determined by additional
factors such as pharmacokinetics and non-genetic factors [24].
1.3.2. Tumour plasticity
During multistep tumour progression, certain clonal expansions
may be elicited by non-mutational changes altering regulation of
gene expression, e.g. through epigenetic mechanisms, i.e. DNA
methylation and histone modifications [25–27]. Human tumours
harbour large numbers of epigenetic changes [28]. Interestingly,
a feature of epigenetics is plasticity [29], implying that epigenetic
changes are subject to microenvironmental influences [28].
It is noteworthy that phenotypic heterogeneity of cancer cells
within a tumour mass may also develop from a genetically homo-
geneous population due to the presence of cells in different states
of differentiation. This phenotypic plasticity can be traced to the
 A. Bergamo et al. / Coordination Chemistry Reviews 360 (2018) 17–33
presence of a subclass of neoplastic cells within tumours, i.e. can-
cer stem cells (CSCs) [30,31]. In recent years, evidence has accumu-
lated that CSCs are a common constituent of most tumours and
they have been shown to express markers that are also present
in the normal stem cells of the tissue of origin, with which they
share self-renewal capability, and have the ability to generate
new tumours [32,33]. The origin of CSCs remains to be clarified
and may even vary from one tumour type to another. The acquisi-
tion of CSC traits has been recently related with the epithelial mes-
enchymal transdifferentiation (EMT) program [34–36]. EMT allows
cancer cells to be disseminated from the primary tumour, and can
also confer the self-renewal capability needed for the clonal expan-
sion at sites of dissemination. The connection between EMT and
CSCs implies that the heterotypic signals that elicit the transdiffer-
entiation process, such as those released by an inflammatory
stroma, may be important in creating and maintaining CSCs. By
definition plasticity is a distinctive feature of CSCs that can shift
to a non-CSCs status and vice versa, but can also turn to produce
stromal cell types as observed in glioblastomas [37–40]. The pres-
ence of CSCs within the tumour mass affects cancer therapies since
resistance to treatments, and disease recurrence, may be attributed
to the lower sensitivity of CSCs to commonly used drugs, and to
their ability to regenerate the tumour once therapy has ceased.
1.3.3. The microenvironment partnership
Most heterogeneity is manifest in the tumour microenviron-
ment (TME), which is populated by a set of specialized cell types
including multipotent stromal cells/mesenchymal stem cells,
fibroblasts, endothelial cell precursors, and immune cells [41].
During tumour progression the abundance and the phenotypic
characteristics of these cell types change, as well as the composi-
tion of the extracellular matrix (ECM) due to the interplay between
the tumour cells (parenchyma) and the mesenchymal cells forming
the tumour-associated stroma. These heterotypic interactions cre-
ate a succession of tumour microenvironments that change with
time and enable primary, invasive and then metastatic growth
[42]. Cancer cell biology is governed by extremely sophisticated
networks of interactions between neoplastic and stromal cells that
affect and, at the same time, are influenced by the evolution of the
surrounding ECM. This continuously changing dynamic is essential
for tumour establishment, growth and dissemination. Indeed, the
reciprocal interactions between cancer and stromal cells activate
dissemination and, in turn, enhance the neoplastic character of
the cancer cells. Moreover, cancer cells can further stimulate the
stroma to facilitate and expedite their reprogramming allowing
them to invade adjacent tissues and disseminate. Such dynamics
characterizes multi-stage tumour development and prevents a full
understanding of cancer pathogenesis.
1.3.4. Where to orientate in such complexity?
There is enormous cancer diversity comprising hundreds of
cancer types and subtypes that affect most organs and tissues of
the body and is brought about by genetic mutations and rearrange-
ments and by epigenetic reprogramming. This multiplicity also
relies on different recruitment of normal supporting cells at differ-
ent rates of disease progression. While this complexity is daunting,
neoplastic disease is the result of an evolutionary process based on
a small set of organizing principles, which display an underlying
order. A rationalization of cancer complexity was shaped in 2000
by Hanahan and Weinberg [43], and was more recently revisited
by the same authors [42]. They traced cancer to eight hallmarks,
‘‘distinctive and complementary capabilities that enable tumour
growth and metastatic dissemination”, allowing the biology of neo-
plastic disease to be understood. These hallmarks, i.e. sustaining
proliferative signalling, evading growth suppressors, activating inva-
sion and metastasis, enabling replicative immortality, inducing angio-
21
genesis, resisting cell death, deregulating cellular energetics, avoiding
immune destruction, are expressed at varying degrees in almost
all tumours. In addition, the acquisition of such features depends
on two ‘‘enabling characteristics” i.e. genome instability and
tumour-promoting inflammation [42].
Cancer is a genetic disease originating from and sustained by
genomic instability. In the ‘‘breakthrough phase” a cell begins to
proliferate abnormally after the acquisition of a ‘‘driver-gene muta-
tion”, i.e. a mutation that confers a selective growth advantage to
the tumour cell [44]. Thus, a Mut-driver-gene is a gene that, if
altered by intragenic mutations, can drive tumorigenesis. During
the following ‘‘expansion phase” a second driver-gene mutation
enables the cell to grow in its environment despite hostile condi-
tions, and subsequent mutations allow cells to invade and metas-
tasize. Sequencing analyses for more than 22,000 cancers have
revealed more than 3 million somatic mutations, but around only
140 Mut-driver-genes [28,44]. Furthermore, considering Mut-
driver-genes at a pathway level, rather than at an individual level,
there are only a limited number of cellular signalling pathways
through which a growth advantage can be gained. All the known
driver genes can be traced to one or more of 12 pathways that reg-
ulate three core cellular processes, these being (i) cell fate (NOTCH,
HH (Hedgehog), APC (Adenomatous Polyposis Coli), Chromatin
modification, Transcriptional regulation), (ii) cell survival (cell
cycle/apoptosis, RAS, PI3K (Phosphoinositide 3-kinase), STAT (Sig-
nal Transducer and Activator of Transcription), MAPK (Mitogen
Activated Protein Kinase), TGF-b (Transforming Growth Factor
beta)) and (iii) genome maintenance (DNA damage control). A typ-
ical tumour contains 2 to 8 driver-gene mutations, moreover the
protein products of genes regulate cell fate, cell survival and gen-
ome maintenance and often interact with one another, so that
the pathways overlap [44]. This means that therapeutic efforts
can be restricted to a few pathways.
1.3.5. Current trends in handling neoplastic diseases
Based on the current understanding of neoplastic diseases the
paradigms of cancer pharmacological treatments are also evolving
with complete cancer eradication often considered to be a seem-
ingly unattainable goal. A better approach is to try to circumvent
neoplastic disease by deploying an array of different strategies.
