Advances in Toxicological Research of the Anticancer Drug Cisplatin

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Advances in Toxicological Research of the Anticancer Drug Cisplatin Luyu Qi, Qun Luo, Yanyan Zhang, Feifei Jia, Yao Zhao, and Fuyi Wang Chem. Res. Toxicol., Just Accepted Manuscript • DOI: 10.1021/acs.chemrestox.9b00204 • Publication Date (Web): 29 Jul 2019 Downloaded from pubs.acs.org on July 29, 2019

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Chemical Research in Toxicology

Advances in Toxicological Research of the Anticancer Drug Cisplatin Luyu Qi,ab Qun Luo,ab Yanyan Zhang,a Feifei Jia,a Yao Zhao*a and Fuyi Wang*abc a

Beijing National Laboratory for Molecular Sciences; National Centre for Mass Spectrometry in Beijing; CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China. b

University of Chinese Academy of Sciences, Beijing 100049, P. R. China.

c

Basic Medical College, Shandong University of Chinese Traditional Medicine, Jinan 250355, P. R. China

ACS Paragon Plus Environment

Chemical Research in Toxicology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

For TOC only Ototoxicity Hepatotoxicity Gastrointestinal Toxicity Hematological Toxicity

Retinal Toxicity Cardiotoxicity Neurotoxicity

Cisplatin Nephrotoxicity


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Abstract

Cisplatin is one of the most widely used chemotherapeutic agents for various solid tumors in the clinic due to its high efficacy and broad spectrum. The antineoplastic activity of cisplatin is mainly due to its ability to crosslink with DNA, thus blocking transcription and replication. Unfortunately, the clinical use of cisplatin is limited by its severe, dose-dependent toxic side effects. There are approximately 40 specific toxicities of cisplatin, among which nephrotoxicity is the most common. Other

common

side

effects

include

ototoxicity,

neurotoxicity,

gastrointestinal toxicity, hematological toxicity, cardiotoxicity and hepatotoxicity. These side effects together reduce the life quality of patients and require lowering the dosage of the drug, even stopping administration, thus weakening the treatment effect. Few effective measures exist clinically against these side effects because the exact mechanisms of various side effects from cisplatin remain still unclear. Therefore, substantial effort has been made to explore the complicated biochemical processes involved in the toxicology of cisplatin, aiming to identify effective ways to reduce or eradicate its toxicity. This review summarizes and reviews the updated advances in the toxicological research of cisplatin. We anticipate to provide insights into the understanding of the mechanisms underlying the side effects of cisplatin



and designing comprehensive therapeutic strategies involving cisplatin.

Keywords: cisplatin; anticancer drug; toxicology; nephrotoxicity; ototoxicity

1. Overview of Cisplatin 1.1 Chemistry of cisplatin Cisplatin, chemically named cis-diamminedichloroplatinum (CDDP), was synthesized by M. Peyrone in 1844 for the first time. However, this compound did not gain much scientific attention until 1965. In this year, Rosenberg found that the electrolytic product of platinum electrodes can inhibit the growth of E. coli and was later characterized to be CDDP.1 After more than 10 years of bench and preclinic research, as well as clinical trials, CDDP was approved by the FDA in 1978 for clinical use as a chemotherapeutic agent with the name cisplatin. Since then, cisplatin has been used to treat various human malignancies, including ovarian cancer, cervical cancer, testicular cancer, head and neck cancer, non-small cell lung cancer and many other solid tumors.2-4 Cisplatin is centered on a platinum atom which coordinates with two chlorine atoms and two ammonia groups to form a planar quadrilateral compound. The two chlorine atoms are on the same side (Figure 1). Initially, it was widely accepted that cisplatin enters cells by passive


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transport. However, studies in recent years have shown that the copper transport protein CTR1 and organic cation transporters (OCTs) also play important roles in the transport of cisplatin.5, 6 Outside cells, cisplatin is not susceptible to hydrolysis due to the high concentration of chloride ions (approximately 100 mM) in blood. Once in cells, cisplatin undergoes slow hydrolysis to form the cationic mono-aqua and/or di-aqua complexes (Figure 1) due to a much lower concentration of chloride ions (4

–

22

mM).7-9

The

mono-aqua

and

di-aqua

complexes

([Pt(NH3)2Cl(OH2)]+ and [Pt(NH3)2(OH2)2]2+ are recognized as highly reactive hydrolysis products of cisplatin and can react more readily with various cellular targets.10 The PtII atom is the reaction center of cisplatin that can interact with various biomolecules via nucleophile coordination or charge-charge interactions. According to the Hard-Soft Acid-Base (HSAB) theory, PtII is a soft acid.11 In consistent with HSAB theory, cisplatin, precisely its hydrolyzed products tend to form stable coordination bonds with soft bases, for instance sulfur-containing nucleophiles such as cysteine and glutathione as well as cysteinyl residues of proteins.12 Nevertheless, they can also react with some borderline bases, particularly nitrogen containing donors such as nucleobases in DNA and RNA, histidine resiudes in proteins and peptides (Figure 1).10, 12, 13



H 3N

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Cl Pt

H 3N

Cl

H 3N

Cl

Cell membrane

[Cl−] = ~100 mM [Cl−] = 4–22 mM

Pt H 3N

Cl

H 3N

H 2O

+ Pt H 3N

Cl

OH

H 3N

H 2O

H 3N

Cl

H 3N

H 3N

OH

Proteins

Nucleus

2+ H 3N

Pt

Pt

H 2O +

H 3N

Pt H 3N

DNA

OH

Small molecules with S, N donors

Pt OH

H 3N

H 2O

Mitochondrial DNA

Figure 1. Hydrolytic procedure and potential molecular targets of cisplatin inside cells.

1.2 Anticancer activity (cytotoxicity) of cisplatin Although cisplatin can bind to various biomolecules, it is generally considered that DNA is the major biological target.10 The cytotoxicity of cisplatin is mainly attributed to interactions with the N7 reactive center on purine residues to form crosslinking complexes, which include 1,2-intrastrand adducts (approximately 90%) and 1,3-intrastrand (5-10%) adducts, in addition to low percentage of monofunctional adducts and interstrand crosslinks (Figure 2).14 In these crosslinking complexes, 1,2-GG and 1,2-AG intrastrand adducts largely account for the


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cytotoxicity of cisplatin.15 This is consistent with 1,2-intrastrand crosslinks being the major forms of DNA adducts. Transplatin mainly forms 1,3-intrastrand and interstrand crosslinks due to stereochemical constraints and is a clinically ineffective isomer of cisplatin.16 The 1,2-crosslinking of cisplatin significantly alters the structure of the target DNA and can be recognized by high mobility group box 1 (HMGB1) protein to form the DNA-Pt-HMGB1 ternary complex, thus blocking DNA replication and transcription and leading to cell cycle arrest.17,

18

The crosslinked DNA adducts can also be recognized by DNA damage response proteins and other nuclear proteins, activating DNA repair and other signal transduction pathways. Eventually, the DNA may be successfully repaired, leading to resistance toward cisplatin.4 If the repair fails, an apoptotic process is initiated.

H3N H3N

Pt

H3N

G G

H3N NH3 G A

Pt

NH3

Pt

G X G

NH3 HO

NH3 Pt

G

NH3

Pt G

NH3

G

Figure 2. Crosslinking complexes on DNA. Cisplatin can interact with DNA to form intrastrand adducts (1,2-d(GpG), 1,2-d(ApG) and 1,3-d(GpXpG)), interstrand adducts (G-G) and monofunctional adducts.



