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R E V I E W A R T I C L E

Cisplatin-induced nephrotoxicity and targets of nephroprotection:an update

Neife Aparecida Guinaim dos Santos

Maria Augusta Carvalho Rodrigues

Nadia Maria Martins Antonio Cardozo dos Santos

Received: 26 January 2012/ Accepted: 14 February 2012 / Published online: 1 March 2012

Springer-Verlag 2012

Abstract Cisplatin is a highly effective antitumor agent

whose clinical application is limited by the inherentnephrotoxicity. The current measures of nephroprotection

used in patients receiving cisplatin are not satisfactory, and

studies have focused on the investigation of new possible

protective strategies. Many pathways involved in cisplatin

nephrotoxicity have been delineated and proposed as tar-

gets for nephroprotection, and many new potentially pro-

tective agents have been reported. The multiple pathways

which lead to renal damage and renal cell death have points

of convergence and share some common modulators. The

most frequent event among all the described pathways is

the oxidative stress that acts as both a trigger and a result.

The most exploited pathways, the proposed protective

strategies, the achievements obtained so far as well as

conflicting data are summarized and discussed in this

review, providing a general view of the knowledge accu-

mulated with past and recent research on this subject.

Keywords Cisplatin Nephrotoxicity Nephroprotection

Oxidative stress Apoptosis Molecular mechanisms

Mitochondria

Cisplatin

Cisplatin (cisplatinum or cis-diamminedichloroplatinum

(II), CDDP) is a highly effective chemotherapeutic drug

whose anticancer activity was accidentally discovered by

the physicistbiologist Barnett Rosenberg, during hisstudies addressing the effect of a platinum electrode-gen-

erated electric field on the division processes of Esche-

richia coli. He observed that the cellular division was

inhibited and a filamentous growth was induced by elec-

trolysis products that were afterward identified as platinum

compounds. Based on this observation, he and his col-

leagues investigated the antitumor activity of platinum

compounds in leukemia L1210- and Sarcoma 180-bearing

mice. The antitumor efficacy of cisplatin was then dis-

covered (Rosenberg et al. 1965,1967,1969).

The clinical use of cisplatin was approved by the FDA

in December 1978 (FDA database). Since then, the

application of cisplatin has been broadened to several

types of cancer and it has been used both alone or com-

bined with other drugs: as first-line treatment, as adjuvant,

or even as neoadjuvant therapy of other procedures such as

surgery or radiotherapy. Currently, the use of cisplatin is

approved to treat bladder cancer, cervical cancer, malig-

nant mesothelioma, non-small cell lung cancer, ovarian

cancer, squamous cell carcinoma of the head and neck,

and testicular cancer (National Cancer Institute database).

Additionally, cisplatin has been used to treat other types of

cancer when the first-line treatment has failed or yet in

specific situations that preclude the standard treatment

(Candelaria et al. 2006; Helm and States 2009; Goffin

et al. 2010; Campbell and Kindler 2011; Ismaili et al.

2011a, b).

Cisplatin chemotherapy is limited by tumor cells resis-

tance and severe side effects such as nephrotoxicity,

neurotoxicity, ototoxicity, and emetogenicity (Wang and

Lippard2005; Pabla and Dong2008). Among these factors,

nephrotoxicity has been reported as the major limiter in

cisplatin therapy (Arany and Safirstein 2003).

N. A. G. dos Santos M. A. Carvalho Rodrigues

N. M. Martins A. C. dos Santos (&)

Department of Clinical, Toxicological Analyses and Food

Sciences of School of Pharmaceutical Sciences of Ribeirao

Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil

e-mail: [email protected]

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DOI 10.1007/s00204-012-0821-7


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The susceptibility of kidneys to cisplatin toxicity

Kidneys are particularly affected by cisplatin, and this has

been attributed mainly to (a) high concentration of cisplatin

in the kidneys and (b) the renal transport systems. Cisplatin

is eliminated predominantly by the kidneys; the biliary and

the intestinal excretion of this drug are minimal. During the

excretion process, the drug is concentrated and even non-toxic blood levels of cisplatin might reach toxic levels in

kidneys. In fact, it has been reported that the concentration

of cisplatin in epithelial tubular cells is fivefold higher than

in blood (Rosenberg1985; Bajorin et al.1986; Gordon and

Gattone1986; Kuhlmann et al.1997; Schenellmann2001).