First, it is necessary to change the perspective and to consider
the treatment of cancer with an integrated, holistic view. Since cur-
ing advanced cancers (those that cannot be eradicated by surgery
and have already metastasized) is unlikely, a more successful route
is to consider cancer a chronic and manageable disease. Therefore,
to reduce morbidity and mortality, efforts to potentiate prevention
and make early diagnosis, two areas that benefit greatly from
recent developments in cancer biology, offer considerable opportu-
nities. In addition, molecular targeted therapies, targeting particu-
lar cancer mechanisms and hallmark capabilities, represent a
significant advance in the treatment of cancer [45,46], but they
are not magic bullets. Indeed, over time, tumours engender resis-
tance to treatment, and relapses often occur after only a few
months [28]. Consequently, it is necessary to target as many cancer
capabilities as possible, rather than merely target a single mecha-
nism. In practice, it is usual to select an array of targets (the ‘‘Targe-
tome”) to develop a broad-spectrum therapeutic approach. This
implies employing a ‘‘network pharmacology” plan, shifting from
a target-oriented approach towards a network-directed strategy,
with the goal of interfering with multiple parts of a biological sys-
tem. Thus, it is possible to directly target the tumour cells or indi-
rectly inactivate and/or neutralize cells of the microenvironment.
However, in order to select which cancer hallmark to target, it is
necessary to consider the detailed cancer biology. The search for
drugs for advanced cancers should not be generic, as each tumour
type has peculiar characteristics depending on the growth stage,
22 A. Bergamo et al. / Coordination Chemistry Reviews 360 (2018) 17–33
Fig. 4. Schematic of the pathways involved in the modulation of the response of tumour cells to platinum drugs.
organ and composition of the microenvironment. Therefore, one or
more molecules sustaining a specific hallmark in a well-defined
tumour, at a particular stage of growth, should be targeted.
Each tumour and even each tumour setting is unique and two
examples are particularly relevant to illustrate this concept. First,
a gene can function differently in different tumour types, as in
the case of NOTCH, which genetic data indicate to be an oncogene
in lymphomas and leukemias and a tumour suppressor gene in
squamous cell carcinomas [47–50]. Second, pathway functions
are different, depending on the organism, cell type, and precise
genetic alterations in a cell [51]. This difference explains why treat-
ment with drugs inhibiting mutant BRAF kinase activity gives dra-
matic remissions in the majority of melanoma patients harbouring
the BRAF V600E mutation [52], whereas the same drugs have no
therapeutic effect in colorectal cancer patients harbouring the
same genetic alteration [53]. The expression of Epidermal Growth
Factor Receptor (EGFR) in colorectal cancer, but not in melanoma,
is liable for the circumvention of the growth-inhibitory effects of
the BRAF inhibitors.
2. Re-visiting the concept of treating tumours with cisplatin in
the era of the targeted therapy
The cytotoxicity of platinum drugs cannot be solely attributed
to the principles of their reactivity with DNA of cancer cells, a con-
cept that has often been used to support the lack of effectiveness of
many derivatives in experimental models [see for example [54]].
The anticancer activity of a platinum-based complex, and indeed
of any metal-based compound, whether expressed as cytotoxicity
or inhibition of cancer growth, depends on the ability of the com-
pound to activate cancer cell death pathways (see the example in
Fig. 3). The study of cell growth and differentiation has revealed
that all cells have several pathways capable of activating their
own suicide or their survival. Tumour cells do not differ from this
general rule, although they may have hidden the death pathways
by overexpression of other signals. Hence, targeted drugs are able
to act against tumours that are apparently resistant to conven-
tional therapies as they disturb the overexpression of these signals.
It appears that only targeted therapies can effectively treat resis-
tant tumours. Note that data from clinical trials suggest that the
anti-tumour effects of the platinum-based drugs depend on the
molecular characteristics of the transcriptome/proteome of the
cells (see below).
It is known that only a small amount of cisplatin that enters a
cancer cell is found in the nucleus and therefore the different cel-
lular responses to platinum-drugs could be based on the differ-
ences in pathways activated by the individual cells rather than
only to DNA binding. In this respect a number of clinical studies
show the dependence of the tumour response to cisplatin on the
presence of specific mutations in specific pathways of the tumour
cells (Fig. 4).
The significantly greater response of non small cell lung cancer
(NSCLC) patients with the WEE1 rs3910384 G/G homozygote geno-
type compared to those with the A/A + A/G genotype to the combi-
nation therapy of cisplatin and gemcitabine [55], suggests the
greater importance of downstream pathways over the initial DNA
damage, where the activity of an important checkpoint, such as
WEE1 for the regulation of the cell cycle progression, becomes
the limiting step for cell survival to the drug-induced changes
[56]. Similarly, the expression of the translational initiating factor
eIF3a negatively modulates the cells capacity to react to the
platinum-induced DNA lesions and, correspondingly, the tumours
in which this factor is down-regulated (e.g. in ovarian cancer,
NSCLC and nasopharyngeal carcinomas) gain a survival benefit
and become resistant to these drugs [57–59].
Growing evidence supports the role of non-coding microRNAs in
the sensitivity/resistance of tumours to platinum drugs. An example
involves miR-193b, a tumour suppressor factor in association with
Mcl-1 (Myeloid cell leukemia 1) in hepatocellular carcinoma, which
becomes determinant to enhance the sensitivity of this tumour to
platinum therapy [60]. In squamous cell carcinoma miR 885-3p also
plays a crucial role, through the modulation of the cell mRNAs of
MDM4 (Mouse Double Minute 4), AKT1 (also known as Protein
Kinase B PKB), BCL2 (B-Cell Lymphoma 2), ATG16L2 (Autophagy
Related 16 Like 2), ULK2 (Unc-51-Like Kinase), CASP2 and CASP3
(Caspase 2 and 3), leading to an increased sensitivity to cisplatin
[61,62]. Similarly, the down-regulation of Breast Related Cancer
 A. Bergamo et al. / Coordination Chemistry Reviews 360 (2018) 17–33
Antigen BRCA1-IRIS, a pathway involved in the promotion of metas-
tasis and in the resistance to anoikis of tumour cells, sensitizes ovar-
ian cancer cells to low doses of platinum therapy [63]. Support to the
role of the presence of BRCA mutations was also given by a study [64]
in patients with metastatic triple negative breast cancer who
received cisplatin or carboplatin in monotherapy. Similarly, another
study showed that oxaliplatin-based therapy of colorectal cancer
patients is much more effective when the tumours are represented
by the KRAS mutant subtypes [65].
