Conjugates of cisplatin and cyclooxygenase inhibitors as potent antitumor agents overcoming cisplatin resistance

Article abstract of DOI:10.1002/cmdc.201402074

Cyclooxygenase-2 (COX-2) is an enzyme involved in tumorigenesis, and inhibitors of the enzyme are increasingly used as adjuvant modulators in anticancer therapies due to their synergistic effects with traditional chemotherapeutics. COX-2 is also reported to cause resistance towards antitumor agents, such as cisplatin. Here, the first covalently linked conjugates of cisplatin and COX inhibitors are reported. These conjugates exhibit concerted transport of both drugs into tumor cells and simultaneous action upon intracellular cleavage. These platinum(IV) complexes show highly increased cytotoxicity compared with cisplatin and are even able to overcome cisplatin-related resistance of tumor cells. While the results reported show that COX-2 inhibition is not directly responsible for the potent activities of these conjugates, they do represent useful tool compounds for the elucidation of the influence of COX inhibitors on the efficacy of antitumor agents. A potent boost: Conjugation of cisplatin with cyclooxygenase (COX) inhibitors creates platinum(IV) prodrugs with highly increased cytotoxicity, which even overcome cisplatin-related resistance in tumor cells. The first covalently linked conjugates of cisplatin with COX inhibitors provide tools for elucidating the involvement of COX in tumorigenesis.

Full text of DOI:10.1002/cmdc.201402074

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DOI: 10.1002/cmdc.201402074
Conjugates of Cisplatin and Cyclooxygenase Inhibitors as
Potent Antitumor Agents Overcoming Cisplatin Resistance
Wilma Neumann,[a] Brenda C. Crews,[b] Lawrence J. Marnett,[b] and Evamarie Hey-Hawkins*[a]
Cyclooxygenase-2 (COX-2) is an enzyme involved in tumorigen-
esis, and inhibitors of the enzyme are increasingly used as ad-
juvant modulators in anticancer therapies due to their syner-
gistic effects with traditional chemotherapeutics. COX-2 is also
reported to cause resistance towards antitumor agents, such
as cisplatin. Here, the first covalently linked conjugates of cis-
platin and COX inhibitors are reported. These conjugates ex-
hibit concerted transport of both drugs into tumor cells and si-
multaneous action upon intracellular cleavage. These plati-
num(IV) complexes show highly increased cytotoxicity com-
pared with cisplatin and are even able to overcome cisplatin-
related resistance of tumor cells. While the results reported
show that COX-2 inhibition is not directly responsible for the
potent activities of these conjugates, they do represent useful
tool compounds for the elucidation of the influence of COX in-
hibitors on the efficacy of antitumor agents.
trasting results have been reported thus far. While several stud-
ies showed positive effects of COX inhibitors on tumor treat-
ment to be COX-2-independent,[6] others even reported antag-
onistic effects.[7] Furthermore, preclinical studies revealed that
cisplatin and other antitumor agents even increased COX-2 ex-
pression in tumor cells.[8]
Prior studies into the influence of COX inhibitors on the effi-
cacy of antitumor agents have used combinatorial treatments
resulting in potential discrepancies between clinical and cell
culture studies. Due to differential pharmacokinetics, delivery
of the drugs to a tumor in vivo may fail to recapitulate admin-
istration of the compounds to cells in culture. To address this
issue, we report the first cisplatin–COX inhibitor conjugates.
The NSAIDs indomethacin and ibuprofen were coordinated at
cisplatin as axial ligands, resulting in platinum(IV) complexes.