The nephrotoxicity induced by cisplatin is dose-dependent

and therefore limits the increase of doses, compromising

the efficacy of the therapy (Hanigan and Devarajan2003).

The toxic effects occur primarily in the renal proximal

tubules, particularly in the epithelial tubular cells of S-3

segment (Werner et al.1995). Glomeruli and distal tubules

are also affected afterward. Impairment of the renal func-tion is found in approximately 2535% of patients treated

with a single dose of cisplatin (Han et al. 2009). Decrease

of 2040% of glomerular filtration, increased BUN (blood

urea nitrogen), and increased serum creatinine concentra-

tions as well as reduced serum magnesium and potassium

levels are frequent in patients treated with cisplatin (Ries

and Klastersky1986; Kintzel2001; Han et al. 2009).

The high concentration of cisplatin in kidneys favors its

cellular uptake by passive diffusion (Gale et al. 1973;

Gately and Howell1993), and this was once considered the

main process through which cisplatin entered and accu-

mulated in cells. More recently, active transport systems

have gained importance and have been associated with

tumor cells resistance as well as the toxicity of cisplatin

(Ishida et al. 2002; Pabla et al. 2009; Burger et al. 2011).

The facilitated transport systems which have been associ-

ated with cisplatin nephrotoxicity are those mediated by the

organic cation transporter OCT2 and more recently, the

copper transporter Ctr1. In 2002, Ishida and colleagues

proposed that cisplatin uptake was mediated by the copper

transporter Ctr1 in yeast and mammals (Ishida et al.2002).

Although Ctr1 is highly expressed in kidney (Sharp2003),

it was first associated with cisplatin uptake by non-renal

cells and only recently a study associated Ctr1 with cis-

platin uptake in renal cells and therefore nephrotoxicity

(Pabla et al. 2009). OCT2 is highly expressed in the

basolateral membrane of proximal tubules and has been

reported to participate in the renal accumulation of

cisplatin (Ludwig et al. 2004; Ciarimboli et al. 2005;

Yonezawa et al. 2005).

It has been reported that OCT1/2 double-knockout mice

treated with cisplatin presented only a mild nephrotoxicity

as well as reduced renal platinum accumulation when

compared to wild-type mice (Ciarimboli et al. 2005).

Additionally, it was reported that the concomitant admin-

istration of imatinib, a cationic anticancer agent, with cis-

platin prevented cisplatin-induced nephrotoxicity by

inhibiting the OCT2-mediated renal accumulation of cis-

platin (Tanihara et al. 2009). In vivo and in vitro studies

have shown that cimetidine inhibits cisplatin renal damage

without affecting its antitumor activity (Katsuda et al.2010). However, in another study with cimetidine in vivo,

only a partial protection against cisplatin-induced nephro-

toxicity was observed. The nephroprotective action of

cimetidine has been attributed to (i) a competitive inhibi-

tion of cisplatin transport by OCT2, since cimetidine is an

organic cation and therefore an OCT substrate (Ciarimboli

et al. 2005); and (ii) inhibition of cytochrome P450 with

blockade of iron release and consequently inhibition of

hydroxyl radicals generation (Baliga et al. 1998). The

protective effect of cimetidine has also been shown in a

clinical trial with nine patients treated with cisplatin,

verapamil, and cimetidine (Sleijfer et al. 1987). Anotherstrategy to blockade cisplatin uptake in renal cells is the

inhibition of Ctr1. In fact, it has been reported that CTR1-

deficient cells accumulate less platinum in their DNA and

are more resistant to the cytotoxic effect of cisplatin than

the CTR1-replete cells (Lin et al. 2002).

The antitumor mechanism versus the nephrotoxic

mechanism

The molecule of cisplatin is formed by a central platinum

ion linked to 2 chloride ions and 2 ammonia molecules.