Another interesting aspect involves the capacity of platinum
drugs to prevent the development of acquired resistance of certain
cancer cells to the targeted therapies. Although there are only a
few examples available, the study with Gefitinib in advanced
NSCLC patients clearly shows that the addition of a platinum ther-
apy prevents the onset of resistance after the initial sensitivity
shown to this specific tyrosine kinase inhibitor (TKI) [66]. This syn-
ergy with targeted therapies is an important aspect of the actual
use of the platinum drugs in cancer chemotherapy and can over-
come cancer resistance due to specific mutations, e.g. the combina-
tion therapy comprising oxaliplatin and dovitinib, a TKI, in
colorectal cancers irrespective of their Ras-Raf mutation state
[67]. In other situations, targeted therapies may suppress the
capacity of cancer cells to repair the damage induced to DNA,
therefore amplifying the activity of platinum drugs, as shown by
the use of a Bcl-2 inhibitor in NSCLC [68].
A new frontier for conventional platinum drugs, i.e. cisplatin,
carboplatin and oxaliplatin, is represented by their utility in com-
bination with the novel anticancer immunotherapies [69]. Since it
was demonstrated that the damage induced by cisplatin or oxali-
platin on tumour cells leads to the release of factors that promote
the recruitment and activation of macrophage-dependent lympho-
cyte reactions against the tumour cells, combinations of platinum
drugs with MoAb-based treatments have found new perspectives
in the clinic [70]. Signs of the induction of immunogenic cell death,
such as the exposure of calreticulin at the cell surface, by the com-
bined regimen of cisplatin plus pyridoxine in NSCLC cells, require
an intact immune system in order to lead to a significant anti-
tumour response [71]. With this action platinum drugs negatively
regulate the signal transducer and activation transcription factor 6
(STAT6) dependent programmed death receptor ligand 2 (PD-L2) in
dendritic cells, resulting in an enhanced immune response against
the tumour cells [72–74].
The feature that connects all these events is the interaction of
the platinum drugs with DNA together with the corresponding
descending events [7]. However, the interaction with DNA is only
one step in the anti-tumour activity of cisplatin and of its clinically
used analogues. Besides inducing DNA lesions, it is equally, if not
more important, that the target cell is unable to repair such damage
or, alternatively, that the platinum drug interacts also with other
targets to lead the cell to activate its death mechanisms [75]. The
interaction with multiple targets, besides nucleic acids, may ulti-
mately be responsible for the success or of the failure of the therapy
[76–79]. Therefore, to some extent platinum drugs behave similarly
to targeted therapies, mimicking what is often observed with small
molecules used to target tyrosine kinase receptors, the proteasome
or something else overexpressed by a cancer cell.
3. Treating tumours or the tumour microenvironment?
Tumours in patients inherently grow in an interactive milieu of
tumour cells and stroma, a term referring to all non-malignant
cells, including endothelial cells, fibroblasts, and infiltrating leuko-
cytes, as well as extracellular matrix proteins. The tumour
microenvironment (TME) produces different types of stimuli cap-
able of endowing tumour cells with aggressive behaviour, which
23
may lead to the induction of malignant traits. It is now established
that the gain of a malignant phenotype is not the result of a direct
effect of the stimuli on tumour cells but, rather, the consequence of
a stimulus-promoted cross-talk between tumour cells and other
cell types within the TME [80]. Furthermore, recent findings have
uncovered novel roles for the TME in modulating therapeutic effi-
cacy, and stromal signatures have been shown to have powerful
prognostic value in predicting treatment outcome [81–84]. There
are many examples of how the TME can affect drug response.
Tumours resistant to alkylating agents become sensitive to the
same agents when grown ex vivo in the absence of other cells
[85]. Colon carcinoma cells injected in orthotopic metastatic sites
show a different response to doxorubicin when compared with
an ectopic subcutaneous implant [86]. Melanoma may become
resistant to inhibitors of mutant V600E BRAF due to Hepatocyte
Growth Factor (HGF), a stroma-derived paracrine growth factor
secreted in the TME [83,84]. Refractoriness to anti-angiogenic ther-
apy in vivo can result from elevation of pro-angiogenic Platelet-
Derived Growth Factor C (PDGF-C) expression by cancer associated
fibroblasts (CAFs) [87]. In glioblastomas, anti-angiogenic therapies
may even increase local invasion and metastasis as cancer cells
may reduce their dependence on a particular hallmark capability
(angiogenesis), becoming more dependent on another (invasion
and metastasis) [42]. This last example introduces a basic notion,
i.e. partially redundant signalling pathways regulate each of the
core hallmark capabilities. In addition, stromal paracrine factors,
acting as mediators of malignant traits, also appear highly redun-
dant [80]. The main consequence for therapeutic design and plan-
ning is that the inhibition of one key pathway in a tumour may not
completely eradicate a hallmark capability [42].
Tumour and non-tumour cells work to the development and
progression of several neoplastic diseases, thereby non-tumour
cells may constitute legitimate targets for therapeutic intervention.
In addition to the cell type, a rationale therapeutic approach should
comprise the orchestrated inhibition of multiple key molecules
and pathways.
A particularly attractive example is the targeting of the immune
cells of the TME. Both the innate and adaptive immune system
infiltrate many tumours [88,89], which may be interpreted as a
sign of inflammatory conditions within the tumour mass, reflecting
an attempt by the immune system to inhibit tumour development.
Now it is recognized that tumour-associated inflammatory cells
have a conflicting dual role. Indeed, both tumour-antagonizing
and tumour-promoting leukocytes can be found in most cancers.
It is now widely accepted that tumour inflammation is a potent
motor that promotes a microenvironment that favours many steps
of carcinogenesis, namely the expansion of genomic aberrations,
cellular transformation, apoptosis evasion, invasion, amongst
others [90–94]. As tumour growth progresses, macrophages and
mast cells secrete matrix degrading enzymes, chemokines and
cytokines, which elicit local stromal cells to recruit circulating
leukocytes into tumour tissue causing an acute inflammatory sta-
tus [95]. However, the imbalance between the two processes driv-
ing the repair of the damaged tissues, i.e. apoptosis and wound
healing, turns an acute process into a chronic inflammation, which
led to the description of tumours as ‘‘wounds that never heal”
[89,96]. The re-establishment of the balance between the contrast-
ing inflammatory responses in tumours is behind the concept of
therapies designed to redirect immune system cells towards
tumour destruction [97,98]. This can be achieved by both selective
anti-inflammatory drugs, and by immune re-education, stimulat-
ing again the immune arm able to combat tumour cells. It seems
likely that cancer immunotherapy will become a major part of
the combination treatment plan for patients with many cancer
types [99]. Indeed, patients with cancers at advanced stages of
growth show a durable anti-tumour response to drugs targeting
24 A. Bergamo et al. / Coordination Chemistry Reviews 360 (2018) 17–33
a a
Fig. 5a. The ruthenium(II) compound [(g6-p-cymene)Ru(6-(2-(2-(1H-imidazol-
1yl))ethoxy)-4-(30 -chloro-40 fluoroanilino)-7-methoxy-quinazolin)Cl2] induces
apoptosis at earlier stage than the ruthenium moiety and the anilinoquinazoline
ligand alone through the inhibition of EGFR and the interaction with the DNA minor
groove [105]. (EGFR = Epithelial Growth Factor Receptor).
