Radiol Oncol 2019; 53(2): 148-158. doi: 10.2478/raon-2019-0018
148
review
Cisplatin and beyond: molecular mechanisms 
of action and drug resistance development in 
cancer chemotherapy
Tomaz Makovec
Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
Radiol Oncol 2019; 53(2): 148-158.
Received 20 July 2018
Accepted 5 September 2018
Correspondence to: Tomaž Makovec, Ph.D., Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 
SI-1000 Ljubljana, Slovenia. Phone: +386 (0)1 543 640; Fax: +386 (0)1 5437 641; E-mail: tomaz.makovec@mf.uni-lj.si
Disclosure: No potential conflicts of interest were disclosed. 
Background. Platinum-based anticancer drugs are widely used in the chemotherapy of human neoplasms. The 
major obstacle for the clinical use of this class of drugs is the development of resistance and toxicity. It is therefore very 
important to understand the chemical properties, transport and metabolic pathways and mechanism of actions of 
these compounds. There is a large body of evidence that therapeutic and toxic effects of platinum drugs on cells are 
not only a consequence of covalent adducts formation between platinum complexes and DNA but also with RNA 
and many proteins. These processes determine molecular mechanisms that underlie resistance to platinum drugs as 
well as their toxicity. Increased expression levels of various transporters and increased repair of platinum-DNA adducts 
are both considered as the most significant processes in the development of drug resistance. Functional genomics 
has an increasing role in predicting patients’ responses to platinum drugs. Genetic polymorphisms affecting these 
processes may play an important role and constitute the basis for individualized approach to cancer therapy. Similar 
processes may also influence therapeutic potential of nonplatinum metal compounds with anticancer activity.
Conclusions. Cisplatin is the most frequently used platinum based chemotherapeutic agent that is clinically proven 
to combat different types of cancers and sarcomas.
Key words: cisplatin; molecular mechanisms; chemotherapy; resistance
Introduction
Drug resistance is a wide spread and well known 
phenomenon among anticancer medications and 
platinum drugs are not exceptions. The use of 
these drugs in chemotherapy is hampered by ex-
trinsic and intrinsic resistance of cells. Although 
many cancer cells are initially susceptible to chem-
otherapy with platinum drugs, over time they may 
develop resistance through more efficient DNA 
damage repair, drug inactivation with glutathione 
and metallothioneins and drug efflux with various 
transport systems located in cell membrane. In this 
review the chemical properties, metabolism and 
transport of platinum and similar compounds and 
how they are implicated in the developing in cell 
resistance and toxicity are described. The knowl-
edge of mechanism of action of these drugs reveals 
mechanisms of resistance and toxicity. The aim of 
this review is also to provide recent data concern-
ing hypersensitivity reactions to platinum-contain-
ing chemotherapy agents. To minimize toxicity, 
resistance and hypersensitivity reactions to plati-
num drugs the new metallodrugs were developed. 
A brief summary of these agents is also presented.
The discovery of platinum 
compounds as anticancer 
agents
Until the mid-1960s, cancer chemotherapy was 
based on purely organic compounds. An accidental 
discovery of anticancer properties of inorganic co-
Radiol Oncol 2019; 53(2): 148-158.
Makovec T / Cisplatin, molecular mechanisms and resistance development 149
ordination compounds based on platinum opened 
the door also for inorganic compounds. In 1965, 
Barnett Rosenberg discovered that platinum com-
plex generated during electrolysis from platinum 
electrodes inhibited binary fission in the Escherichia 
coli bacteria. His group investigated the influence 
of alternating currents of different frequencies on 
the ability of the cells to divide. To their surprise, 
they found that certain frequencies of a current re-
duced the number of cells growing in the media to 
a large extent. They also discovered that bacteria 
were transformed into long rods which indicated 
that the cells were growing but not dividing. With 
a number of control experiments, they showed that 
while electric current itself has no influence on cell 
division, the current was causing a small amount of 
metal on the surface of the platinum electrodes to 
dissolve as a complex; these chemical substances, 
apart from the electric current, were affecting the 
growth of E. coli. Suspecting Pt4+, which elemental 
platinum in the electrode was being oxidized into, 
they first tested a sample of (NH4)2PtCl6 and found 
no effect on the growth of the bacteria. However, if 
the solution of (NH4)2PtCl6 was irradiated by a light 
source, the resulting solution became very effective 
in inhibiting the division of E. coli. They found that 
Pt2+ species were produced in photoreactions and 
subsequently they tested many platinum complex-
es, the six coordinate octahedral cis-[PtCl4(NH3)2], 
with Pt4+ ion and cis-[PtCl2(NH3)2], with Pt2+ ion 