Neither the antitumor activity nor the nephrotoxicity of

cisplatin results from the heavy metal platinum itself, since

both effects are stereospecific to the cis isomer, not

occurring with the trans isomer (Goldstein and Mayor

1983). Instead, the cytotoxicity of cisplatin is related to

highly reactive aquated metabolites, whose formation is

determined by the concentration of chloride ions. As the

intracellular concentration of chloride (20 mM) is lower

than the blood concentration (100 mM), cisplatin remains

unaltered in the bloodstream, but undergoes hydrolysis in

the intracellular environment, originating positively

charged molecules in which one or two chloride ions have

been replaced by water. These aquated forms easily react

with the nuclear DNA, forming covalent bonds with purine

bases, primarily at the N7 position, resulting in 1,2-intra-

strand crosslinks, which are the main responsible for the

genotoxic effects of cisplatin. These crosslinks between

DNA and cisplatin lead to the impairment of replication

and transcription, resulting in cell cycle arrest and even-

tually apoptosis (Jamieson and Lippard 1999; Wong and

Giandomenico1999; Cohen and Lippard2001; Wang and

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Lippard2005). The apoptosis triggered by DNA damage is

mediated by the tumor suppressor gene p53 that activates

pro-apoptotic genes and repress anti-apoptotic genes (Jiang

et al. 2004; Norbury and Zhivotovsky 2004; Jiang and

Dong 2008). The dividing tumor cells are particularly

susceptible to DNA damage, and the anticancer activity of

cisplatin has been mainly attributed to DNA adducts for-

mation (Eastman 1999; Hanigan and Devarajan 2003).However, some studies have suggested that nuclear DNA

adducts formation may not be the only determinant of

cisplatin pharmacological effect and that mitochondrial

DNA (mtDNA) might be a more common target of cis-

platin binding, due to its weaker repair (Olivero et al. 1997;

Gonzalez et al.2001; Yang et al.2006; Cullen et al.2007).

In adult humans, proximal tubular cells are non-divid-

ing; therefore, the formation of adducts with DNA might

not play a key role in cisplatin nephrotoxicity (Wainford

et al. 2008). Besides nuclear and mitochondrial DNA,

cisplatin targets other cellular components such as RNA,

proteins, and phospholipids and distinct mechanisms havebeen associated with the toxic effects of cisplatin on

healthy renal cells. Oxidative damage and inflammatory

events might explain the effects on other cellular constit-

uents and have been associated with cisplatin-induced

nephrotoxicity (Cvitkovic 1998; Ali and Al Moundhri

2006; Yao et al.2007; Pabla and Dong2008). Several lines

of evidence indicate that cisplatin nephrotoxicity is mainly

associated with mitochondria-generated oxygen reactive

species (ROS) (Matsushima et al. 1998; Somani et al.

2000; Chang et al. 2002; Wang and Lippard2005; Santos

et al. 2007; Santos et al. 2008). Alterations in renal

hemodynamic modulators have also been associated with

the toxic effects of cisplatin on kidneys (Hye Khan et al.

2007).

It has been suggested that cisplatin is conjugated with

reduced glutathione (GSH) in the liver and reaches the

kidney as a cisplatinGSH conjugate, which is cleaved to a

nephrotoxic metabolite mainly by the action of gamma-

glutamyl transpeptidase (GGT), an enzyme primarily

located in the brush border of the proximal convoluted

tubule of the kidney. The metabolite formed is a highly

reactive thiol/platinum compound that interacts with mac-

romolecules leading eventually to renal cell death (Ward

1975; Wainford et al. 2008). The interference in this bio-

transformation pathway has been proposed as an approach

to prevent the formation of the nephrotoxic metabolite and

therefore, minimizing cisplatin nephrotoxicity. It has been

demonstrated that GGT-deficient mice are resistant to the

nephrotoxic effects of cisplatin (Hanigan et al. 2001).

Additionally, studies have demonstrated that inhibition of

GGT with acivicin, both in mice and in rats, protected

against the nephrotoxicity of cisplatin (Hanigan et al. 1994;

Townsend and Hanigan 2002). The participation of other

enzymes such as aminopeptidase N (AP-N), renal dipepti-

dase (RDP), and cysteine-S-conjugate beta-lyase (CS

lyase) in this toxificant pathway has been reported. The

following sequence has been proposed: after cisplatinGSH

conjugates are secreted into the proximal tubule lumen and

cleaved by GGT, a cysteineglycine conjugate is formed

and then cleaved by the cell surface aminopeptidases,

AP-N, or RDP, to a cysteine conjugate, which is thenreabsorbed into proximal tubular cells and finally metabo-

lized by CS lyase to toxic reactive thiols resulting in

nephrotoxicity (Hanigan et al. 1994; Townsend and Hani-

gan2002; Townsend et al.2003; Zhang and Hanigan2003).

