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 extrinsic and intrinsic resistance of cells. Although many cancer cells are initially susceptible to chemotherapy 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 knowledge of mechanism of action of these drugs reveals mechanisms of resistance and toxicity. The aim of this review is also to provide recent data concerning hypersensitivity reactions to platinum-containing chemotherapy agents. To minimize toxicity, resistance and hypersensitivity reactions to platinum drugs the new metallodrugs were developed. A brief summary of these agents is also presented.
Until the mid-1960s, cancer chemotherapy was based on purely organic compounds. An accidental discovery of anticancer properties of inorganic coordination compounds based on platinum opened the door also for inorganic compounds. In 1965, Barnett Rosenberg discovered that platinum complex generated during electrolysis from platinum electrodes inhibited binary fission in the
Rosenberg and his group concluded that compounds capable of inhibiting
Turning these findings into a useful commercial product was a hard task at that time. When Rosenberg carried out his investigations, all anticancer 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 effective 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 provide information about the safety and the efficacy for the Food and Drug Administration (FDA). In 1978, the FDA approved cisplatin for use in cancer chemotherapy. Suddenly, it was appropriate for inorganic chemists to send their compounds to Cancer Institutes for screening for antitumor activities.4 This resulted in a number of new platinum and non-platinum based compounds that showed promise to become successful anticancer compounds. Since its discovery, five other platin drugs have received approval in various countries: besides carboplatin and oxaliplatin there are another three gaining approval in single markets; nedaplatin in Japan, lobaplatin in China and heptaplatin in Korea.5
The behaviour of cisplatin in aqueous solution is presented in Figure 1.
The chemistry of cisplatin is completely different from all other chemistries of typical organic anticancer drugs. In blood, the concentration of 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
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 infusion, it is impossible to predict the composition of species
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 passive diffusion. Uptake of cisplatin by cells was proportional to the total concentration of cisplatin in the cell culture medium up to 3 mM concentration and was not saturable.10 The most likely candidates for passive diffusion through hydrophobic lipid bilayer are neutral species without the charge such as cisplatin and monohydroxo form (
As forms
Since the therapeutic range of cisplatin is narrow we cannot overcome the cell resistance simply 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 transporter,
Beside the copper-transporting proteins GSH and metallothioneins may also influence cisplatin transport. These cysteine rich, low molecular weight proteins are involved in intracellular inactivation 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
The inter-individual variability of the efficacy of platinum based chemotherapy as well as its toxicity
is the result of the genetic variability in genes involved in drug metabolism, drug transport and DNA repair. Therefore, the determination of genetic markers such as genetic polymorphisms in these genes may provide the hints about the optimal cisplatin regimens for personalized therapy.
Both uptake and efflux transporters are subject to genetic variability. Polymorphic transporters are involved in processes that increase the intracellular level of the drug: transport with copper transporters 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 multidrug extrusion transporter-1 (MATE1).27
The presence of single nucleotide polymorphisms in all transporters shown in Figure 2 influence 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.