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1.3 Toxicity of cisplatin Although cisplatin has become a common drug for the clinical treatment of solid tumors, its use has been largely limited due to the inherent and acquired resistance and severe toxic side effects in normal tissues.2,

3

Cisplatin resistance has been extensively explored and is

mainly attributed to the decreased cellular drug accumulation, enhanced DNA repair, defective apoptosis signaling pathways, and factors or pathways indirectly associated with cisplatin-DNA damage (such as deactivation of cisplatin by glutathione, methionine and other sulfur-containing molecules).4,

19-21

Additionally, translesional synthesis

(TLS) of DNA also plays a role in cisplatin resistance.22, 23 It has been demonstrated that DNA polymerase eta (pol eta) and a complex of Pol zeta

and

Rev1

can

bypass

DNA

damage

adducts,

including

cisplatin-crosslinked intrastrand adducts, in vitro and in vivo, thus developing drug resistance.24-27 Unfortunately, the exact mechanism of various side effects induced by cisplatin largely remains unclear, although many efforts have been made in this field during the past decades. Nephrotoxicity appears to be the major limiting factor of cisplatin in cancer therapy, and ototoxicity, neurotoxicity, gastrointestinal toxicity and hematological toxicity are also common in the clinic. Cardiotoxicity, hepatotoxicity, retinal toxicity, SIADH (syndrome of inappropriate antidiuretic hormone, an uncommon but potentially life-threatening


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toxicity)28 and other toxicities such as hypersensitivity reactions and reproductive toxicity, are occasionally presented in the clinic.29 Besides, secondary malignancies caused by cisplatin may also happen in the clinic.30-32 The presence of these toxic side effects severely reduces the life quality of patients. Therefore, it is essential to deeply understand the pathogenesis of various toxic side effects of cisplatin to help eliminate or reduce the annoying side effects of this drug. This article mainly focuses on advances in the research on the toxic side effects of cisplatin in recent years, and reviews the possible pathogenesis of the side effects, to better understand the pathogenesis of cisplatin side effects for improving its clinical effectiveness.

2. Clinical Toxic Side Effects of Cisplatin 2.1 Types and clinic manifestations of the toxic side effects of cisplatin In 1971, for the first time, Kociba and Sleight found that cisplatin can induce renal toxicity in animals before approval of its clinical use. They observed tubular necrosis, high serum creatinine and elevated levels of urea in the blood of tested mice treated with cisplatin.33 Nephrotoxicity was later reported in initial clinical trials of cisplatin chemotherapy34 and occurs in almost one-third of patients undergoing cisplatin treatment.35 Clinically, higher serum creatinine, lower glomerular filtration, hypomagnesemia and hypokalemia can often be seen after 10 days of



cisplatin administration.35-37 The long-term effects of cisplatin on renal function have not been fully understood, but the administration of cisplatin is believed to cause subclinical or permanent reduction in the glomerular filtration rate.38, 39 Clinically, using hydration and diuretics, the nephrotoxicity caused by cisplatin can be greatly alleviated. Besides, the most common side effects of cisplatin are ototoxicity and neurotoxicity. Tinnitus and hearing loss can occur in the early stages after the injection of cisplatin. Most of the deafness caused by cisplatin is irreversible. Hearing loss presents mainly at cisplatin treatment with high frequency and high dose greater than 60 mg/m2.40 Almost all patients will be affected when the dose reaches 150 – 225 mg/m2. Patients receiving 20 mg/m2 of cisplatin daily for 5 days developed less hearing loss than those receiving 100 mg/m2 of cisplatin for 1 day.41 The incidence of ototoxicity is also related to age and gender. Young children are more susceptible to hearing loss due to cisplatin than adults,42-44 and men are more likely to develop hearing loss than women.45 Neurotoxicity arising from cisplatin administration mainly manifests as peripheral sensory neuropathy. Central nervous side effects have also been reported, e.g. hemiparesis, status epilepticus and coma.46 The dorsal root ganglia have the highest platinum level, making them the primary location of cisplatin damage. The secondary types of toxic side effects of cisplatin are


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gastrointestinal toxicity and hematological toxicity. The former includes nausea and vomiting (CINV), anorexia, weight loss, and diarrhea.47-49 Among them, CINV is the most common side effect of cisplatin. More than 90% of patients develop it in the clinic. Hematological toxicities caused by cisplatin include thrombosis, leukopenia, neutropenia, thrombocytopenia and anemia.50-52 Raynaud’s phenomenon, caused by vasospasm, occurring in up to 37% of patients, is the most common vascular toxicity of cisplatin. Myelosuppression refers to a status of low levels of white cells, red cells, and platelets, due to the influence of cisplatin on all blood cells, which are produced by bone marrow. In addition to the toxic side effects mentioned above, other side effects of cisplatin, such as cardiotoxicity, hepatotoxicity, and visual toxicity, may also occur clinically. Cardiotoxicity is rare in the clinic and has a significant correlation with the concentration and dose of the cisplatin treatment. Its main manifestation is electrophysiological changes, arrhythmias, myocarditis, pericarditis, mild blood pressure changes, myocardial infarction, cardiomyopathy, cardiac failure, angina and congestive heart failure.53, 54 Cisplatin can also cause damage to the liver sinusoids, making patients feel abdominal pain and swelling. Like interferon, cisplatin can lead to considerable ocular morbidity. At the therapeutic dose, it can cause marked irreversible visual loss.55 Other toxicities, like hypersensitivity reactions (ranging from skin to



anaphylaxis) and reproductive toxicity induced by cisplatin, show an uncommon occurrence.56 Clinically, even if cisplatin cures a certain type of tumor, there may be some long-term toxic side effects, nainly manifested

as secondary malignancies, which have been widely studied

among survivors of testicular cancer.57-59

2.2 Clinical countermeasures for the toxic side effects of cisplatin During the battle against the nephrotoxicity of cisplatin, several pharmacological, molecular and genetic approaches have been developed to protect the kidney based on the proposed toxicology. The most used strategy is pre- and post-hydration using mannitol or hypertonic saline in the clinic,60,

61

although there is no direct evidence that diuretics can

provide any added benefit.62, 63 Sometimes, antiemetics are also used to prevent fluid loss because of vomiting. Recently, drugs designed to clear reactive oxygen species (ROS) induced by cisplatin, for example, sodium thiosulfate64 and tetrahydrocurcumin,65 have been investigated to protect patients against nephrotoxicity. Various antioxidants have been investigated to eliminate ototoxicity caused by cisplatin. They are mainly nucleophilic molecules containing sulfur, selenium, carboxylic acid or alcohol groups, e.g. amifostine, WR-1065,66 N-acetylcysteine,67 sodium thiosulfate,68 D-methionine,69


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allopurinol and ebselen.70 Unfortunately, most of them have been shown to mitigate ototoxicity only in model animals or in vitro. Whether they could protect humans against ototoxicity and whether they would affect the cytotoxicity of cisplatin demand further studies. Because the mechanism by which cisplatin kills tumors may be basically consistent with the mechanism by which cisplatin causes ototoxicity, it is not preferable to systematically use ototoxic protective agents in patients, and local administration may be more effective.71, 72 Glucocorticoids are the most studied agent for local administration against cisplatin ototoxicity. It has been shown that the additional preoperative use of glucocorticoids intratympanically can stabilize and improve the hearing preservation rates of model animals treated with cispaltin.73 However, transtympanic and intratympanic (IT) puncture as local administration techniques of ototoxic protective agents are clinically discarded because they are too aggressive. Furthermore, almost no reliable treatment is available to prevent or eliminate neurotoxicity induced by cisplatin. The co-administration of antiemetic drugs with cisplatin is largely successful to relieve nausea and vomiting caused by cisplatin.74,