that were effective in arresting the cell division.1
Rosenberg and his group concluded that com-
pounds capable of inhibiting E. Coli division could 
also be useful for treating cancer. They found that 
planar complex which contained Pt2+ ion with cis 
configuration - later known as cisplatin - was very 
effective at arresting sarcoma 180 and leukaemia 
L1210 cells while trans isomer exhibited little an-
titumor activity.1 This observation also led to the 
discovery of the effectiveness of this compound at 
regressing the mass of sarcomas in rats.2
Turning these findings into a useful commer-
cial product was a hard task at that time. When 
Rosenberg carried out his investigations, all an-
ticancer drugs approved for use in the United 
States were organic compounds, either natural or 
synthetic. Anything which contained heavy metal 
(platinum is the second neighbour of mercury) was 
treated as a toxic compound that should be kept 
away from humans. For this reason, Rosenberg 
convinced the National Cancer Institute that they 
carried out more extensive animal tests on the 
platinum complexes. The compound was very ef-
fective in those human cancers where other forms 
of chemotherapy resulted in no improvements and 
in 1979 he patented his new discovery - the use of 
cisplatin. He couldn’t patent the compound since it 
had been synthesized 100 years earlier by Peyrone.3 
Later in 1979, the Bristol-Myers (now Bristol-Myers 
Squibb), who intensively researched anticancer 
drugs, carried out additional investigations to pro-
vide information about the safety and the efficacy 
for the Food and Drug Administration (FDA). In 
1978, the FDA approved cisplatin for use in can-
cer chemotherapy. Suddenly, it was appropriate 
for inorganic chemists to send their compounds to 
Cancer Institutes for screening for antitumor activ-
ities.4 This resulted in a number of new platinum 
and non-platinum based compounds that showed 
promise to become successful anticancer com-
pounds. Since its discovery, five other platin drugs 
have received approval in various countries: be-
sides carboplatin and oxaliplatin there are another 
three gaining approval in single markets; nedapl-
atin in Japan, lobaplatin in China and heptaplatin 
in Korea.5
Chemistry of cisplatin
The behaviour of cisplatin in aqueous solution is 
presented in Figure 1. 
The chemistry of cisplatin is completely differ-
ent from all other chemistries of typical organic 
anticancer drugs. In blood, the concentration of 
FIGURE 1. The behaviour of cisplatin in aqueous solution. Cisplatin (1) is a bright-
yellow solid; when dissolved in water it is attacked by water molecules and as a 
result one of the chloride ions is eliminated and monoaqua (2) species is formed. 
Diaqua species (3) is formed when the second water molecule replaces the 
chloride ion. Water replaces chloride ions because the metal and nitrogen form 
stronger bond than metal and the chloride ion. Bound water became very acidic 
and at physiologic pH became completely deprotonated – as a monohydroxo form 
(4), and the product of the dissociation of the second proton from the diaqua form is 
dihydroxo species (6). Logarithms of rate constants (pK1, pK-1, pK2 and pK-2) are given 
for 25 ºC and of dissociation constants (pKa1, pKa2 and pKa3) for 27 ºC. 
Radiol Oncol 2019; 53(2): 148-158.
Makovec T / Cisplatin, molecular mechanisms and resistance development150
the chloride ion is about 105 mM and, according 
to Le Chatelier’s principle, the loss of the chloride 
ion from cisplatin is suppressed by the chloride ion 
in solution; the reaction shown in Figure 1 does 
not progress very far to the right (from 1 to 2). 
According to the first order kinetics for conversion 
from 1 to 2, the half-life for cisplatin at 35.5 ºC is 
1.05 h. The binding of a water molecule to the Pt2+ 
ion makes water very acidic and monoaqua spe-
cies 3 is dissociated in the monohydroxo complex 
4. So in an aqueous solution with the high chloride 
concentration the forms 1, 2 and 4 predominate. In 
the cytoplasm, where chloride ion concentration is 
only 4 mM, the equilibria is shifted to the right and 
forms 3, 5 and 6 predominate. A common route of 
cisplatin administration is the infusion of the so-
lutions such as Platinol® and Plationol®AQ, which 
contain 3.3 mM cisplatin (1 mg/ml) and 154 mM 
sodium chloride, NaCl (normal saline solution). 
Since the pH is adjusted to pH about 4 solution 
in Platinol contains mainly (95%) of species 1 and 
only smaller amounts of 3 and 4.
Uptake and removal of cisplatin 
from cells
Cisplatin in blood
Since the concentration of chloride in blood is 
lower than in the infusion solution (105 versus 154 
mM), the equilibria (Figure 1) is shifted to the right. 
Because the carbonate and phosphate ions react 
with aquated cisplatin forms and because some 
platinum binds to protein that is being eliminated 
in significant amounts via the urine during the in-
fusion, it is impossible to predict the composition 
of species 1 – 6 according to the data in Figure 1. 
This system is far from the chemical equilibrium. 