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 | c.181C > T, c.480C > G, c.1022C > T, c.1222A > G, c.1390G > A, c.1463G > T | |
OCT2 | 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 | EL | |
CTR1 | rs10981694 A>C | |
CTR2 |
Efflux of platinum drugs | ||
---|---|---|
MATE1 | p.Gly64Asp and p.Val480Met: reduced transport of oxaliplatin | |
MATE2 | p.Gly211Val | |
ATP7A | c.2299G > C (p.Val767Leu) and c.4390A > G (p.Ile1464Val) | |
ATP7B | 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
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
Polymorphisms of DNA-platinum drug adducts repairing enzymes
Protein | Gene | Polymorphisms |
---|---|---|
DNA-adduct repair system | ||
ERCC1 | c.8092C>A, c.C354T | |
XRCC1 | c.C580T, c.A1196G | |
XRCC3 | p.Thr241Met, c.C241T | |
XPD | p.Lys751Gln, c.A2251C, c.C2133T | |
XPG | c.T242C | |
XPA | 5’UTR |
Metabolism of platinum-based drugs | ||
---|---|---|
MDR1 | c.T3435C | |
GSTP1 | c.A313G |
in these processes. The polymorphic A1196G allele 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
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 resistance in cancer cells, several studies have reported conflicting results.31 The association between polymorphisms in
Although allergic reactions to cisplatin are rare, with later cisplatin derivatives, carboplatin and oxaliplatin the allergic reactions are more common. Still they are less frequent than with anticancer drugs which names end with “mab” and other drugs that contain proteins. Hypersensitivity reactions to platinum generally occur after multiple cycles of therapy – they are acquired and are consistent 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 hypersensitivity 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 reactions occur more frequently in patients receiving certain drug combinations such as carboplatin – paclitaxel as compared to carboplatin in combination with pegylated lyposomal doxorubicin.35
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 synergistic 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 accumulation in part by increasing Ctr1 multimerization and thus greater cisplatin accumulation. Increased Ctr1 multimerization following hyperthermia treatment (41°C) in vitro, compared to normothermic controls (37°C), was observed suggesting that there may be a mechanism for an increased cisplatin uptake 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 cervical cancer with a conjunction of cisplatin and ionizing 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 chemotherapeutic 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 delivery 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 nanoparticles and cisplatin greatly inhibits the growth of glioblastoma cells compared to the free cisplatin and synergy with radiation therapy.40 An important 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 nanoplatform 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 ovarian cancer tumours from the mice without recurrence during a 35-week long study.41
The next step in the research includes the attachment of the transport system for delivering nanoparticles 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 exhibit 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 reproductive system is the use of selenium nanoparticles (Nano-Se). Nano-Se particles, due to their strong antioxidant potential are suitable to prevent cisplatin induced gonadotoxicity. Co-administration with cisplatin significantly improves the sperm quality, serum testosterone and spermatogenesis in male rats.46 Lipoplatin is another example of bias cisplatin toxicity. These nanoparticles of 110 nm average diameter are composed of lipids and cisplatin. After intravenous administration it escapes clearance from macrophages and the half-life of lipoplatin 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 cancer cells can be achieved with electroporation in the process of electrochemotherapy.49,50,51 This method increases the cytotoxicity up to 80-fold in cisplatin-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-hydroxymethylpyridine)2] applied with electroporation as drug delivery method53.
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 mitochondria, cisplatin attacks other organelles by forming adducts with functional groups on proteins, especially with the sulphur atom in cysteine and methionine 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 colon cancer cells, it causes intracellular acidosis, increases fluidity of membrane through promotion of lipid rafts and the induction of apoptosis via
Zinc fingers that bind to the DNA and regulate gene expression are also cisplatin targets. An example 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 reaction 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 molecules 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 microtubules into tubulin, the nonfilamentous structures appear only if the diaqua derivative of cisplatin 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 microtubule formation.57
Thioredoxin reductase (TrxR) has selenocysteine residue at the C-terminus that is an excellent target for platinum drugs. Both cisplatin and transplatin can irreversibly inactivate this enzyme. Since a large percent of cisplatin in the cell is inactivated 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 ions. One of them is bridging opposing strands of RNA in an interstrand crosslink.
The problem with cisplatin is that it may be inactivated 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
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 distinct compounds with general formula
During a 40-year-long period between the development 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 action may facilitate the development of anticancer drugs based on these compounds.
In
In the last decade, several of platinum and other metal complexes have been created and tested for anticancer activity in order to bypass the drawback of existing metal anticancer chelates. The enormous spectrum of transition metal combinations 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 produce metal complexes which can outperform the existing drugs and provide more effective chemotherapy and less toxicity.
The other field of intensive research is the investigation 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 compounds summarized in this review may therefore help the oncologist to better understand the mechanism of their cytostatic action.