75

Because most CINV in patients is induced by the release of 5-hydroxytryptamine (5-HT), ondansetron, a 5-HT3 antagonist, can also be used to reduce cisplatin-induced CINV. Clinically, methods such as blood transfusions and the administration of broad-spectrum antibiotics



are used to fight against some hematological toxicities caused by cisplatin. Battle against cardiac toxicity induced by cisplatin has met very little success clinically.76 Many drugs and natural extracts have been investigated to eliminate the hepatotoxicity caused by cisplatin in model animals.77-80 Although positive effects have been achieved, the role of protecting the liver in humans has not been verified. Because the probability of the occurrence of clinical visual toxicity is not high, few reports have addressed treatments that would relieve visual toxicity caused by cisplatin. In-depth characterization of the cisplatin mutational signature in human cell lines may help to avoid secondary malignancies caused by cisplatin.81 According to the abovementioned measures to clinically respond to the various side effects caused by cisplatin, it is evident that most of the countermeasures are based on the presenting symptoms, which may reduce the cytotoxicity of cisplatin while relieving its toxicity. However, for most of the side effects of cisplatin, no effective protection measures have been identified clinically thus far. It is also notable that new toxic side effects may be introduced by the co-administration of new drugs. Only by designing drugs based on the pathogenesis of each side effect can the various side effects be fundamentally alleviated or removed without compromising the cytotoxicity of cisplatin. Next, we will


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highlight the advances in research on the toxicity of cisplatin, as well as countermeasures designed accordingly.

3. Research Progress in the Toxicology of Cisplatin 3.1 Nephrotoxicity The exact mechanism underlying the nephrotoxicity of cisplatin remains unclear, although it has been studied for decades. Histologic examination has suggested that the kidneys in patients suffered from cisplatin-induced renal failure showed changes in the collecting duct, distal tubule and S3 of the proximal tubule.82 It is widely accepted that nephrotoxicity is due to direct and indirect damage to kidneys. The mechanism by which cisplatin causes tubular damage and leads to renal failure is very complex, involving many biomolecules and processes associated with each other, as shown in Figure 3 and discussed below.83-85



Figure 3. Proposed mechanism by which cisplatin causes tubule damage, leading to renal failure.

3.1.1 Accumulation of cisplatin in the kidney by membrane transportation It was believed that cisplatin enters cells by passive transport. However, studies in recent years have suggested that cisplatin also enters renal tubular cells by transporter-mediated/facilitated diffusion. Studies have shown that organic cation transporters (OCTs) and CTR1, a copper transporter, are involved in mediating the uptake of cisplatin. Thus far, three isoforms of OCTs (OCT1, OCT2 and OCT3) have been identified


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in humans, and OCT2, which is expressed primarily in the kidney,86 is thought to be the major transporter for cisplatin uptake.87 This was demonstrated by cimetidine, a substrate of OCT2, reducing cisplatin uptake, and cisplatin nephrotoxicity in vivo88 and cytotoxicity in vitro.87, 89 That cisplatin-induced nephrotoxicity in HEK293 cells transfected with the rat OCT2 transporter was enhanced87 also supports this conclusion. CTR1, which is expressed in the proximal tubular cells of adult kidney and cardiac tissue,5,

90

is believed to play a role in cisplatin uptake,

although no evidence has been demonstrated in vivo. An in vitro study reported that the downregulation of CTR1 significantly reduced cisplatin uptake and cytotoxicity.5 These two membrane transporters work together to lead to a disproportionate distribution of cisplatin in the body. Additionally, multidrug and toxin extrusion 1 (MATE1), which is expressed in the brush-border membrane of renal proximal tubules, has been shown to be involved in cisplatin-induced nephrotoxicity through mediating the efflux of cisplatin. It has been reported that the genetic deletion of MATE1 in a mice model makes it more susceptible to cisplatin nephrotoxicity.91 3.1.2 Conversion of cisplatin into toxic metabolites In the kidney, cisplatin can bind to glutathione, an abundant endogenous antioxidant in renal tubular cells, to form glutathione conjugates.

This

process

is

catalyzed


by

the

enzyme


glutathione-S-transferase



(GST).92

Next,

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by

gamma-glutamyl

transpeptidase (GGT) and aminotransferase N (APN), the glutathione conjugates

are

cleaved

to

cysteinyl-glycine-conjugates

and

cysteine-conjugates, respectively, after passing through the tubular cells.92,

93

After being transported into proximal tubular cells, the

cysteine-conjugates are further metabolized to highly reactive thiols by cysteine-S-conjugate beta-lyase.94,

95

These reactive thiols, which may

bind to essential proteins within the proximal tubular cells, are more potent nephrotoxins. 3.1.3 Damage to DNA As described above, the hydrolytic products of cisplatin can bind to nuclear DNA, forming intrastrand and interstrand crosslinking products. This will lead to impaired replication and transcription of DNA, causing cell cycle arrest, which, in turn, triggers a cascade of signal transductions and eventually initiates apoptosis. The tumor suppressor protein p53, which suppresses anti-apoptotic and activates pro-apoptotic genes, mediates the apoptosis caused by DNA damage.96 Kaushal et al. suggested that the executioners caspase-6 and -7 are transcriptional targets of p53 in cisplatin injury. Inhibition of p53 activation by a p53 inhibitor was shown to suppress the transactivation of caspase-6 and -7 genes in an in vivo model of cisplatin nephrotoxicity, eventually preventing renal failure.97 However, some have argued that the formation


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of DNA adducts may not play a major role in cisplatin nephrotoxicity because proximal tubule cells do not divide in adult males. They suggested that mitochondrial DNA or other mitochondrial targets, instead of nuclear DNA, are more important in mediating cisplatin-induced cell death.98 Positively charged cisplatin metabolites after hydrolysis prefer to enter negatively charged mitochondria. The renal proximal tubule is one of the segments with the highest densities of mitochondria in the kidney. This may explain why the renal proximal tubule has particular sensitivity to cisplatin toxicity. Additionally, the poor repair capabilities of mitochondrial DNA also make them the most common binding target for cisplatin.98 3.1.4 Alterations of the cell transport system (ionic homeostasis) A few studies have shown that cisplatin interferes with water transport and interrupts ionic homeostasis in renal tubular cells, resulting in a reduced ion reabsorption rate and ultimately increased excretion of these ions in the urine.99-101 Both in vivo and in vitro, it has been identified that cisplatin can inhibit the activity of transporters located in the brush border, leading to renal tubular dysfunction.100 Furthermore, the glomerular filtrate was forced to flow back into the blood circulation because of the loss of the junctions between viable cells and/or tubular epithelial cells, producing an apparent decrease in GRF.100 When administered intravenously, cisplatin will bind to various plasma



proteins, particularly albumin102-104 and transferrin,13 which may lead to dysfunction of the targeted proteins and/or inactivation of cisplatin.13, 103 The binding of cisplatin with the cysteine group in proteins may block the anti-oxidation effect of the protein.103 Our group previously reported that cisplatin can crosslink with two histidine residues of serum albumin, occupying the binding site of zinc in the protein and interfering with the body's intake of zinc.104 This may be closely related to zinc deficiency syndrome, manifesting hyperzincuria and hypozincemia, in patients receiving cisplatin chemotherapy.105 3.1.5 Mitochondrial dysfunction The swelling of mitochondria is one of the earliest histopathological changes due to clinic use of cisplatin.106 The accumulation of cisplatin in the mitochondria of renal cells was believed to cause mitochondrial dysfunction, mainly characterized by increased production of reactive oxygen species (ROS). This affects mitochondrial respiratory complexes and function, decreasing the absorption of calcium in mitochondria and resulting in the release of pro-apoptotic factors that eventually lead to renal tubular cell death.107,

108

Moreover, cisplatin can disrupt

mitochondrial energetics, which may contribute to nephrotoxicity. The energy in the proximal tubule is mainly derived from oxidation of fatty acids, which can be inhibited by cisplatin in proximal tubule cells and in the mouse kidney through the downregulation of PPAR-α mediated