A major part (68 – 98%) of cisplatin is bound to the 
blood plasma proteins, especially on human serum 
albumin (HSA)6. One molecule of HSA binds five 
molecules of cisplatin. cis-[PtCl(NH3)2]+ is bound 
to nitrogen atom from His105 and His288 and 
sulphur atoms from Met329, Met298 and Met548. 
Treatment of HSA with cisplatin also leads to the 
formation of adduct between cis-[Pt(NH3)2]2+ and 
His67 and His247. Since both histidine residues are 
involved in the transport of Zn2+ ions to the cell by 
HSA7, this may be the reason why some patients 
on therapy with cisplatin have zinc imbalance in 
their body.8 For study of binding of platinum com-
pounds to human serum proteins a novel method 
for accessing of Pt using conjoint liquid chroma-
tography has also been developed.9
Cisplatin uptake from blood into a cell
The first step for platinum drugs to exert their 
therapeutic as well as toxic effects is to enter the 
cells. This process is complex and not completely 
understood. Cisplatin enters a cell mainly by pas-
sive diffusion. Uptake of cisplatin by cells was 
proportional to the total concentration of cisplatin 
in the cell culture medium up to 3 mM concentra-
tion and was not saturable.10 The most likely can-
didates for passive diffusion through hydrophobic 
lipid bilayer are neutral species without the charge 
such as cisplatin and monohydroxo form (1 and 4, 
respectively in Figure 1). But studies with the in-
hibitors of active transporters suggested that there 
must also be other uptake mechanisms.11 Recently, 
a lot of attention has been given to the active modes 
of the uptake.12 The most likely candidates for the 
transport of cisplatin into a cell by facilitated dif-
fusion are the copper transporters Ctr1 (SLC31A1) 
and Ctr2 (SLC31A2, copper importer).13 This trans-
membrane protein has an extracellular domain 
that is rich in methionine and histidine residues. 
It has been suggested that both metals, platinum 
and copper, use Ctr1 as their entry route into the 
cell although the chemistry of these two metals is 
quite different. Switching between different oxi-
dation states has pivotal role in the transport of 
copper. Whereas copper exists in two biological 
oxidation states as Cu+ and Cu2+ ions, the cisplatin 
exists only in one stable biologically accessible oxi-
dation state with Pt2+ ion. Because platinum cannot 
switch between different oxidation states, the up-
take of cisplatin into the cell by this protein might 
be blocked. An additional factor that throws doubt 
on Ctr (1 and 2) as a main transporter of cisplatin 
is the reaction of extracellular methionine residue 
with Pt2+ resulting in formation of a stable Pt2+-S 
bond, similar to the bond between Pt2+ and methio-
nine residues in HSA. Since the transport of Pt2+ 
ion through Ctr would require a facile breaking 
and reforming of the Pt2+-S bond, the thermody-
namic and kinetic parameters of this bond would 
exclude the Ctr as an entry route for cisplatin. 
Furthermore, cis-ammonia molecules would be 
lost during cisplatin transfer with Ctr due to trans 
effect. Additionally, excessive copper in extracellu-
lar fluid triggers an internalization and degrada-
tion of Ctr protein. This acute regulatory response 
has also been reported following exposure of hu-
man ovarian carcinoma cells to cisplatin, but such 
response was not observed in other types of cancer 
cells.14 Although many studies have shown that 
cisplatin can bind to Ctr, none has shown that Pt2+ 
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Makovec T / Cisplatin, molecular mechanisms and resistance development 151
ion can actually be transported into a cell by this 
mechanism.15 Arnesano and Natile16 hypothesized 
that the interaction of cisplatin with Ctr leads to pi-
nocytosis and vesicular transport of cisplatin into 
the cell, thus protecting the drug from inactivation 
with glutathione (GSH) and metallothioneins (MT) 
which are present in cells.
As forms 2, 3 and 5 shown in Figure 1 are cati-
ons, led investigators to examine the involvement 
of organic cation transporters (OCTs, SLC22A) in 
cisplatin transport across the membrane. This as-
sumption was strengthened by the observation that 
OCTs are expressed in tissues sensitive to cisplatin 
toxicity. It was shown that both OCT1 (SLC22A1) 
and OCT2 (SLC22A2) are implicated in transport 
of cisplatin into the HEK 293 cells as well as the 
other cell lines.17 Under physiological conditions, 
cisplatin may also undergo a transformation in cis-
platin carbonato complexes, which are anionic spe-
cies and these forms may be transported into the 
cell by organic anion transporters (OATs, SLC22A). 