b ruthenium(II) chloride, K-[Ru(bpy)2-(o-tFPIP)]Cl2 induces autophagy by increasing
Fig. 5b. Examples of Ru(II) and Ru(III) derivatives of 4-anilinoquinazoline.
pathways of the immune response, such as the T-cell receptors
Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) and programmed
death ligand 1 (PD-L1), in therapeutic approaches that can be tai-
lored also to different TMEs [99,100].
4. Metal-complexes can target the determinants of tumour
malignancy
While DNA is often the assumed target of metal-based drugs,
recent studies show that some compounds act via non-DNA dam-
aging mechanisms and are able to target the hallmarks of cancer.
Indeed, these mechanisms might be much more prevalent than
currently thought as most new metal-based anticancer compounds
are merely evaluated for cytotoxic effects in vitro and compared to
cisplatin, as mentioned above.
Here we report selected examples of metal-complexes by cate-
gorizing them according to the specific cancer hallmark affected by
the compound.
4.1. Sustaining proliferative signalling
The uncontrolled proliferation of cancer cells is enabled by
growth factors that interact with cell-surface receptors in which
Fig. 6a. Examples of metal compounds that contrast the resistance of tumour cells
to cell death mechanisms. The ruthenium polypyridyl complex RuPOP ([Ru(phen)2-
p-MOPIP][PF6]2) induces mitochondria-mediated and caspase-dependent apoptosis
[106]. NiPT, a nickel pyrithione compound potently inhibits two deubiquitinases
associated to the 19S proteasome [109,110]. The ruthenium complex K-WH0402
(K-bipyridine 2-(2-trifluoromethphenyl)imidazole[4,5-f][1,10]phenanthroline
the expression of Beclin-1 and the conversion of the cytoplasmic form of
microtubule-associated protein 1 light chain 3 (LC3 I) to LC3 II [114]. (LC3 I =
Light Chain 3 I; LC3 II = Light Chain 3 II; UPS = Ubiquitin-Proteasome System).
Fig. 6b. Structures of ruthenium polypyridyl (RuPOP) complexes.
binding subsequently leads to a number of down-stream signalling
pathways. The epidermal growth factor receptor (EGFR) is at the
forefront of many of these pathways and several therapeutic
strategies have been developed to target it [101,102]. A series of
dual-functional ruthenium anti-tumour complexes exploit the
‘‘pharmacophore conjugation” strategy [103–105]. These complexes
contain 4-anilinoquinazoline ligands, an EGFR inhibitor. The EGFR
inhibitory activity is retained and, in addition, a high affinity
towards DNA via minor groove binding was observed. In particular,
both Ru(II) and Ru(III) derivatives of 4-anilinoquinazoline have
anti-proliferative activity towards the EGF-stimulated growth of
MCF-7 human breast cancer cells [103,104]. Related complexes
with a 6-(2-(2-(1H-imidazol-1yl))ethoxy)-4-(30 -chloro-40 fluoroani
lino)-7-methoxy-quinazoline) ligand were shown to induce apop-
tosis at an earlier stage than the 4-anilinoquinazoline-based com-
pounds (Figs. 5a and 5b) [105].
 A. Bergamo et al. / Coordination Chemistry Reviews 360 (2018) 17–33
Fig. 7. Structure of K-WH0402.
4.2. Resisting cell death
Among cell death mechanisms, apoptosis is considered a hurdle
to cancer development and growth. Elucidation of molecular cir-
cuitries governing the apoptotic process has revealed various
inducing stresses, both naturally occurring during tumorigenesis,
or consequent to anti-cancer therapy. Certain ruthenium com-
pounds display anti-cancer properties through the activation of
apoptotic processes (Figs. 6a and b). For example, a series of ruthe-
nium functionalised polypyridyl complexes, e.g. [Ru(phen)2-p-
MOPIP][PF6]2 (RuPOP) induce mitochondria-mediated and
caspase-dependent apoptosis in human cancer cell lines, thus
exerting anti-proliferative activity [106]. RuPOP suppresses the
expression of the anti-apoptotic Bcl-2 and Bcl-xL (B-cell lymphoma
extra large) proteins, and up-regulates the expression of the pro-
apoptotic protein Bad (Bcl-2 associated death promoter). These
changes lead to loss of the mitochondrial membrane potential
and to the release of apoptogenic factors such as cytochrome c
and apoptosis inducing factor (AIF). More recently, RuPOP was
shown to synergistically enhance tumor necrosis factor-related
apoptosis inducing ligand (TRAIL)-induced apoptosis in the triple
negative breast cancer cell line MDA-MB-231, suggesting that the
combined treatment of RuPOP and TRAIL represents a novel strat-
egy to inhibit the growth of this aggressive subtype of breast can-
cer [107].
Cancer cell apoptosis can be induced by metal complexes
through the inhibition of the ubiquitin–proteasome system (UPS)
[108]. Notably, proteasome inhibition alters the homeostatic
mechanisms of cell protein catabolism, inducing cell death. Metal
complexes based on copper, zinc and nickel exhibit this activity
[109,110]. Notably, the nickel pyrithione compound NiPT potently
inhibits the UPS by targeting Ubiquitin C-terminal Hydrolase L5
(UCHL5) and Ubiquitin-specific protease 14 (USP14), two deubiq-
uitinases associated with the 19S proteasome, leading to apoptosis
in both cultured cancer cells and cells from acute myeloid leukae-
mia patients. The proteasome inhibition of NiPT has been validated
in a xenograft model in nude mice where it affects tumour growth.