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expression of genes associated with cellular fatty acid consumption.109, 110 3.1.6 Oxidative and nitrosative stress It has been recognized for years that oxidative and nitrosative stress play an important role in nephrotoxicity induced by cisplatin.111 As mentioned above, once entering cells cisplatin will be hydrolyzed, the resulting hydrolysates will react with thiol-containing molecules, such as glutathione, a well-recognized cellular antioxidant.4, 35 This will lead to the inactivation and depletion of glutathione and related antioxidants, eventually leading to the accumulation of ROS. Additionally, it was reported that the activity of mitochondrial respiration complexes I – IV are reduced by 15-55% after the administration of cisplatin, which will also result in ROS generation.108 On the other hand, cisplatin may induce the generation of ROS in the microsomes through the cytochrome P450 (CYP) system. Both in vivo and in vitro, it has been identified that CYP is a crucial source of iron for ROS formation during cisplatin administration. In CYP2E1-null mice, ROS accumulation induced by cisplatin was attenuated, as well as kidney damage.112 Although it is well known that oxidative stress plays a role in cisplatin nephrotoxicity, the critical molecular targets of ROS remain unclear. Because ROS has a broad reactivity, it may target and modify various molecules in the cells, such as DNA, proteins and lipids, resulting in cellular stress. It seems that ROS is involved in the activation of some



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important signaling pathways involved in cisplatin nephrotoxicity, including apoptotic pathways. For example, hydroxyl radicals would be rapidly produced by renal tubular cells when they are incubated with cisplatin.113

The

general

antioxidant

N-acetylcysteine

and

dimethylthiourea (DMTU) can suppress the accumulation of hydroxyl radical, activation of p53, and nephrotoxicity induced by cisplatin in vivo in C57BL/6 mice and in cultured tubular cells.113 These observations showed that ROS may represent early signals that are partially responsible for the activation of some signaling pathways that cause cell death, kidney injury, and renal failure due to cisplatin nephrotoxicity. In addition to kidney injury, oxidative stress also stimulates renal cells to produce a cytoprotective response. This is best explained by heme oxygenase 1 (HO-1), a redox-sensitive microsomal enzyme that catalyzes the degradation of heme into iron, biliverdin and carbon monoxide.114-117 It was reported that the overexpression of HO-1 can ameliorate apoptosis induced by cisplatin in an in vitro model.115 Compared with WT mice, the HO-1-deficient littermates were more sensitive to renal injury induced by cisplatin.115 However, the exact mechanism underlying the cytoprotective effects of HO-1 remains unknown. Nitrosative stress is also involved in cisplatin-induced kidney damage. The administration of cisplatin in rats can result in a significantly increased activity of nitric oxide synthase (NOS). It can catalyze the


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formation of peroxynitrites (ONOO−), which can in turn react with superoxide anions, leading to cisplatin-induced renal damage.118 The co-administration of N-G-nitro-L-arginine methyl ester, an inhibitor of NOS, with cisplatin can markedly reduce renal toxicity.119 3.1.7 Inflammation in cisplatin nephrotoxicity Evidence has suggested that cisplatin nephrotoxicity is strongly associated with an inflammatory response.120 Cisplatin can induce many inflammatory cytokines and chemokines, including the activation of phosphorylation and translocation of nuclear factor kappa B (NF-κB) from the cytosol to the nucleus. Activation of this nuclear factor promotes the transcription of some specific genes encoding inflammatory mediators.120 This increases the production of tumor necrosis factor alpha (TNF-α) in renal tubular cells, an important pro-inflammatory cytokine that is actively involved in systemic inflammation induced by cisplatin. Studies have also shown that TNF-α is produced mainly by resident kidney cells, not infiltrating inflammatory cells, during cisplatin nephrotoxicity.121 It can trigger tissue damage and tubular cell death through TNF receptor type 1 (TNFR1) and TNF receptor type 2 (TNFR2). However, it has been demonstrated in mice that cisplatin nephrotoxicity is signaled through TNFR2, not TNFR1, at least for those mediated by TNF-α.122 TNF-α is a key upstream regulator in the inflammatory response induced by cisplatin. It can coordinate the



activation of many proinflammatory cytokines and induce the expression of adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1), E-selectin and vascular cell adhesion molecule 1 (VCAM-1), promoting the inflow of inflammatory cells in tissues. Taking these together, it can be concluded that TNF-α plays an important role in the regulation of the inflammatory response to cisplatin. Tissue injury caused by cisplatin leads to the release of damage-associated molecular pattern molecules (DAMPs), which subsequently activate TLR4. The activation of TLR4, in turn, led to the production of various chemokines and cytokines.123 Moreover, many immune cells, such as neutrophils, macrophages, T cells, treg cells and dendritic cells, are also involved in cisplatin nephrotoxicity.124-129 3.1.8 Activation of mitogen-activated protein kinase (MAPK) The mitogen-activated protein kinase (MAPK) signaling pathway also plays an important role in cisplatin nephrotoxicity. MAPK consists of several highly conserved threonine/serine protein kinases, which eventually lead to the activation of JNK (Jun N-terminal kinase), ERK (extracellular signal-regulated kinase) and p38.130, 131 Using in vivo and in vitro experimental models of cisplatin nephrotoxicity, researchers have described the different activation patterns of these three MAPK pathways.36, 37 However, the roles of specific MAPKs in cisplatin-induced kidney injury appear to be very complicated and may vary among


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different studies. The production of JNKs and p38 is induced by apoptotic pathways, the inflammatory response and cellular stress initiated by various stressful physical, biological and chemical stimuli. An in vivo study using a rat model has shown that the co-administration of cisplatin with the JNK inhibitor

SP600125

can

protect

renal

cells

against

cisplatin

nephrotoxicity.132 Similarly, the role of p38 in cisplatin nephrotoxicity has been revealed both in vitro and in vivo. Using pharmacological inhibitors of p38, nephrotoxicity induced by cisplatin is reduced in the rat models. p38 plays a role by regulating TNF-α production in renal tubular cells rather than by directly regulating tubular cell injury.133 The cascade of ERKs is triggered primarily by cell survival growth factors and cell death. ERK1 and ERK2 are the most widely studied among the eight known ERK isoforms.130, 131, 134 Upon phosphorylation, these two ERKs are activated by MEK (MAPK/ERK kinase) 1 and MEK2. It has been shown that ERK1/2 were activated and accumulated in mitochondria during cisplatin administration.135 Inhibition of ERK1/2 with U0126, a pharmacological MEK inhibitor, could ameliorate cisplatin-induced apoptosis and mitochondrial dysfunction.136 3.1.9 Activation of apoptotic pathways High doses of cisplatin cause necrosis, whereas apoptosis is induced by a lower concentration of cisplatin.137 It is generally believed that



apoptosis is one of the most important mechanisms of cisplatin nephrotoxicity. Several pathways of apoptosis have been identified, including the intrinsic pathway centered on mitochondria, extrinsic pathway mediated by death receptors, and endoplasmic reticulum (ER)-stress pathway (Figure 4). Among the three pathways, the intrinsic pathway, involving the mitochondria, is the major one. The administration of cisplatin causes cellular stress, which subsequently activates Bax and Bak, two pro-apoptotic proteins of the Bcl-2 family, and results in the alteration of the mitochondrial membrane, leading to the release of apoptogenic factors such as apoptosis-inducing factor (AIF), cytochrome C and endonuclease G from the mitochondria into the cytosol.138, 139 The released cytochrome C will bind to the adaptor protein Apaf-1 and induce its conformational changes, activating caspase-9, which, in turn, leads to activation of several downstream caspases for caspase-dependent apoptosis.138, 139 By contrast, after being released from the mitochondria, endonuclease G and AIF will accumulate in the nucleus, leading to apoptosis in a caspase-independent manner.140


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H 3N

Cl Pt

H 3N

Cl

OCT2/ CTR1

Death receptor H N 3 pathway H3N

+ H2O ER stress Pt Cl

Mitochondrial pathway AIF and endonuclease G

Cytochrome C

Caspase-8 Caspaseactivation independent

Caspase-9 Caspase-12 activation activation

Apoptosis Figure 4. Apoptotic pathways activated by cisplatin in renal tubular cells. Cisplatin activates both intrinsic mitochondrial pathway (brown) and extrinsic death receptor pathway (yellow) of apoptosis. In addition, ER stress may also be induced (blue). Activation of these pathways leads to caspase-dependent or -independent apoptosis.