The transport of platinum drugs by OAT may also 
explain the nephrotoxicity of these substances.18 
Both OCT and OAT mediated cisplatin nephro-
toxicities are observed in 30% of patients. OCT2 is 
specifically expressed in the kidneys and for this 
reason it is a suitable target for the investigating 
of the protection against nephrotoxicity. The tissue 
specific expression of OCT may be also critical for 
the development of ototoxicity as well as periph-
eral neurotoxicity.19
Cisplatin transport out of the cells
Since the therapeutic range of cisplatin is nar-
row we cannot overcome the cell resistance sim-
ply by increasing the dose. Resistance to cisplatin 
is a consequence of the enhanced removal of the 
drug that enters a cell and the efficiency of DNA 
repair mechanisms, which remove lethal adducts 
between DNA and cisplatin. Another copper trans-
porter, ATP7A and closely related ATP7B, which 
deliver copper into the organelles and are respon-
sible for removing the excess copper out of a cell, 
may also be involved in the cisplatin-induced re-
sistance.20 Mutation in ATP7B gene produces ac-
cumulation of copper in the body, a state known 
as Wilson’s disease21, while the mutation in ATP7A 
gene has the opposite effect and is responsible for 
a copper deficiency, known as the Menkes dis-
ease.22 Both ATP7A and ATP7B can bind cisplatin 
at cysteine residue in their N-terminal metal bind-
ing domains forming a stable Pt2+-S bond. Elevated 
levels of these proteins correlate with a diminished 
accumulation of cisplatin and consequently with 
lower cytotoxicity.23
Beside the copper-transporting proteins GSH 
and metallothioneins may also influence cispl-
atin transport. These cysteine rich, low molecular 
weight proteins are involved in intracellular inacti-
vation of platinum and other similar drugs through 
coordination to thiol groups. An overexpression of 
metallothionein in the tumour cells is present in 
70% of the patients with oesophageal cancer and 
it is correlated with resistance to cisplatin.24 It was 
shown that GSH and cisplatin form anionic bis Pt2+-
GSH complexes which can be refluxed from leu-
kaemia cells in the presence of ATP.25 Later it was 
shown that multidrug resistance-associated pro-
tein MRP2 (ABCC2) and OAT were responsible for 
the efflux of this complex.26 Since the formation of 
the adduct between cisplatin and two deprotonat-
ed forms of GSH prevents the drug from reacting 
with DNA and other targets, MRP2 and OAT are 
important factors in detoxification of the cell from 
cisplatin. Due to combination of uptake and export 
transporters only 1% of administered drug reaches 
the site of action within the cells. Cellular traffic of 
cisplatin is summarized in Figure 2. 
Clinical applications 
Genetic background as a determinant of 
cisplatin-based drug response
The inter-individual variability of the efficacy of 
platinum based chemotherapy as well as its toxic-
FIGURE 2. Traffic of cisplatin (CP). 1, passive diffusion, 2, passive 
diffusion blocked. See text for explanations. CP: cisplatin, 
DACP: diaqua cisplatin, OCT: organic cation transporter, 
OAT: organic anion transporter, Ctr: copper transporter, 
MRP: multidrug resistance-associated protein, ATP7: copper-
transporting P-type ATPase, MATE: multidrug extrusion 
transporter, GSH: glutathione, MT: metallothionein.
Radiol Oncol 2019; 53(2): 148-158.
Makovec T / Cisplatin, molecular mechanisms and resistance development152
ity is the result of the genetic variability in genes 
involved in drug metabolism, drug transport and 
DNA repair. Therefore, the determination of genet-
ic markers such as genetic polymorphisms in these 
genes may provide the hints about the optimal cis-
platin regimens for personalized therapy.
Both uptake and efflux transporters are subject 
to genetic variability. Polymorphic transporters are 
involved in processes that increase the intracellu-
lar level of the drug: transport with copper trans-
porters Ctr1 and 2 and organic cation transporters 
OCT 1 and 2. The same is true for the transporters 
that are involved in the efflux of cisplatin from the 
cell and resistance, copper-transporting ATPases 
ATP7A and ATP7B, organic anion transporters, 
OAT, glutathione and metallothionein, multidrug 
resistance-associated protein MRP2 as well as mul-
tidrug extrusion transporter-1 (MATE1).27 
The presence of single nucleotide polymor-
phisms in all transporters shown in Figure 2 influ-
ence the response of patients to platinum drugs 
in a great extent and this influence is dependent 
on both, the type of platinum drug and the type 
of cancer cells.28 The data on these polymorphisms 
are summarized in the Table 1.
The main mechanism of resistance is a DNA-
platinum drug adducts repairing system. 
Polymorphisms of DNA-adduct repair enzymes 
also play a role in sensitivity towards platinum-
based chemotherapy (Table 2). X-ray repair cross-
complementing group 1 (XRCC1), excision repair 
cross complementation 1 (ERCC1) and xeroderma 
pigmentosum complementary group (XPA, XPD 
and XPG) are enzymes that play the crucial role 
in these processes. The polymorphic A1196G al-
lele in XRCC1 gene is present in 20-38% of lung 
cancer patients.29 A number of studies have been 
performed to investigate the association of XRCC1 
gene polymorphisms with platinum drug efficacy 
but the results are inconsistent.