More stable than cisplatin and its platinum(II) analogues, plati-
num(IV) compounds can be administered orally,[9] and the in-
creased lipophilicity imparted by axial ligands facilitates com-
pound uptake.[10] Reduction of platinum(IV) compounds by
redox-active biomolecules, such as glutathione and ascorbate,
causes intracellular cleavage of the linkage between the NSAID
and cisplatin, allowing these conjugates to act as pro-
drugs.[10b,11] Release of cisplatin together with two equivalents
of the NSAID could enable a dual action with the latter pre-
venting COX from tumor-promoting activities and interfering
with the action of cisplatin. The covalent conjugation ensures
concerted transport of both drugs into tumor cells and may
promote enrichment of the complexes in COX-2-expressing
tumors.[12]
Cisplatin and its derivatives are among the most widely used
chemotherapeutic agents for the treatment of multiple types
of cancer.[1] However, platinum-based antitumor therapy is
complicated by severe side effects as well as intrinsic and ac-
quired resistance of tumor cells. Resistance mechanisms in-
clude decreased influx, increased efflux, and detoxification of
the drugs, as well as interference with apoptotic pathways that
are usually activated by the compounds.[2] Implicated in cispla-
tin resistance is cyclooxygenase-2 (COX-2), a key enzyme in the
biosynthesis of prostaglandins. COX-2 is overexpressed in
many tumors, and it plays a role in tumor initiation and pro-
gression.[3] It is also associated with poor outcome in several
types of cisplatin-treated cancer.[2d,4] Thus, COX inhibitors, in-
cluding nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., in-
domethacin) and COX-2-selective inhibitors (e.g., celecoxib),
are used as chemopreventive and adjuvant chemotherapeutic
agents. Clinical studies have shown synergistic effects when
COX inhibitors are administered in combination with various
antitumor agents, such as cisplatin, paclitaxel, and doxorubi-
cin.[5] However, the mechanism by which COX-2 is involved in
tumorigenesis is still largely unknown, and furthermore, con-
The NSAIDs were coordinated at the metal center of cispla-
tin via their carboxyl groups (Figure 1). Thus, intracellular re-
duction of the platinum(IV) complexes directly releases the
drugs without any derivatization (Scheme 1) and enables direct
comparison with studies of combinatorial treatments. The syn-
thesis was achieved by treating oxoplatin (cis,trans,cis-
[PtCl2(OH)2(NH3)2]) with the acyl chloride of the respective
NSAID in the presence of a base (for methods and characteri-
zation data, see Supporting Information).[13] Due to the large
[a] W. Neumann, Prof. Dr. E. Hey-Hawkins
Institut fꢀr Anorganische Chemie, Universitꢁt Leipzig
Johannisallee 29, 04103 Leipzig (Germany)
E-mail: hey@uni-leipzig.de
[b] B. C. Crews, Prof. Dr. L. J. Marnett
Department of Biochemistry, Vanderbilt Institute of Chemical Biology
Vanderbilt University School of Medicine
23rd Avenue South & Pierce, Nashville, TN 37232 (USA)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201402074.
Scheme 1. Reduction of the platinum(IV) conjugates releases cisplatin and
the respective COX inhibitor.
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Figure 2. Reduction of conjugate 2 with ascorbic acid (AscH2) at 378C; time-
1
resolved H NMR spectra (400 MHz, [D6]DMSO); sections of the aromatic and
aliphatic region.
Figure 1. Structures of the conjugates 1 (with indomethacin) and 2 (with
ibuprofen).
compatible with the clearance rate of such drugs in the body.
While reduction potential and rate probably influence the
pharmacological properties of the platinum(IV) complexes,
they do not necessarily correlate with their cytotoxicity.
aromatic ligands, the conjugates are practically insoluble in
water but can be dissolved in polar aprotic solvents, such as
DMSO and DMF.
In solution, 1 and 2 are inert towards ligand exchange but
can be irreversibly reduced to more labile platinum(II) com-
pounds (Scheme 1). Thus, their pharmacological profile is sig-
nificantly influenced by their reduction potential, and this in
turn depends on the nature of the axial ligands. Reduction
occurs most readily with axial chloro ligands, least readily for
axial hydroxo ligands, and is intermediate for axial carboxylato
ligands.[14] If the potential is too high, reduction occurs in the
blood resulting in severe side effects (e.g., tetraplatin, systemic
toxicity).[15] In contrast, an excessively low reduction potential
results in excretion of the intact compound (e.g., iproplatin,
weak activity).[16] The cyclic voltammograms of the conjugates
showed only one peak, corresponding to the irreversible re-
duction of platinum(IV) (Figures S1 and S2 in the Supporting
Information). Conjugate 1 (EP =À0.36 V vs normal hydrogen
electrode (NHE) in DMF) showed a higher reduction potential
than 2 (EP =À0.68 V vs NHE in DMF), which could be caused
by the more strongly electron-withdrawing indole system and
increased steric bulk favoring ligand dissociation. The reduc-
tion potentials of the conjugates, which were comparable to
those of other reported platinum(IV) carboxylato complexes,[17]
should ensure in vivo stability in blood during transport but
enable intracellular reduction. Indeed, the conjugates were re-
duced by ascorbate, an important cytoplasmic reducing agent.
Reduction rates also increase with increasing electronegativi-
ty of the axial ligands and are likely to influence biological
properties of platinum(IV) compounds.[14] The reduction of the
The COX inhibitory potency of each conjugate was deter-
mined using purified COX-2 and the COX-1 isoform. Conjugate
1 was a potent COX inhibitor with a 100-fold selectivity for
COX-2 (IC50(COX-1): 4.1 mm; IC50(COX-2): 0.045 mm) and, to the
best of our knowledge, is the first highly selective COX-2 inhib-
itor containing a metal center described to date. This complex
is much more potent than other reported metal complexes of
NSAIDs, which were less potent or COX-1-selective.[18] The
structure of 1 resembles that of indomethacin esters, which
were shown to be COX-2-selective inhibitors.[19] The inhibition
potency of 1 suggests a strong interaction with the COX-2
enzyme that could contribute to targeted delivery into COX-2-
overexpressing tumor cells.[12] In contrast, 2 showed no COX in-
hibition (Table S3 in the Supporting Information). Ibuprofen
itself is a weak, rapidly reversible inhibitor of COX,[20] and this
probably results in only weak binding of 2.