In the extrinsic pathway, binding of the death receptors by ligands results in the recruitment and activation of caspase-8, which leads to the



activation of downstream caspases to trigger apoptosis.141 Major death receptors contain Fas, TNFR1 and TNFR2. Following the administration of cisplatin, the upregulation of Fas and Fas ligand, which are associated with apoptosis, can be seen in cultured human proximal tubular cells.142 On the other hand, in a TNFR1-deficient mouse model, amelioration of tubular cell apoptosis and renal failure induced by cisplatin were observed, suggesting that TNFR1 signaling is involved in cisplatin nephrotoxicity.143 However, TNFR2 was found to be mainly responsible for the signaling pathway of TNF-α as mentioned above.122 The endoplasmic reticulum (ER)-stress pathway is also involved in tubular cell apoptosis during cisplatin administration. Capase-12, which localizes at the cytosolic face of the ER and is activated by ER stress, is the key initiator caspase in the ER pathway.144 Liu and Baliga observed activation of caspase-12 in LLC-PK1 cells treated with cisplatin, which was alleviated upon anticaspase-12 antibody transfection.145 The Ca2+-independent phospholipase A2 (ER-iPLA2) is another ER-associated protein and has been implicated in cisplatin injury. It has been shown that cisplatin-induced apoptosis can be retarded by a pharmacological inhibitor of ER-iPLA2 in primary rabbit proximal tubular cultures.146 This protein may act upstream of caspase-3 and downstream of p53 in the apoptotic pathway. p53 has also been thought to engage in the induction of apoptosis in


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renal toxicity due to cisplatin treatment. The DNA damage induced by cisplatin activates p53, leading to the induction of apoptotic genes, including PIDD (p53-induced protein with death domain) and PUMA-α (p53-upregulated modulator of apoptosis). Activation of PIDD can activate caspase 2, leading to the release of AIF from mitochondria, which eventually induces caspase-independent apoptosis. Activation of PUMA-α by cisplatin invalidates the anti-apoptotic function of Bcl-XL, a member of the Bcl-2 family, releasing Bax to open more mitochondrial permeability transition pores (MPTPs), and inducing apoptosis.138, 147 3.1.10 p21 and cell cycle regulation in cisplatin nephrotoxicity It has been proposed that cell cycle proteins, such as cyclin-dependent kinase (CDK) family members and cyclins, are major molecular regulators of kidney cell death caused by cisplatin nephrotoxicity. The quiescent cells in the kidney enter the cell cycle, and the p21 gene, a cell cycle inhibitor, is simultaneously upregulated by cisplatin treatment.148-150 The balance between CDKs and p21, a CDK inhibitor, is the critical factor in cisplatin nephrotoxicity, determining whether the renal tubular cells will survive or undergo cell death. Studies have shown that both the addition of p21 and pharmacological inhibitor of CDKs can protect renal cells from cisplatin-induced nephrotoxicity in vitro.151 Similarly, p21-null mice are more sensitive to cisplatin-induced kidney failure than WT ones. 148

Moreover, by dominant-negative mutation, it was revealed that the



Page 30 of 69

inhibition of CDK2 can protect tubular cells from cisplatin-induced apoptosis, suggesting that CDK2 may be a critical cell-killing molecule in renal toxicity induced by cisplatin.152 3.1.11 Prevention of cisplatin nephrotoxicity In addition to the clinical measures for the treatment of cisplatin nephrotoxicity, based on the proposed toxicological processes described above, several co-drugs were designed. They are mainly divided into the following categories: (a) inhibitors against the uptake of cisplatin. OCT2 and CTR1 have been shown to be involved in the transport of cisplatin. Thus, inhibitors of these proteins, such as cimetidine and copper, may be used to reduce cisplatin nephrotoxicity.5,

88, 153

It has been shown that

probenecid can reduce the platinum concentration located at kidney tubules, diminishing cisplatin nephrotoxicity without affecting cisplatin’s cytotoxicity.154 (b) Regulators of cisplatin biotransformation. Because cisplatin can be converted into nephrotoxin by several enzymes, inhibitors of these enzymes, e.g. acivicin, may reduce cisplatin nephrotoxicity.155 Chelating agents, such as diethyldithiocarbamate, can also be used to remove platinum from renal tubules.156 (c) Oxidative stress relievers. Several studies have suggested that antioxidants, such as tetrahydrocurcumin,65 sodium thiosulphate,157 amifostine158 and N-acetyl cysteine,68 may be used as oxidative stress relievers to reduce cisplatin nephrotoxicity. (d) Inflammation antagonists. Inflammation plays an


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important role in cisplatin-induced toxicity. Therefore, inhibitors of TNF-α production can significantly improve cisplatin-induced renal failure.159, 160 It has been proven that agonists of PPAR-α can alleviate the nephrotoxicity of cisplatin in vivo.109, 161 Additionally, interleukin-10 can be used to ameliorate acute renal injury induced by cisplatin.162 (e) Inhibitors of apoptotic pathways. Because p53 plays an important role in the induction of apoptosis in renal toxicity, pharmacological inhibitors against p53 may be applied to reduce the renal toxicity of cisplatin.163 By the administration of siRNA targeted to p53, Molitoris et al. observed that the renal failure associated with cisplatin treatment was attenuated.164 The inhibitors against caspases were also demonstrated to reduce the renal toxicity induced by cisplatin.165 (f) MAPK inhibitors. Several studies have shown that the renal failure caused by cisplatin treatment can be partially diminished using inhibitors of MEK/ERK/p38, such as PD09059, U0126 and SKF-86002.133, 136, 166, 167 (g) Cell cycle inhibitors. p21 is involved in the protection of renal cells from injury and death during cisplatin administration, a recent study suggested that inhibitors of CDK2 can protect renal tubular cells against cisplatin injury.168

3.2 Ototoxicity In addition to nephrotoxicity, ototoxicity is also very common in cisplatin treatment. It has been recently demonstrated that cisplatin has a long retention time in human cochlea.169 Up to 93% of patients who have



undergone

cisplatin

administration

would

Page 32 of 69

develop

irreversible

sensorineural hearing loss, which decreased the quality of life in cancer survivors.170 The exact mechanism of ototoxicity induced by cisplatin is not clear either. However, it has been generally accepted that the excessive generation of reactive oxygen species (ROS) in cochlear cells plays a crucial role in hearing loss. The administration of cisplatin can induce the activation of the NADPH oxidase isoform NOX3, leading to a sharp increase in superoxide production.171 Superoxide produces hydrogen peroxide, which, in turn, is catalyzed by iron to form a very reactive hydroxyl free radical. This radical reacts with polyunsaturated fatty

acids

(PUFA)

to

form

the

4-hydroxynonenal (4-HNE) (Figure 5).172

extremely

toxic

aldehyde,

Because NOX3 is located in

the cochlea, the inhibition of the enzyme activity can be used to treat hearing loss during cisplatin treatment. Based on the same concept, antioxidants such as sodium thiosulfate, methionine, amifostine and glutathione ester were also utilized to protect the inner ear from ototoxicity during chemotherapy with cisplatin.173


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Figure 5. Proposed mechanism by which cisplatin causes cell death, leading to ototoxicity.