Recent studies also investigated Major Vault 
Protein (MVP) present as the main component of 
the vault in normal tissues as well as in malignant 
cells, including ovarian cancer, colon carcinoma 
and acute myeloid leukaemia.30 Although MVP has 
been linked to the development of multidrug re-
sistance in cancer cells, several studies have report-
ed conflicting results.31 The association between 
polymorphisms in MVP gene and platinum resist-
ance has not yet been confirmed probably due to 
the limited number of patients.32
TABLE 1. Polymorphisms of transporters that influence the efficacy of platinum drugs
Protein Gene Genetic polymorphisms or expression level (EL) that influences the outcome of platinum-based therapy
Uptake of platinum drugs
OCT1 SLC22A1 c.181C > T, c.480C > G, c.1022C > T, c.1222A > G, c.1390G > A, c.1463G > T
OCT2 SLC22A2 c.160C > T, c.481 T > C, c.493A > G, c.495G > A, c.808G > T, c.890C > G, c.1198C > T, c.1294A > C 
OCT3 SLC22A3 EL
CTR1 SLC31A1 rs10981694 A>C
CTR2 SLC31A2
Efflux of platinum drugs
MATE1 SLC47A1 p.Gly64Asp and p.Val480Met: reduced transport of oxaliplatin
MATE2 SLC47A2 p.Gly211Val
ATP7A ATP7A (MNK) c.2299G > C (p.Val767Leu) and c.4390A > G (p.Ile1464Val)
ATP7B ATP7B (WND)
c.1216G > T (p.Ala406Ser), c.1366G > C (p.Val456Leu), c.2495A > G (p.KLys32Arg), c.2785A > G 
(p.Ile929Val), c.2855G > A (p.Arg952Lys), c.2871delC (P957PfsX9), c.3419 T > C (p.Val1140Ala), 
c.3836A > G (p.Asp1279Gly), c.3886G > A (p.Asp1296Asn) and c.3889G > A (p.Val1297Ile)
EL = expression level
TABLE 2. Polymorphisms of DNA-platinum drug adducts repairing enzymes
Protein Gene Polymorphisms
DNA-adduct repair system
ERCC1 ERCC1 c.8092C>A, c.C354T
XRCC1 XRCC1 c.C580T, c.A1196G
XRCC3 XRCC2 p.Thr241Met, c.C241T
XPD XPD p.Lys751Gln, c.A2251C, c.C2133T
XPG c.T242C
XPA 5’UTR
Metabolism of platinum-based drugs
MDR1 c.T3435C
GSTP1 GSTP1 (FAEES3) c.A313G
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Makovec T / Cisplatin, molecular mechanisms and resistance development 153
Allergic reactions to cisplatin
Although allergic reactions to cisplatin are rare, 
with later cisplatin derivatives, carboplatin and 
oxaliplatin the allergic reactions are more com-
mon. Still they are less frequent than with antican-
cer drugs which names end with “mab” and other 
drugs that contain proteins. Hypersensitivity reac-
tions to platinum generally occur after multiple 
cycles of therapy – they are acquired and are con-
sistent with type 1 IgE-mediated hypersensitivity. 
In patients presenting with severe hypersensitivity 
reactions to carboplatin it is feasible to replace it 
with cisplatin. Overall incidence of hypersensitiv-
ity to platinum agents is 5 – 20% for cisplatin and 
occurs mostly between 4th-8th course of infusion. 