Autophagy is a key process induced when cells suffer stresses
such as nutrient deficiency [111,112]. Cells break down intracellu-
lar proteins and organelles, through lysosome-mediated degrada-
tion, to recycle the resulting catabolites and to use them for
metabolism and biosynthesis. Growing evidence indicates that
autophagy and apoptosis are intertwined [113]. The pro-
apoptotic protein Bcl-2 binds Beclin-1, which is responsible for
triggering the canonical autophagy pathway. A ruthenium com-
plex, K-bipyridine 2-(2-trifluoromethphenyl)imidazole[4,5-f]
[1,10]phenanthroline ruthenium(II) chloride, K-WH0402 (Fig. 7),
induces autophagy in hepatocellular carcinoma cells HCCLM6
through a Beclin-1-dependent pathway [114]. K-WH0402
increases the expression levels of Beclin-1 and decreases the inter-
action between Beclin-1 and Bcl-2. In addition, it promotes the
conversion of the cytoplasmic form of microtubule-associated pro-
25
Fig. 8a. Examples of anti-angiogenic metal compounds. The 8-hydroxyquinoline
ruthenium(II) complexes BQ ([Ru(bpy)2(8-HQ)]+) and PQ ([Ru(phen)2(8-HQ)]+)
interfere with the binding of bFGF to its receptor thus disrupting the down-stream
signalling pathway and suppressing several features of endothelial cells [124]. Ru-
SeNPs (ruthenium(II) polypyridyl functionalized selenium nanoparticles) interact
also with bFGF causing profound change of its conformation [125]. (bFGF = basic
Fibroblast Growth Factor; bFGFR = basic Fibroblast Growth Factor Receptor).
b
Fig. 8b. Structure of 8-hydroxyquinoline ruthenium(II) complexes [Ru(bpy)2(8-
HQ)]+ (BQ) and [Ru(phen)2(8-HQ)]+ (PQ) (left) and the complex that has been
attached ot selenium nanoparticles (right).
tein 1 light chain 3 (LC3 I) to LC3 II, which is a marker of
autophagosome accumulation. It is worth noting that autophagy
appears to have a conflicting role on cancer cells and on tumour
progression depending on the stimulus and the cell type
[115,116]. In this case, however, the induction of autophagy inhi-
bits tumour growth and progression in agreement with the activity
of a series of ruthenium(II) compounds containing a b-carboline
alkaloid as ligand [117].
4.3. Inducing angiogenesis
During cancer progression angiogenesis is always in play, which
is triggered mainly by vascular endothelial growth factor-A (VEGF-
A) and its receptors, and by members of the fibroblast growth fac-
tor (FGF) family [118,119], and countered by factors that oppose
angiogenesis such as thrombospondin-1 (TSP-1) [119,120].
Anti-angiogenesis agents have been introduced in various clin-
ical cancer chemotherapies [121–123], and metal-based com-
plexes also have been investigated for their anti-angiogenic
potential. 8-Hydroxyquinoline ruthenium(II) complexes [Ru
(bpy)2(8-HQ)]+ (BQ) and [Ru(phen)2(8-HQ)]+ (PQ) suppress the
proliferation, migration, invasion, tube formation and microvessel
growth of endothelial cells in vitro [124]. The mechanism of action
involves interfering with binding of bFGF to its receptors on the
cell surface and the consequent inactivation of bFGF-mediated sig-
nalling (Figs. 8a and 8b). The ability to interact with bFGF was
26 A. Bergamo et al. / Coordination Chemistry Reviews 360 (2018) 17–33
a selenium nanoparticles (Ru-SeNPs) [125]. In the presence of Ru-
Fig. 9a. Examples of metal compounds that inhibit invasion and metastasis. The
ruthenium complex RAWQ11 ([(g6-C6H6)Ru(H2iip)Cl]Cl) inhibits invasion and
metastasis through the targeting of miR-21 that affects downstream PTEN and
AKT pathway [127]. RuPOP ([Ru(phen)2-p-MOPIP](PF6)22H2O) suppresses the
phosphorylation of FAK and then inactivates AKT and ERK signalling [107]. The
phosphorylation of FAK is central also in the mechanism of action of the ruthenium
compound NAMI-A ([ImH][RuCl4(DMSO)Im) [130], and the vanadium compound
VOChrys ([VO(chrysin)2EtOH]2) [131]. (AKT/PKB = Protein Kinase B; MMP-9 =
Matrix Metallo Proteinase 9; p-ERK = phospho-Extracellular signal Regulated
Kinase; p-FAK = phospho-Focal Adhesion Kinase; PTEN = Phosphatase and Tensin
homologue; uPA = urokinase-type Plasminogen Activator; uPAR = urokinase-type
Plasminogen Activator Receptor).
b
Fig. 9b. Structure of the ruthenium(II) complex RAWQ11.
Fig. 10. Structure of NAMI-A (top, left), VOChrys (top, right) and the 15-LOX-1
inhibitors [Ru([9]aneS3)(dmso)(N,N- or N,O-donor ligand)]2+ and [(g6-p-cymene)
(RuCl(O,O-ligand)]Cl inhibit (bottom).
demonstrated also for ruthenium(II) polypyridyl functionalized
SeNPs, bFGF undergoes a dramatic change of conformation, as
showed by circular dichroism experiments, and the direct interac-
tion of Ru-SeNPs was further confirmed by their ability to protect
bFGF from trypsin digestion. Other ruthenium(II) complexes have
been shown to provide angiostatic cancer treatments in vivo when
optimally combined with other agents [126].
4.4. Activating invasion and metastasis
Over the past decade the mechanisms underlying invasion and
metastasis have been the subject of numerous investigations and,
although many aspects need to be clarified, relevant features of
these processes have been revealed. The role of cell-to-cell and
cell-to-ECM adhesion molecules has been ascertained, as well that
of matrix-degrading enzymes, of epithelial to mesenchymal transi-
tion (EMT), and of the heterotypic contributions emanating from
the tumour stroma. Correspondingly, many metal compounds have
been tested as inhibitors of cancer cell invasion and metastasis,
both in vitro and in vivo, and evaluated for their potential to target
these malignant characteristics (Figs. 9a and 9b). A ruthenium
complex of formula [(g6-C6H6)Ru(H2iip)Cl]Cl (RAWQ11) inhibits
the invasion and metastasis of MDA-MB-231 cells, changing their
morphology, affecting the number of focal adhesions, and contrast-
ing the invadopodia formation [127]. These functional effects
result from the down-regulation of miR-21 and the subsequent
up-regulation of PTEN (Phosphatase and tensin homolog) that
leads to the negative regulation of the AKT pathway. This pathway
is considered to be central in metastasis inhibition induced by
another ruthenium complex, i.e. RuPOP [Ru(phen)2-p-MOPIP]
(PF6)2 (Fig. 6b), in MDA-MB-231 cells [107]. RuPOP inactivates
AKT and ERK (extracellular signal-regulated kinase) signalling by
decreasing the expression levels of their phosphorylated forms,
via the suppression of the phosphorylation of the Focal Adhesion
Kinase (FAK) at Tyr397. An additional effect of impaired FAK acti-
vation corresponds to the down-regulation of the ECM degrading
enzymes including urokinase-type plasminogen activator (uPA),
urokinase-type plasminogen activator receptor (uPAR), and matrix
metalloproteinase 9 (MMP-9), that FAK usually stimulate through
the Ras/MEK/ERK and PI3K/Akt pathways [128,129].