Additionally, the apoptosis response plays a role in ototoxicity induced by cisplatin. A few studies have suggested that the mitochondrial pathways are involved in the apoptosis of auditory cells during cisplatin



administration. The apoptosis response, such as the activation and redistribution of cytosolic Bax, as well as the release of cytochrome C from the mitochondria, can be seen in cochlear hair cells derived from cisplatin-treated guinea pigs.174 Similarly, in another study, the authors observed that cisplatin-induced apoptosis through mitochondrial pathway in HEI/OC1 cells was linked to the truncation of Bid and translocation of Bax from the cytosol to mitochondria, as well as the release of cytochrome C.175 The released cytochrome C can, in turn, activate caspase-9 and -3, resulting in the cleavage of fodrin located in the cuticular plate of cisplatin-damaged outer hair cells and DNA strand breaks by caspase-activated deoxyribonuclease, ultimately leading to apoptosis (Figure 5).174, 176 It has been previously demonstrated that, using specific inhibitors of caspase-9 and caspase-3 in intracochlear perfusion, cisplatin-induced hair cell death and hearing loss can be diminished.174 As mentioned earlier, p53 plays an important role in the apoptotic pathway of cisplatin nephrotoxicity. Similarly, p53 is also an important regulator of apoptosis induced by cisplatin in the auditory system. Using pifithrin-α, an inhibitor of p53, the hair cell damage induced by cisplatin can be attenuated significantly.177, 178 The protection effect was associated with the decreased production of p53, caspase-1 and caspase-3.177 In addition to caspase- and p53-dependent apoptosis, inflammatory cytokines, such as TNF-α, interleukin (IL)-1 and IL-6, may mediate


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cisplatin ototoxicity. Cells treated with cisplatin show overexpression of NF-κB and extracellular regulatory kinase (ERK) 1/2, which stimulate proinflammatory cytokines (Figure 5). This results in the rearrangement of the actin cytoskeleton, nuclear fragmentation and cell death.179 The administration of cisplatin can also result in the activation of large conductance potassium channels, causing alterations in the ion balance and triggering of pro-apoptotic pathways that ultimately lead to cell death.180 Because CTR1, a main transporter of cisplatin, is highly expressed in the cochlea, it is also implicated in ototoxicity. Therefore, copper sulfate, a substrate of CTR1, can be used to decrease the accumulation of cisplatin, thus protecting against hearing loss induced by cisplatin.181 Many other transporters (OCTs, transient receptor potential channel family members, and calcium channels) are involved in cisplatin influx, thus also associated with ototoxicity resulting from cisplatin treatment, the details can been seen in another review.182

3.3 Neurotoxicity Cisplatin causes peripheral neuropathy in 30% of patients treated with the drug.183 The peripheral sensory neuropathy induced by cisplatin is a dose-limiting side effect, which usually occurs when the cumulative dose exceeds 500 mg/m2 for cisplatin.184,

185

Two mechanisms underlying

cisplatin neurotoxicity have been proposed: (a) arising from the damage of nuclear DNA, and (b) resulting from the damage of mitochondrial



DNA. As described earlier, cisplatin binds to the N7 of purine residues on DNA after entering cells to form crosslinking complexes.14 Upon DNA damage by cisplatin binding, cells will initiate related signal transduction pathways, particularly the nucleotide excision repair (NER) pathway, to repair the damages. Eventually, DNA may be successfully repaired, allowing cell survival. Otherwise, the cells would initiate an apoptotic process, ultimately leading to cell death, by which cisplatin kills cancer cells. However, for neurons, such action causes neurotoxicity.186, 187 In the nervous system, dorsal root ganglia (DRG) are the main target of cisplatin.188 Because there is an abundant fenestrated capillary network and no blood-brain barrier in DRG, cisplatin can easily enter sensory neurons.187-189 It has been shown that CTR1 and OCT2, which are overexpressed in neurons, are involved in the uptake of cisplatin into DRG neurons.190,

191

The DNA repair ability of DRG neurons is an

important factor determining the severity of cisplatin neurotoxicity.192 The NER pathway in the peripheral nervous system is not efficient, thus the DNA lesions caused by cisplatin cannot be effectively repaired by NER, leading to the incorrect transcription of ribosomal RNA and incomplete protein synthesis. DRG neurons require a high level of active transcription to support their quick metabolism, large size and long axons. Therefore, cisplatin-induced DNA damage could result in neuronal


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atrophy.193 It has been reported that cisplatin-induced DNA damage could trigger apoptosis in DRG both in vivo and in vitro.194, 195 Cisplatin administration in dorsal root ganglia cells was demonstrated to lead to upregulation of apoptosis-related genes,194 which was involved in the activation of p53, translocation of Bax, release of mitochondrial cytochrome C, as well as the activation of caspase-3 and -9 in neuronal cells. In 1998, Gill and Windebank reported that DRG neurons struggled to re-enter the cell cycle after the administration of cisplatin.196 Similarly, an elevated expression of genes associated with cell cycle regulation was observed by Alaedini and colleagues.194 This event could be a prognosticator for the triggering of neuronal cell death.196 In addition to binding to nuclear DNA, cisplatin can also bind to mitochondrial DNA directly. It was first described by Podratz et al. that cisplatin can cause mitochondrial dysfunction in DRG neurons.183 Cisplatin-mitochondrial DNA adducts inhibit the replication and transcription of mitochondrial DNA, leading to morphological changes in mitochondria. This can lead to energy failure, disruption of the electron transport chain and overproduction of ROS, promoting the expression of apoptotic proteins, mitochondrial membrane depolarization, opening of the mitochondrial permeability transition pore and intracellular calcium accumulation. Because most mitochondria are located in the axons of



Page 38 of 69

neurons, mitochondrial dysfunction may lead to the degeneration of the axonal transport.186 A few studies have reported that cisplatin can affect the expression of mitochondrial fission and fusion proteins in peripheral nerves.197 These proteins manage the shape, size and number of mitochondria. Initially, it was thought that cisplatin could reduce calcium channel currents, especially in small-diameter neurons of rat DRG.198 However, in a recent study, the concentration of calcium in rat DRG was revealed to be increased through N-type calcium channels after exposure to cisplatin.199 Consequently, caspase-3 was activated, inducing neuron apoptosis.

3.4 Gastrointestinal toxicity Gastrointestinal toxicities, including nausea, vomiting and diarrhea, arising

from

cisplatin

treatment

are

also

common

clinically.

Approximately 70-80% of patients develop nausea and/or vomiting during cisplatin administration.200 Although the exact mechanism of gastrointestinal toxicity is unclear, it was linked to ROS-mediated oxidative stress. By directly reacting with cellular components, such as proteins, lipids and DNA, the highly reactive radicals induced by cisplatin can lead to extensive mucosal damage.201 Cisplatin can increase the content of free fatty acids and trigger autocatalytic lipid peroxidation in intestinal mucosal cells.202 The long-chain free fatty acids might affect the


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structure and function of the plasma membrane and subcellular membrane, especially the mitochondrial membrane, which may cause the release of cytochrome C from the mitochondria, finally leading to apoptosis.