On entering tumor cells, the conjugates could act as plati-
num(IV) compounds or be reduced with release of cisplatin
and the NSAID.[21] To study the cytotoxicity of the conjugates
and the influence of the coordinated NSAIDs, proliferation
assays were carried out using a panel of four tumor cell lines
with different sensitivities towards cisplatin and different levels
of COX-2 expression (Table 1; see also, Table S2 in the Support-
ing Information). Both conjugates showed a markedly in-
creased cytotoxicity compared with cisplatin, with sub-micro-
molar IC50 values. The conjugates are some of the most active
in the class of platinum(IV) carboxylato complexes, most of
which exhibit potencies similar to that of cisplatin.[17a,22] Conju-
gates 1 and 2 were even able to completely overcome cispla-
tin resistance in MDA-MB-231 breast cancer cells, with an up
to 400-fold lower IC50 value than that of cisplatin.
1
conjugates by ascorbic acid at 378C was monitored by H NMR
spectroscopy (Figure 2; see also, Figures S3–S6 in the Support-
ing Information). In each case, about 40% of the platinum(IV)
complex was reduced over three days, a rate that could be
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show strongly increased cytotoxicity compared with
cisplatin and even overcome cisplatin-related resist-
ance in tumor cells. Although the indomethacin con-
jugate is a potent COX-2-selective inhibitor, these
complexes seem to execute their cytotoxic action via
COX-2-independent mechanisms. These conjugates
provide tools for the elucidation of the influence of
COX inhibitors on platinum-based antitumor agents.
Table 1. IC50 values [mm] of cisplatin and conjugates 1 and 2, as determined in prolif-
eration assays for different tumor cell lines with incubation times of 24 h and 72 h.
Compd
HCT 116[a]
24 h 72 h
OVCAR3[b]
MDA-MB-231[c]
1483 HNSCC[d]
24 h
72 h
24 h
72 h
24 h
72 h
Cisplatin
1
2
22.3
2.5
0.22
12.0
1.1
0.065
10.7
7.7
1.5
2.07
2.2
0.13
159.8
20.1
1.05
20.0
1.65
0.05
8.6
3.5
0.54
2.0
0.69
0.045
[a] Colorectal carcinoma, no COX-2 expression. [b] Ovarian adenocarcinoma, COX-2 ex-
pression. [c] Breast adenocarcinoma, COX-2 expression. [d] Head and neck squamous
cell carcinoma, high COX-2 expression. The cell growth experiment values are the
mean of six replicates with standard deviation less than 10% (and less than 5% for
95% of the values).
Acknowledgements
This work was supported by the Fonds der Chemischen
Industrie (doctoral grant for W.N.), the Graduate School
The cytotoxic potency of the conjugates in the cell lines was
“Building with Molecules and Nano-objects (BuildMoNa)” funded
by the Deutsche Forschungsgemeinschaft, the US National Insti-
tutes of Health (CA89450), and the German Academic Exchange
Service (PPP USA). The authors thank Umicore AG & Co. KG for
the generous donation of chemicals and are grateful to Carol
Rouzer for editorial assistance.
unrelated to COX-2 expression (Table 1). Furthermore, conju-
gate 2 was more active than 1 despite its complete absence of
COX-2 inhibitory activity and the lower potency of ibuprofen
as compared with indomethacin. These data suggest that the
cytotoxicity of the complexes is unrelated to the COX-2 inhibi-
tory activity of the conjugates or the parent NSAIDs. Consis-
tently, combinatorial treatment of the cancer cells with cispla-
tin and the respective NSAID (ratio 1:2) did not reveal any in-
crease in cytotoxicity over that of cisplatin alone (Table S2 in
the Supporting Information).
Keywords: antitumor agents
·
cyclooxygenases
·
drug
delivery · drug design · inhibitors · prodrugs
The mechanism by which NSAID conjugation increases the
cytotoxic potency of cisplatin is unclear. Hydrophobic ligands
increase the lipophilicity of the platinum complex thereby facil-
itating transport through the cell membrane.[10,22a,b] Thus, it is
possible that the coordinated NSAIDs promote the transport
and accumulation of cisplatin in tumor cells. Oxidized cisplatin
derivatives are also kinetically inert, which prevents detoxifica-
tion of the drugs in the extracellular matrix and intracellularly,
for example, by coordination of sulfur-containing pro-
teins.[10b,23] Cisplatin irreversibly binds to a large extent to
plasma proteins leading to substantially decreased uptake into
cells.[24] Thus, increasing inertness of the metal complex to-
wards ligand exchange should enhance the efficacy of the anti-
tumor drug by increasing the probability that the complex
reaches the cellular target intact and thereby also decreases
side effects.
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