The incidence is 1 – 44% for carboplatin and 10 – 
20% for oxaliplatin.33 The most striking difference 
between carboplatin hypersensitivity, compared 
to hypersensitivity to nonplatinum drugs, is that 
the cumulative risk of hypersensitivity reactions 
increases with the number of infusions and there 
is no evidence of plateau.34 Hypersensitivity reac-
tions occur more frequently in patients receiving 
certain drug combinations such as carboplatin – 
paclitaxel as compared to carboplatin in combina-
tion with pegylated lyposomal doxorubicin.35 
Cisplatin and multimodal treatment and 
novel approaches
Since hyperthermia enhances cytotoxic effects of 
cisplatin, the trimodal combination of platinum 
drugs with hyperthermia and radiation can lead 
to potent synergistic interaction.36 There is a syn-
ergistic effect of regional hyperthermia (39-43ºC) 
and cisplatin anti-tumour efficacy, if cisplatin is 
encapsulated in temperature-sensitive liposomes 
used for targeted drug delivery. It is hypothesized 
that hyperthermia increases cisplatin accumula-
tion in part by increasing Ctr1 multimerization and 
thus greater cisplatin accumulation. Increased Ctr1 
multimerization following hyperthermia treat-
ment (41°C) in vitro, compared to normothermic 
controls (37°C), was observed suggesting that there 
may be a mechanism for an increased cisplatin up-
take in heat-treated cells. Hyperthermia enhanced 
cisplatin-mediated cytotoxicity in wild type (WT) 
cells with a dose modifying factor (DMF) of 1.8 
compared to 1.4 in Ctr1-/- cells because WT cells 
contained greater levels of platinum compared to 
Ctr1-/- cells.37
Since the atomic number of platinum is high, 
78, it is possible to produce Auger electrons and/
or Auger radiation upon treating the platinum 
drug with ionizing radiation. Treatment of cervi-
cal cancer with a conjunction of cisplatin and ion-
izing radiation increased survival and disease free 
intervals and became a part of standard care for the 
treatment of cervical cancers.38 The »Trojan horse« 
treatment of glioblastoma involves gold (atomic 
number 79) nanoparticles and attached molecules 
of cisplatin. Treated cultured glioblastoma cells in 
preclinical studies absorb nanoparticles and DNA 
binds platinum attached to nanoparticles. After 
radiation, both gold and platinum serve as high 
atomic number radio sensitizers that emit Auger 
electrons and radiation. The resulting assembly 
of gold nanoparticles with attached cisplatin and 
antibodies after radiation exhibit both chemo-
therapeutic power to cancer cells as well as Auger-
mediated secondary electron emission, which 
cause DNA double strand breaks adjacent to the 
cisplatin bound to DNA.39 Binding cisplatin to gold 
nanoparticles is also a strategy to enhance the de-
livery of cisplatin through the blood brain barrier. 
A combination with a magnetic resonance-guided 
ultrasound intensifies glioblastoma treatment. It is 
demonstrated that the assembly of gold nanopar-
ticles and cisplatin greatly inhibits the growth of 
glioblastoma cells compared to the free cisplatin 
and synergy with radiation therapy.40 An impor-
tant reactive oxygen species (ROS) scavenger DJ-
1 protein (PARK7) modulates different oncogenic 
pathways that support the growth and invasion of 
ovarian cancer cells. This cancer targeted nanoplat-
form based on siRNA-mediated suppression of DJ-
1 protein outperforms cisplatin alone. Three cycles 
of siRNA-mediated DJ-1 therapy combined with a 
low dose of cisplatin completely eradicated ovar-
ian cancer tumours from the mice without recur-
rence during a 35-week long study.41
The next step in the research includes the attach-
ment of the transport system for delivering nano-
particles with cisplatin to the target.42 Mice treated 
with hyaluronic-acid conjugated mesoporous silica 
nanoparticles carried TWIST-siRNA and cisplatin 
exhibited specific tumour targeting and reduction 
of tumour burden.43 
Another important aspect of novel approaches 
to cisplatin chemotherapy is to reduce cisplatin 
toxicity. The two other approved platinum-based 
chemotherapeutics, carboplatin and oxaliplatin ex-
hibit improved nephrotoxicity44 and ototoxicity45 
profiles, but are also less efficient than cisplatin. 
This challenge could be addressed by harnessing 
a nanotechnology-based strategy. An example of 
the cisplatin toxicity prevention on the reproduc-
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Makovec T / Cisplatin, molecular mechanisms and resistance development154
tive system is the use of selenium nanoparticles 
(Nano-Se). Nano-Se particles, due to their strong 
antioxidant potential are suitable to prevent cis-
platin induced gonadotoxicity. Co-administration 
with cisplatin significantly improves the sperm 
quality, serum testosterone and spermatogenesis 
in male rats.46 Lipoplatin is another example of bi-
as cisplatin toxicity. These nanoparticles of 110 nm 
average diameter are composed of lipids and cis-
platin. After intravenous administration it escapes 
clearance from macrophages and the half-life of li-
poplatin is 120 h.47 Attachment of platinum drugs 
to nanoparticles passively targets solid tumours 
through the enhanced permeability. Lipoplatin 
exerted negligible nephrotoxicity, ototoxicity and 
neurotoxicity in Phase I human studies.48
For poorly permeable platinum drugs such as 
cisplatin and similar low lipophilic analogues, a 
higher doses are needed to exert therapeutic effect 
and consequently toxicity is more pronounced. To 
mitigate this effect an enhanced influx into the can-
cer cells can be achieved with electroporation in the 
process of electrochemotherapy.49,50,51 This method 
increases the cytotoxicity up to 80-fold in cispl-
atin-sensitive as well as cisplatin-resistant tumour 
types.52 Other approach include the synthesis of 
novel platinum compounds with more lipophilic 
leaving groups with potential antitumor effect. 
One such candidate is trans-[PtCl2(3-hydroxym-
ethylpyridine)2] applied with electroporation as 
drug delivery method53.