FAK is emerging as a target of other metal complexes. The
ruthenium compound [RuCl4(DMSO)Im][ImH] (NAMI-A, Fig. 10)
reduces FAK auto-phosphorylation on Tyr397 by a mechanism
involving the a5b1 integrin, which modulation determines the
anti-migratory effect of NAMI-A in a colorectal cancer cell line,
and presumably being important for the anti-metastatic activity
displayed in a model of hepatic metastases in vivo [130]. An oxo-
vanadium(IV) complex with a flavonoid chrysin ligand [VO
(chrysin)2EtOH] (VOChrys) is also able to reduce the phosphoryla-
tion level of in situ expressed FAK, leading to alteration of the
related cell signalling pathway [131]. Ruthenium complexes devel-
oped as 15-lipoxygenase-1 (15-LOX-1) inhibitors for inflammatory
and respiratory diseases [132] could also exhibit anti-metastatic
properties. Lipoxygenases catalyse the formation of signalling
molecules such as leukotrienes, lipoxins and eoxins from polyun-
saturated fatty acids, which have a role in inflammatory lung dis-
eases [133]. Two types of complexes with the general formula
[Ru([9]aneS3)(dmso)(N,N- or N,O-donor ligand)](PF6)2 and [(g6-p-
cymene)(RuCl(O,O-ligand)]Cl (Fig. 10) inhibit 15-LOX-1 in the
micromolar range, comparable to that of a known 15-LOX inhibi-
tor, and occurring through an uncompetitive mechanism. LOXs
also have a role in cancer, both pro- and anti-metastatic, depending
on the type of tumour [134,135]. In a melanoma model, the prod-
ucts of 15-LOX-1 enzymatic activity potentiate the lung homing of
B16F10 melanoma cells in vivo and favour the in vitro adhesion on
 A. Bergamo et al. / Coordination Chemistry Reviews 360 (2018) 17–33 27

collagen and fibronectin [136]. Notably, the 15-LOX-1 products

stem from the activation of ERK and FAK signalling pathways, b
thereby up-regulating the adhesion and the metastatic potential
of B16F10 melanoma cells. The inhibition of 15-LOX-1 by the
ruthenium compounds in this tumour model could therefore break
FAK signalling and attenuate the downstream metastatic regula-
tory proteins.

4.5. Genome instability and mutation

Alterations to the genome provide cancer cells with acquired

functional capabilities that allow them to survive, proliferate and
disseminate, e.g. by inactivating tumour suppressor genes. Among
the caretaker genes that maintain genome integrity, BRCA1 is
involved in the repair of DNA double-strand breaks, protein ubiq-
uitination, and transcriptional regulation [137], therefore its muta-
tions enhance the risk of developing cancers. Correspondingly, an
impaired BRCA1 function in chemotherapy treated patients is
related to increased sensitivity to treatment and improved survival
following platinum-containing regimens [138,139]. The ruthenium
(II) complexes containing the bidentate ligand 5-chloro-2-
(phenylazo)pyridine interact with the holo, Zn2+-bound BRCA1
protein affecting its overall conformation, and impairing the
BRCA1-mediated ubiquitination, in particular it reduces the BRCA1
E3 ligase activity (Fig. 11a and 11b) [140]. Both these findings are
observed also with platinum-based drugs [141,142] and other
ruthenium compounds [143]. The final effects of the direct interac-
tion of these ruthenium compounds with the BRCA1 RING domain
is cell death by apoptosis in breast tumour cell lines, suggest that
this protein could be an attractive target for metal-complexes, in
particular for the treatment of triple negative breast cancers.
Besides genome instability conferred by mutations, cancer cells
earn selective advantages through epigenetic mechanisms that
affect the regulation of gene expression. Most of the current
knowledge on DNA-adduct formation of metal-based drugs was
derived from studies with naked, i.e. protein-free, DNA, or short
oligonucleotide fragments. However, the actual substrate for
DNA-targeting agents is chromatin, where DNA is packed around
histone proteins in well-defined nucleosome core particles (NCPs).
a [148].
Fig. 11a. Metal compounds affecting genome caretakers and epigenetic mecha-
nisms. The ruthenium(II) complexes containing the bidentate ligand 5-chloro-2-
(phenylazo)pyridine interact with BRCA1 protein affecting its overall conformation,
and impairing the BRCA1-mediated ubiquitination [140]. RDC11 [Ru(II)(phenan-
throline)(j-C,N-(2-phenyl-pyridine)(NCMe)2]PF6 binds to histones H3.1, H2A and
H2B in cells and in vitro on purified histones [150]. (BRCA1 = Breast Cancer 1; H2A
= Histone 2A; H2B = Histone 2B; H3 = Histone 3; H4 = Histone 4).
Fig. 11b. Structures of the ruthenium(II) complexes containing the bidentate 5-
chloro-2-(phenylazo)pyridine ligand (top) and RAPTA-C and RAED-C (bottom).
NCPs exhibit unique conformational features, determined by the
DNA sequence, which influences where the histone proteins prefer
to localize [144,145]. In addition, DNA conformational features are
also affected by nucleosome positioning, i.e. the same sequence
positioned at different histone binding sites displays different con-
formational features, and is cell-type and cell-status dependent
[146]. In other words, beside epigenetic differences such as DNA
methylation, type of histones and their acetylation, cancer and
healthy cells can be distinguished on the basis of their nucleosome
positioning and compaction state depending on the particular gene
and its activation status. The understanding of the sequence-
dependent properties of nucleosomes has shown that small mole-
cules can selectively recognize nucleosomal DNA, opening the way
for highly site-selective nucleosomal double helix recognition by
metal-based compounds [146]. Studies on [(g6-p-cymene)Ru(1,3,
5-triaza-7-phosphaadamantane)Cl2] RAPTA-C [147] show it to be
associated with the protein component of chromatin in treated
cancer cells, in agreement with the formation of adducts in the
nucleosome core at specific histone protein sites detected in vitro
Conversely, [(g6-p-cymene)Ru(ethylenediamine)Cl]PF6
RAED-C, a ruthenium compound differing from RAPTA-C in only
an apparently modest ligand substitution, associates mainly with
the DNA.