203

Because mitochondrial DNA is more susceptible to

cisplatin damage due to lack of histone complexation and NER, cisplatin can induce mitochondrial functional injury more effectively than nuclear DNA damage. The dysfunction of mitochondria may trigger a cascade of signal transduction pathways, eventually leading to apoptosis and necrosis of intestinal cells.203 Superoxide dismutase (SOD), glutathione reductase (GR), catalase (CAT), glutathione S-transferase (GST), and thioredoxin reductase (TR), GSH and total-SH components together constitute the intestinal antioxidant defense system. It has been reported that cisplatin can inhibit the activities of enzymes in the intestine, such as SOD, CAT, GR, GST and TR (Figure 6).201,

204

Thus, a depleted

antioxidant defense system and an enhanced reactive oxygen production lead to oxidative stress. Therefore, antioxidants, such as caffeic acid204 and chrysin,205 can partially ameliorate gastrointestinal toxicity induced by cisplatin in model animals. Cisplatin-generated ROS also play a role in mediating apoptosis. It has been shown that cisplatin-induced mucositis is associated with the upregulation of proapoptotic Bak and Bax proteins, p38, p53 and IL-6.205 Additionally, activation of NF-κB and TNF-α has been observed in the



intestine during cisplatin administration.206 Increased TNF-α recruited and accumulated inflammatory cells, which, in turn, damaged surrounding intestinal tissue. Taken together, cisplatin-induced oxidative stress activates inflammation and apoptosis, leading to cell death in the intestine. The reduction of the appetite-stimulating hormone ghrelin has been also thought to play an important role in the development of cachexia induced by cisplatin.207 Thus, the glucagon-like peptide-2 (GLP-2, a pleiotropic hormone) analog was shown to counteract the mucosal gastric fundus damage in mice.208

Figure 6. Cisplatin disrupts the antioxidant defense system in the intestine by inhibiting the activities of certain enzymes, such as superoxide


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dismutase

(SOD),

catalase

(CAT),

glutathione

reductase

(GR),

glutathione S-transferase (GST) and thioredoxin reductase (TR), and promotes the generation of reactive oxygen species (ROS), leading to oxidative stress and apoptosis.209

3.5 Cardiotoxicity Compared with the toxicities mentioned above, cardiotoxicity is not a common

side

effect

of

cisplatin.

However,

clinical

cases

of

cisplatin-induced cardiotoxicity have increased over the past decade.210 The exact mechanism of cisplatin cardiotoxicity requires further investigation. It has been thought that cisplatin produces cardiotoxicity because of multiple factors, such as damage to DNA, ROS-mediated oxidative stress, inflammation and MAPK signaling.211 For example, cisplatin was revealed to cause significant damage to both nuclear and mitochondrial DNA in a rat model of cardiac toxicity.212 Oxidative stress appears to be the main mechanism underlying cisplatin-induced cardiotoxicity. The cellular antioxidant system, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-px) and peroxidase (POD), which scavenge ROS via redox reactions, was thought to be involved in the oxidative stress imposed by cisplatin (Figure 6).212 An increase in leaked cardiac enzymes, ROS concentration and lipid peroxidation, as well as a decrease



Page 42 of 69

in coronary flow, have been observed in the isolated heart of rats after cisplatin treatment.213 Decreased levels of SOD and glutathione were also reported

in

the

cardiac

tissue

of

cisplatin-treated

rats.212

As

abovementioned, ROS can directly damage mitochondria, open the mitochondrial

permeability

transition

pore

(mPTP),

and

cause

mitochondrial membrane depolarization and mitochondrial swelling, as well as cytochrome C release into the cytoplasm, eventually activating the caspase cascade and initiating the apoptosis of cardiomyocytes.211 Additionally, oxidative stress activates p53, which, in turn, activates Bax and

promotes

apoptosis.

Because

cardiomyocytes

have

more

mitochondria than other cells due to exuberant energy metabolism, cisplatin-induced mitochondrial dysfunction may have an important influence on the energy status of cardiomyocytes. It has been confirmed that

resveratrol,214

apocynin,215

α-lipoic

acid,212

and

propionyl-L-carnitine216 can protect cardiomyocytes against ROS. It has been previously demonstrated that cardiomyocytes produce many inflammatory factors and chemokines after cisplatin administration, resulting in the infiltration of neutral granulocytes, translocation of NF-κB and increased production of TNF-α, eventually causing damage to cardiomyocytes

and

cardiomyocyte/tissue

tissues.217 inflammation

In

this

regard,

reducing

may

help

alleviate

cisplatin

cardiotoxicity.215


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3.6 Hematological toxicity and hepatotoxicity Hematological toxicity is generally not a significant problem during cisplatin administration. Thus, few studies have been reported on its mechanism. Because intravenous cisplatin can easily enter various blood cells and its ultimate target is DNA, myelosuppression seems to be associated with the death of rapidly dividing cells in the bone marrow. A few studies have shown that hypomagnesemia may play an important role in acute vascular events induced by cisplatin.218 It was also proposed that cisplatin can affect hematopoietic stem cells,219 likely explaining the hematological toxicity induced by cisplatin. The hepatotoxicity of cisplatin has been thought to arise from induced generation of ROS in the epithelial cells of the sinusoids, particularly in mitochondria.220, 221 The generated ROS results in an increase in various cytokines, eventually leading to apoptosis and other cellular damage of healthy liver cells. It was found that the level of hepatotoxicity is linked to the CYP450 levels, especially those of CYP2E1 and CYP4A11. The mechanism of hepatotoxicity is closely related to the direct attack of cisplatin on these enzymes, which promotes the generation of ROS.222 Given that ROS induced by cisplatin lead to increased levels of cytokine, the co-administration of infliximab, a drug that can abrogate cytokine levels by blocking the action of tumor necrosis factor-α, may help to limit the liver damage of cisplatin.223



Page 44 of 69

3.7 Effects of genetic variations on various toxicities In addition to factors such as age, gender, mode of administration, and dosage, which may affect the toxicity of cisplatin, patients with different genotypes show different frequencies of various side effects. Through pharmacogenomics, the possibility of toxic side effects in patients can be predicted before treatment, and then the dosage could be adjusted to achieve the best therapeutic effect. Studies on the relationship between the side effects of cisplatin and genotypes have focused on the relationship of nephrotoxicity and ototoxicity induced by cisplatin with the genotypes. An association was found between genetic variations, such as variations in SLC16A5224, ACYP2225-227, WFS1227, COMT226,

228-231,

TPMT226, 228-232, ABCC3232, SOD2233 and GSTT1234, and cisplatin-induced ototoxic effects. Regarding nephrotoxicity induced by cisplatin, variations in SLC22A2 and ERCC1/2 also play a role.235-238 Further research is demanded to assess the clinical value of modifying treatment based on all genotypes reported thus far.

4. Remarks and Outlook After forty years of research and development, although the exact mechanism of the toxicity caused by cisplatin has not been fully clarified, the clinical manifestations of the various side effects of cisplatin have been well understood, and the biochemical processes involved have been extensively explored. Nephrotoxicity is the most common clinically and