Non-DNA targets for cisplatin
The principle target of cisplatin is the DNA as 
the platination of the DNA is lethal to the cell. 
However, the other targets are also very important 
and may contribute to the lethal effect on the cell. 
Cisplatin, among others, attacks mitochondria and 
triggers the production of ROS, destroys lysosomes 
inducing the release of lysosomal proteases and 
degrades endoplasmic reticulum which results 
in the deregulation of calcium storage and in the 
misfolded proteins.54 Beside the DNA in mitochon-
dria, cisplatin attacks other organelles by forming 
adducts with functional groups on proteins, espe-
cially with the sulphur atom in cysteine and me-
thionine side chains. 
A membrane-bound Na+/H+ exchanger protein 
(NHE) is one of the non-DNA targets for cisplatin. 
When cisplatin binds to this protein in human co-
lon cancer cells, it causes intracellular acidosis, in-
creases fluidity of membrane through promotion 
of lipid rafts and the induction of apoptosis via 
fas pathway and cell death.55 Since the membrane 
is the first barrier that cisplatin must cross, NHE 
may be the first target for cisplatin in cancer cells. 
Adducts between NHE and cisplatin occur in a few 
minutes after adding cisplatin to the culture me-
dium, whereas cisplatin-DNA adducts occur at a 
much slower rate after about an hour.
Zinc fingers that bind to the DNA and regulate 
gene expression are also cisplatin targets. An ex-
ample is 31-amino-amino-acid long zinc finger, 
that is the DNA-binding domain of the enzyme 
DNA-polymerase-a, a very important enzyme for 
accurate synthesis of genetic information.56 Four 
thiolate groups from cysteine residues coordinate 
the zinc atom in zinc fingers. Cisplatin reacts with 
the Zn2+ ion in a stepwise manner to substitute 
the coordinated Zn2+ ion from the finger. The re-
action between a zinc finger and cisplatin is faster 
than between cisplatin and DNA. That means that 
the zinc fingers could be the targets for platinum 
drugs. Cisplatin changes the structure of DNA-
polymerase-a and this could be the mechanism by 
which the drug blocks DNA replication and causes 
cell death.
Another protein target is tubulin. These 50 kDa 
proteins must be assembled into microtubules and 
disassembled rapidly during mitosis and mol-
ecules that interfere with this process can push the 
cell into a cell-cycle arrest and the cell dies. Even 
in the presence of an anticancer drug paclitaxel, 
which stabilizes and prevents disassembly of mi-
crotubules into tubulin, the nonfilamentous struc-
tures appear only if the diaqua derivative of cispl-
atin is present. GTP is required for the formation 
of filaments and since platinum drugs react readily 
with N7-atom in guanine, this is the mechanism of 
the deprivation of the necessary energy for the mi-
crotubule formation.57
Thioredoxin reductase (TrxR) has seleno-
cysteine residue at the C-terminus that is an excel-
lent target for platinum drugs. Both cisplatin and 
transplatin can irreversibly inactivate this enzyme. 
Since a large percent of cisplatin in the cell is inac-
tivated by GSH into GS-Pt, Ishikawa surprisingly 
found that GS-Pt can also inactivate TrxR.58 In the 
presence of cisplatin, cells also produce increased 
level of stress response and DNA-binding proteins. 
RNA is another molecule that has been largely 
overlooked as a possible candidate for the cisplatin 
attack and also contains suitable positioned bases. 
DeRose with the co-workers have shown that 4 to 
20-fold more platinum binds to RNA compared to 
DNA.59 Helix 18 of 18S rRNA binds three platinum 
Radiol Oncol 2019; 53(2): 148-158.
Makovec T / Cisplatin, molecular mechanisms and resistance development 155
ions. One of them is bridging opposing strands of 
RNA in an interstrand crosslink.
Cytotoxic metals
The problem with cisplatin is that it may be inac-
tivated into transplatin during the uptake into the 
cell via Ctr1 transporter. To avoid this problem 
other derivatives of platinum drugs have been 
synthesized, where two ligands are interconnected 
and trans effect is decreased. Oxaliplatin, nedapl-
atin, lobaplatin, heptaplatin and carboplatin have 
both oxygen ligands in one molecule as bidentate 
ligand. Oxaliplatin, lobaplatin and heptaplatin 
have also nonleaving amino ligands as parts of the 
bidentate molecule. 
The next generation of cisplatin-like drugs tend 
to be structurally similar to the approved drugs 
and they are expected to operate via a similar 
mechanism of action. More than five thousand dis-
tinct compounds with general formula cis-PtA2X2, 
where A is the symbol for ammine or a substitut-
ed ammine and X is anionic bidentat ligand, have 
been synthesized until now. The effort put into the 
elucidation of mechanisms of tumour resistance to 
cisplatin and other platinum based drugs triggered 
the boom also in other metal based cytostatics. 