A very recent work of the same authors further documents the
discovery that metal-based compounds can form site-specific
adducts on the histone proteins that package DNA into the nucle-
osome [149]. Auranofin and [(g6-toluene)Ru(1,3,5-triaza-7-phos
phaadamantane)Cl2] RAPTA-T (Fig. 12) both form histone protein
adducts in the nucleosome core, albeit at distantly related sites.
In addition, the presence of RAPTA-T facilitates auranofin adduct
formation. The synergism by RAPTA-T and auranofin appears to
be mediated via an allosteric mechanism within the nucleosome
and yields a synergistic activity in killing cancer cells. Further
recent findings also support the ability of other ruthenium com-
pounds to interact with histones. An a organoruthenium complex
[Ru(II)(phenanthroline)( j -C,N-(2-phenyl-pyridine)(NCMe)2]PF6
(RDC11) binds to histones H3.1, H2A and H2B in cells and in vitro
on purified histones (Fig. 11a). In addition, RDC11 impacts on H3
post-translational modification, in which these changes are differ-
ent from those caused by cisplatin, and they are also observed
in vivo, corroborating their significance. Such epigenetic regulation
suggests that RDC11 might alter several signalling pathways [150].
28 A. Bergamo et al. / Coordination Chemistry Reviews 360 (2018) 17–33
Fig. 12. Structure of RAPTA-T (left), auranofin (center) and RDC11 (right).
a phorylation from the Warburg effect (Fig. 13a). A possible target to
Fig. 13a. Metal compounds interfering with glucose metabolism. Cisplatin affects
several molecules of glucose metabolism, such as PDK, GLUT1 and HK-2/VDAC
interaction [158,159]. The cyclometalated ruthenium(II) complex [Ru(phpy)
(bpy)2]+ (bpy = 2,20 -bipyridine, phpyH = 2-phenylpyridine) is a non-competitive
inhibitor of LDH [163]. (GLUT1 = Glucose Transporter 1; HK-2 = Hexokinase 2; LDH
= Lactate Dehydrogenase; PDH = Pyruvate dehydrogenase; PDK = Pyruvate Dehy-
drogenase Kinase; VDAC = Voltage-Dependent Anion Channel).
b
Fig. 13b. Structures of [Ru(bpy)3]2+ (left) and the cyclometalated 2-phenylpyrid-
inato ruthenium(II) complex [Ru(phpy)(bpy)2]+ (right).
4.6. Reprogramming energy metabolism
The Warburg effect describes the metabolic shift from oxidative
phosphorylation to aerobic glycolysis that takes place in tumours
[151–153]. To implement this switch cancer cells up-regulate the
expression of pyruvate dehydrogenase kinase (PDK) and glucose
transporters, notably GLUT1, in order to increase glucose uptake
and utilization [154–156]. Tumour cells benefit from this shift with
the increased glycolysis allowing the utilization of glycolytic inter-
mediates in various synthetic pathways for molecules needed for
assembling new cells. In addition, the switch to aerobic glycolysis
allows tumour cells to evade apoptosis [157]. Interestingly, it has
been shown that cisplatin re-directs cancer cells to oxidative phos-
achieve this effect is PDK, which mRNA levels are reduced by cis-
platin treatment, limiting the final step of glycolysis by inhibiting
pyruvate dehydrogenase (PDH) activity and subsequently the flux
of pyruvate into the Krebs cycle [158]. The interference with glu-
cose metabolism can also proceed through the cisplatin-induced
detachment of hexokinase 2 (HK2) from voltage-dependent anion
channels (VDAC) [159]. This binding provides access to mitochon-
drial ATP, therefore it has been suggested that up-regulation of
hexokinase expression is responsible for the Warburg effect
[160]. Conversely, the interruption of the HK2-VDAC binding fos-
ters the activation of pro-apoptotic proteins [159]. In support of
this mechanism is the finding that AKT, which inhibits apoptosis
and stimulates the binding of HK2 to VDAC, is highly activated in
cisplatin-resistant ovarian cancer cells [161].
The anti-metabolic activity of cisplatin was also demonstrated
in breast and cervical cancer cells [162]. In these models, cisplatin
reduces glycolysis by suppression of glycolysis-related proteins
such as GLUT1, GLUT4 and LDH (Lactate dehydrogenase), restrain-
ing cell growth and proliferation. These effects take place through
down-regulation of the integrin b5/FAK signalling pathway. Ruthe-
nium compounds also impact on tumour metabolism, notably on
LDH activity [163]. The cyclometalated 2-phenylpyridinato ruthe-
nium(II) complex [Ru(phpy)(bpy)2]+ (bpy = 2,20 -bipyridine, phpy
H = 2-phenylpyridine), is cytotoxic towards gastric and colon can-
Fig. 14. Metal compounds that act on the immune system. Platinum compounds
potentiate the activation of T cells [74]. Notably, oxaliplatin induces tumour-
specific immune responses [172], and cisplatin prompts granzyme-B tumour cell
killing. The ruthenium(II) organometallic compound UNICAM-1 ([Ru(p-cymene)(bis
(3,5 dimethylpyrazol-1-yl)methane)Cl]Cl) reverses tumour-elicited immune sup-
pression by significantly reducing the number of Treg cells infiltrating the primary
tumour [174]. (CTLs = Cytotoxic T Lymphocytes; MDSC = Myeloid Derived Suppres-
sor Cells; PD-L 2 = Programmed Death Ligand 2; STAT6 = Signal Transducer and
Activator of Transcription 6; Treg = T Regulatory cells).
 A. Bergamo et al. / Coordination Chemistry Reviews 360 (2018) 17–33
Fig. 15. The structure of UNICAM-1.
cer and inhibits purified LDH (Figs. 13a and 13b). The kinetic inhi-
bition mechanism reveals a non-competitive inhibition, suggesting
that the compound does not interact with the enzyme near the lac-
tate/pyruvate or NAD+/NADH binding sites. Inhibition of LDH
activity was confirmed also in treated cancer cells, and it could
be part of the mode of action of this compound, although it is unli-
kely to account for the entire cytotoxic effect. Interestingly, the
related polypyridine ruthenium(II) complex [Ru(bpy)3]2+, where
one Ru-N bond replaces one Ru-C bond, interacts with LDH differ-
ently, and correspondingly is not cytotoxic to tumour cells.