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has been thought to be a consequence of damage imposed by cisplatin in renal tubular cells where cisplatin metabolizes into toxins and enhances the generation of ROS, leading to mitochondrial dysfunction and the induction of inflammation and apoptosis. Cisplatin-induced ROS generation is also believed to play a crucial role in other side effects of cisplatin, such as ototoxicity and cardiotoxicity. The increased generation of ROS induces a cascade of apoptotic and inflammatory responses, accounting for the occurrence of such toxicities. Few studies have reported on the mechanism of hematological toxicity, hepatotoxicity and other side effects of cisplatin due to their low incidence in the clinic. However, cisplatin-induced ROS generation was also shown to be closely related to cisplatin-induced hepatotoxicity. Therefore, further studies in the pathways of cisplatin-induced ROS generation, as well as its roles in downstream signaling pathways will be very helpful to more comprehensively understanding in the various side effects of cisplatin. Additionally, cisplatin attack of nuclear DNA and mitochondrial DNA in neurons has been demonstrated to be a major factor involved in neurotoxicity. Some nuclear DNA-binding proteins, e.g. HMGB1 and TBP, compete with the NER system for binding to cisplatin adducts, leading to their inefficient repair.18 Because cisplatin exerts cytotoxicity also via attacking DNA, genomic studies would provide new insights into distinguishing which genes damaged by cisplatin lead to cytotoxicity and



which genes damaged by cisplatin cause toxicity. Since the off-targeting reactivity of cisplatin determines its side effects, it is possible to regulate its reactivity to reduce its toxicity. The reactivity of a platinum drug primarily depends on the stability of its leaving groups in aquesou solution.12 More unstable leaving groups usually lead to more reactive platinum moiety and higher binding rate to both the targets and unwanted biological molecules, which therefore results in higher activity as well as more toxic side effects. Based on this structure-activity relationship, carboplatin and oxaliplatin were developed so as to reduce toxicity of cisplatin. Replacing the chlorido ligands of cisplatin with more stable leaving groups (Figure 7), in particular chelating ligands can significantly reduce the rate of hydrolysis of platinum complexes. Consequently, carboplatin and oxaliplatin have less side effects than cisplatin. Compared to cisplatin, carboplatin rarely causes nephrotoxicity and neurotoxicity, while myelosuppression is its main side effect.239 Oxaliplatin hardly causes nephrotoxicity and ototoxicity, with a major toxicity being peripheral neuropathy.240 Given the large differences between the side effects of cisplatin, and carboplatin and oxaliplatin, the further study in the molecular mechanisms of toxicity of carbopplatin and oxaliplatin will be very helpful for designation of anticancer drugs with lower toxic side effects and higher activity.


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Figure 7. The chemical structure of carboplatin and oxaliplatin.

Generally, a toxic side effect of a drug is related to multiple biological processes. To clarify the specific mechanism of a certain toxicity, it is essential to determine all the molecules involved in the process, including biomolecules related to biological functions and associated cellular components. Numerous biomolecules are involved in the toxicity of cisplatin, making the toxicological research of cisplatin a great challenge. Thanks to the development of various omics techniques, the comprehensive proteomics,243,

studies 244

using

genomics,241

lipidomics245 and metabolomics244,

transcriptomics,242 246

have attracted

increasing interest. With the application of these omics approaches, we can explore the changes in vivo more easily and effectively, such as alteration in the expression level of certain genes, difference in posttranslational modifications of signaling proteins, and changes in the content and location of endogenous lipids and metabolites arising from



cisplatin administration. These omics data will provide more molecular evidences to elucidate the toxicology of cisplatin. After discovering a gene or protein involved in the side effects of cisplatin, the recently developed gene editing technique CRISPR/dcas9 could be used to further study the role and function of the gene or the protein in the toxicity of cisplatin. Most toxicological studies in cisplatin have been performed on animal models or human cells cultured in vitro. Because the models and cells used, as well as the manner and dosage of administration, may vary from case to case, the results obtained may also be different, even contradictory. In addition to the impact of individual differences, the absence of a single standard is a huge problem. Regarding this issue, statistical analysis based on large-scale research on animals or cultured cells would be benefit for summarizing a broader and precise toxicological mechanism of cisplatin.

Although the use of cisplatin leads to broad toxic side effects, this drug is still widely used clinically as a first-line drug, indicating its power as an anticancer drug. To make cisplatin have a brighter future, managing these side effects of cisplatin should be a priority. This includes improved tumor-delivery strategies, e.g. the use of nanoparticles, macrocycles and polymers as delivery vehicles247-250 and additional nanoformulations, such as formulating with proteins, peptides and metal-organic frameworks.251,


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252

Moreover, the further study in the role of Rev1-Pol zeta pathway in

translesion synthesis over cisplatin DNA crosslinking adducts may also help to overcome cisplatin resistance and to reduce the toxicity of cisplatin. Overall, we believe that further toxicological studies on cisplatin that focus on deciphering its toxic mechanism and finding ways to reduce or eradicate its side effects will make cisplatin have a wider application in the future.

AUTHOR INFORMATION Corresponding Authors * E-mail: [email protected] (FYW); [email protected] (YZ)

ORCID Luyu Qi: 0000-0002-7212-6214 Yanyan Zhang: 0000-0002-2048-145X Yao Zhao: 0000-0003-0613-8708 Fuyi Wang: 0000-0003-0962-1260

Notes The authors declare no competing financial interest. ACKNOWLEDGMENT We thank the National Natural Science Foundation of China (Grant Nos.



21575145, 21635008, 21621062, 91543101, 21790390 and 21790392, and the Beijing Municipal Natural Science Foundation (No.7182190) for support. YZ also thank the Youth Innovation Promotion Association of CAS (No. 2017051).

Biographies Luyu Qi received his B.S. degree in pharmaceutical engineering from Beijing Institute of Technology in 2016. He is now a PhD student of Fuyi Wang’s group at the Institute of Chemistry, Chinese Academy of Sciences. His research focuses on studying the DNA damage by metal based anticancer agents.

Qun Luo obtained her PhD degree in 2007 from the Technical Institute of Physics and Chemistry, the Chinese Academy of Sciences (TIPC-CAS), then joined Prof. Fuyi Wang’s group at the Institute of Chemistry, the Chinese Academy of Sciences (ICCAS) as a postdoctoral fellow, and is now an associate professor in the same group. Her research interests focus on the development of multi-targeted anticancer drugs, and exploring novel analytical methods based on mass spectrometry, fluorescence imaging and biotechnology to study the interactions between anti-tumor compounds and biological targets.


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Yanyan Zhang obtained her BSc and MSc degrees from Nanjing University in 2012 and 2015, respectively. Then, she received her PhD degree in analytical chemistry from the Institute of Chemistry, Chinese Academy of Sciences in 2018 and was appointed as a research assistant professor in Fuyi Wang’s group. Her research interests focus on the applications of mass spectrometry including in situ liquid secondary ion mass spectrometry, and electrospray ionization mass spectrometry in fields of electrochemistry and bioanalytical chemistry.

Feifei Jia received her PhD degree in 2016 from Tianjin University, then joined the Prof. Fuyi Wang’s group at the Institute of Chemistry, Chinese Academy of Sciences (ICCAS) as a postdoctoral fellow. Her research interests include the investigation of interactions between metal-based anticancer complexes and proteins or DNA, the development of the secondary ion mass spectrometry imaging methods and their related biomedical applications.

Yao Zhao received his B.S. and M.S. degree in chemistry from Nanjing University in China, in 2005 and 2008, respectively. He received his Ph.D. degree of chemistry in 2012 from the University of Warwick, UK, supervised by Prof. Peter Sadler. Then, he joined the Institute of Chemistry, Chinses Academy of Sciences, and is now an associate



professor in Fuyi Wang’s group. He has coauthored over 40 peer-reviewed scientific articles and reviews. His research focuses on the development of metal based anticancer agents and study of their mechanisms of action by means of biophysics and biochemical methods, including mass spectrometry and NMR.

Fuyi Wang obtained his B.S. and M.S. degrees from Central China Normal University in 1983 and 1991, respectively, and received his PhD degree in 1999 from Wuhan University. Then he worked as research fellow and research associate in University of Edinburgh in Peter Sadler’s group at the University of Edinburgh. In 2007, Dr. Wang was awarded with the Hundred Talent Program Professorship of the Chinese Academy of Science (CAS) and joined the Institute of Chemistry, CAS as a full professor in chemistry. He has published more than 110 peer-reviewed research articles. His research is concentrated on the rational design of multi-targeting anticancer agents and the development of novel analytical methods, in particular mass spectrometry-based methods to investigate drug-target interactions.

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