During a 40-year-long period between the devel-
opment and the final approval of cis-, carbo- and 
oxaliplatin, the search for nonplatinum anticancer 
drugs yielded some interesting compounds. Better 
understanding of their chemistry and mode of ac-
tion may facilitate the development of anticancer 
drugs based on these compounds.
Ruthenium Organometallic ruthenium (II) arene 
compounds are emerging as a new class of promis-
ing anticancer drugs. They show selective activity 
against certain cancer cells and low toxicity. Due 
to octahedral coordination sphere, ruthenium com-
plexes have higher degree of specificity and size 
discrimination and exert lower toxicity and faster 
elimination from the body, in contrast to square 
planar geometry of platinum (II) compounds. 
Well known species NAMI-A and KP1019, which 
are currently in clinical trials, is opening new ap-
proaches in cancer treatment. The cellular targets 
of ruthenium compounds have not yet been identi-
fied with certainty. Despite the fact that DNA has 
been assumed to be the primary target, recent re-
sults show that several proteins have been recog-
nized as the binding partners.60 In particular, these 
proteins are glutathione S-transferase, HSA and 
transferin.61 NAMI-A binds to the exposed imida-
zole (histidine) on HSA and apo-transferrin, but 
only weakly on DNA and RNA. The main effect 
of NAMI-A is to stop a tumour from spreading, a 
process known as metastasis. 60 
Gold, palladium. In arthritic patients receiv-
ing gold +3 and +1 compounds as therapy it was 
observed that gold possesses anticancer activ-
ity.62 The mechanism of the action of gold com-
pounds, for example a gold phosphine ligands 
[Au(dppe)2]+, is still unknown, although, most 
researchers believe that the site of action of this 
compound is the mitochondria in the cells. Such 
compounds also produce breaks in DNA and al-
so serve as a bridge between protein and DNA. 
Complexes with gold and palladium, depending 
on dose, reduce the proliferation of ovarian and 
breast cancer as well as myeloid leukaemia and 
lymphatic cell line. Compounds with selenium li-
gands in general induce stronger effects than com-
pounds with sulphur ligands. The IC501 for prolif-
eration of SUP-B15 cells was 50% lower with Au-Se 
compounds in comparison with Au-S compounds 
and around a quarter lower in the case of Ru-Se 
and Pd-Se compounds in comparison with Ru-S 
and Pd-S compounds.63 The mechanism of action 
is composed of the inhibition of metabolism and 
proliferation and it also includes apoptosis and 
oxidative stress by ROS production.
In titanium, as in cisplatin, there are two chlo-
ride-leaving ligands in cis position present in ti-
tanocene dichloride and the molecule is neutral in 
charge. Since this compound showed no nephro- 
or myelotoxicity in preclinical studies, it was en-
tered into clinical trials.64 The trials revealed that 
the compound was active against colon 38 carci-
noma and B16 melanoma cells. In treating ovarian 
cancer cells, titanocene dichloride displayed high-
er activity than cisplatin. While investigating the 
mechanism of action, a far more complicated pic-
ture has appeared indicating multiple cellular pro-
cesses that can be triggered by titanium anticancer 
compounds.65 The exact site of binding is not es-
tablished, but since Ti4+ is a hard base, negatively 
charged oxygens on the phosphate groups of DNA 
form bonds with the ion and thus disable DNA.66
Vanadium, niobium, molybdenum and rhenium 
complexes – early transition metal based antitumor 
drugs and a large spectrum of other transition met-
als have also been tested for anticancer activity. For 
most of them, the intercalation with DNA atoms is 
not required for activity. Proteins, such as human 
topoisomerase 1 and thioredoxin reductase, are 
only a few of the possible targets of these transition 
metal complexes.67
Radiol Oncol 2019; 53(2): 148-158.
Makovec T / Cisplatin, molecular mechanisms and resistance development156
Conclusions
In the last decade, several of platinum and other 
metal complexes have been created and tested for 
anticancer activity in order to bypass the draw-
back of existing metal anticancer chelates. The 
enormous spectrum of transition metal combina-
tions and a plethora of ligands combinations have 
produced extremely broad spectrum of anticancer 
complexes – more than 5000 only with platinum. 
Each of them has its own mechanism of action and 
the continuation of work on this field could pro-
duce metal complexes which can outperform the 
existing drugs and provide more effective chemo-
therapy and less toxicity. 
The other field of intensive research is the inves-
tigation of genetic polymorphisms as an approach 
to the optimal metal-based chemotherapy for a 
particular individual and probably it represents 
the plateau of this type of treatment. The solid 
knowledge of the molecular mechanisms of action 
and genetic basis of interindividual variability of 
response to cisplatin and other metal based com-
pounds summarized in this review may therefore 
help the oncologist to better understand the mech-
anism of their cytostatic action.
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