4.7. Evading immune destruction
In recent years, an increasing body of evidence suggests the
two-faced role of the immune system in tumour formation and
progression. Notably, the innate and adaptive arms of the immune
system can be instrumental in tumour eradication [164,165]. How-
ever, cancer cells may escape the actions put in place by the
immune system to hold them in check. For example, cancer cells
secrete immunosuppressive factors to restrain the activity of cyto-
toxic T lymphocytes (CTL) and natural killer (NK) cells [166,167]. In
addition, cancer cells can hamper the actions of CTLs by mobilizing
inflammatory cells possessing immunosuppressive features, such
as regulatory T cells (Tregs) and myeloid-derived suppressor cells
(MDSCs) [168,169]. Recent reports have shed light on the modula-
tion of the immune system by metal-compounds as part of their
anti-tumour mechanism of action, including several examples of
platinum compounds (Fig. 14) [72,170]. Platinum compounds
potentiate the activation of T cells via dendritic cells (DCs) through
the inhibition of the STAT6 signalling pathway that causes the
down-regulation of the T cell-inhibitory molecule programmed
death ligand 2 (PD-L 2) [74,171]. Oxaliplatin causes immunogenic
cell death, a combination of tumour cell stress and death that can
induce tumour-specific immune responses, through non-DNA-
binding effects [172]. In addition, platinum drugs sensitize cancer
cells to CTL-mediated attack, e.g. cisplatin promotes granzyme-B
killing by increasing the expression of mannose-6-phosphate on
the cell surface [173].
The ruthenium(II) organometallic compound [Ru(p-cymene)(bi
s(3,5dimethylpyrazol-1-yl)methane)Cl]Cl (UNICAM-1, Fig. 15)
reverses tumour-elicited immune suppression by significantly
reducing the number of Treg cells infiltrating the primary tumour
in an experimental model of triple negative breast cancer [174].
This effect is accompanied by an increase in CD4+ and CD8+ T lym-
phocytes. The modulation of the immune system by UNICAM-1
seems related to the reduction of Cyclooxygenase 2 (COX2) expres-
sion and is considered to be the prominent mechanism responsible
of the in vivo anti-tumour effects.
The categorization of metal compounds on the basis of the tar-
geted hallmarks as reported above should be taken with caution.
Alternative categories are sometimes possible since partially
redundant signalling pathways regulate each of the core hallmarks
capabilities and the same targets can belong to different pathways
and be involved in different cellular processes. An alternative view
is that there are two types of metal drugs, those with a functional
organic moiety attached that induces the response, e.g. the 4-
29
anilinoquinazoline compounds, and comparatively simple and less
rational compounds that affect cancer hallmarks eliciting some
intriguing effects. Both classes of compounds are important in can-
cer chemotherapy, the former being more targeted whereas the
latter induce a broad range of responses on both the tumour and
TME.
5. Conclusions
Analysis of the most recent data on the anti-tumour activity of
platinum drugs is providing new insights into their mechanism of
action. Unlike targeted drugs used in cancer chemotherapy, plat-
inum drugs and more generally most metal-based anticancer
drugs, do not target an overexpressed pathway. Rather, they have
in common the same target, e.g. cellular DNA, and their different
reactivity distinguishes how they bind that target, e.g. how
strongly, for how long, etc. This paradigm has long supported the
concept that the resistance to these therapies is mainly based on
the acquired (or innate) capacity of the tumour cells to repair the
DNA lesions. However, this view is losing impact and new, consis-
tent evidence, supports alternative possibilities that resistance or
sensitivity is a matter of the characteristic hallmark pathways
exhibited by the cancer cells. The necessity to treat more targets
in the same cell in order to acquire a stronger and sustained cyto-
toxicity is well known, but becomes more relevant with the intro-
duction of the targeted drugs. However, cells are able to overcome
targeted drugs by rearranging the pathways that sustain their sur-
vival. Since the binding of a molecule to the DNA may rapidly
induce the activation of death pathways, it is not surprising that
platinum drugs have been (and are still) used in order to synergize
with the targeted therapies for the treatment of many human car-
cinomas. It is also apparent that most metal-based drugs have
more than one target and potentially multiple targets. This charac-
teristic should be considered as an opportunity that has not yet
received an adequate attention. Moreover, certain non-targeted
drugs, e.g. NAMI-A and RAPTA-C, do not primarily bind to DNA,
which opens up further options in cancer treatment. Indeed,
NAMI-A and cisplatin were shown to function synergistically when
applied in combination [175]. Rational design of metal-based com-
pounds to target the multiple targets that sustain cancer hallmarks
would limit the off-targets effects often observed with drugs that
affect additional targets beyond their own target. A better under-
standing of the ability of metal-based drugs to interact with pro-
teins and other cell components (e.g. organelles such
mitochondria rather than miRNAs or long non-coding RNAs, ribo-
somes and ribozimes rather than the cell cytoskeleton and its com-
ponents) should drive the design of more effective compounds.
When the ruthenium compound cis-dichlorotetrakisdimethylsul
phoxideruthenium(II) was demonstrated to control the metastatic
ability of cancer cells, the complexity of the biological phe-
nomenon of the metastatic growth and the limited knowledge of
the molecular aspects involved, prevented the precise mechanism
of that action being disclosed [176]. Subsequent research with the
second generation ruthenium complexes (NAMI [RuCl4(DMSO)Im]
Na and its analogues) have provided some insights into the
potency of their anti-metastasis ability, albeit with limited useful
information on the mechanism of action, except a subtle sugges-
tion to a crucial role of the DMSO ligand(s) [177]. More recently,
data showing the lack of penetration of NAMI-A into the cell and
the capacity to interact with integrins positioned on the outer cell
membrane [130,178–180] are amongst the most important find-
ings that might be useful for the synthesis of novel metal-based
drugs.
Combined, these findings should represent the new paradigm
for the definition of new and innovative metal-based drugs for
30 A. Bergamo et al. / Coordination Chemistry Reviews 360 (2018) 17–33
the treatment of malignant tumours, i.e. drugs that change the way
the tumours interact with the healthy cells in the niche of the pri-
mary or secondary sites by creating an in-hospital environment in
which tumour cells cannot receive the signals necessary to allow
them to divide and grow. To achieve this effect it is necessary to
have a drug capable of interacting with more than one target and
the metal-based drugs, because of their capacity to fill the biolog-
ical space with a number of ligands, variably oriented in a tri-
dimensional way, can do that more efficiently than organic mole-
cules. Finally, although beyond the scope of this review, it should
be stressed that, beyond focusing on the cancer target/pathways,
there are important strategies that influence the status of the effi-
cacy/effectiveness of metal-based compounds for cancer therapy.
These include formulation aspects, modulation of the uptake and
more generally on the bio-distribution of the active species, as well
as on their capacity to synergise with novel therapeutic biotechno-
logical interventions [182,183]. These key PK-PD aspects need to
be considered when developing efficient anticancer metal drug
therapies.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest
None.
Acknowledgements
The authors would like to thank the EU COST Actions from D1 to
CM1105 and the entire inorganic chemistry community that took
part in stimulating and profitable reflections and collaborations.
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