The inhibition of CS lyase with amino oxyacetic acid was

protective in mice treated with 15 mg/kg cisplatin (Town-

send and Hanigan2002); however, opposing data have been

reported. According to a more recent study, AP-N, RDP,

and CS-lyase inhibition were non-protective against neph-

rotoxicity in mice treated with 10 mg/kg cisplatin and/or in

rats treated with 6 mg/kg cisplatin (Wainford et al. 2008).

A second-generation platinum-protecting disulfide drugnamed BNP7787 (disodium 2,2-dithio-bis-ethane sulfo-

nate, dimesna, TavoceptTM) was developed to specifically

inactivate the toxic platinum species found in normal

organs in order to reduce or prevent common toxicities of

platinum chemotherapeutic drugs (Hausheer et al. 1998).

BNP7787 is selectively taken up by the kidneys where it is

converted into mesna (Ormstad and Uehara 1982).

BNP7787 may accumulate in renal tubular cells, where it

can exert its protective effects against cisplatin-induced

nephrotoxicity by direct covalent conjugation of mesna

with cisplatin (Hausheer et al. 2011a). Besides the forma-

tion of this inactive adduct with cisplatin, other mecha-

nisms might be involved in the protection: (a) inhibition of

GGT, (b) inhibition of AP-N, and (c) inhibition of CS

lyase (Hausheer et al. 2010, 2011b). Additionally, it was

reported that BNP7787 does not interfere in the antitumor

activity of cisplatin in human ovarian cancer cell lines in

vitro or in nude mice bearing human ovarian cancer

xenografts (Boven et al. 2002). The drug is currently

undergoing global Phase III studies (Hausheer et al. 2011a).

Mechanisms of cell death in cisplatin-induced

nephrotoxicity

Cisplatin induces two models of cell death: apoptosis and

necrosis. Initially, only necrosis was associated with the

renal damage induced by cisplatin (Goldstein and Mayor

1983); afterward, the induction of apoptosis was also

demonstrated. A study published in 1996 demonstrated that

high concentrations of cisplatin (800 lM) induced necrosis

in primary cultures of mouse proximal tubular cells, while

lower concentrations (8 lM) led to apoptosis (Lieberthal

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et al. 1996). More recently, several studies have demon-

strated that both the mechanisms of cell death are induced

by cisplatin in vivo (Baek et al. 2003; Tsuruya et al.2003;

Wang and Lippard2005). The relative contribution of both

types of cell death, apoptosis, and necrosis, to cisplatin

nephrotoxicity has not been established yet (Bonegio and

Lieberthal 2002; Faubel et al. 2004). However, apoptosis

has been in the spotlight in the last years. Necrosis has been

mainly associated with high doses of cisplatin, severe

mitochondrial damage, and ATP depletion, whereas

apoptosis is a process dependent on ATP energy and

therefore associated with the milder mitochondrial altera-

tions resulting from therapeutic doses (Lieberthal et al.

1998; Ueda et al. 2000; Hanigan and Devarajan 2003;

Wang and Lippard2005).

Different apoptotic pathways are triggered by cisplatin

in renal tubular epithelial cells (RTEC). The main reported

pathways are (a) the intrinsic pathway, which is triggered

by mitochondria and (b) the extrinsic pathway, which is

mediated by TNF (tumor necrosis factor) receptor/ligand

and Fas (APO -1 or CD95)/Fas ligand systems (Ramesh

and Reeves2002). Additionally, the endoplasmic reticulum

stress (ER stress) pathway has also been demonstrated in

cisplatin-induced apoptosis in RTEC (Liu and Baliga

2005). The mechanisms of nephrotoxicity induced by

cisplatin are summarized in Fig.1, and the potential

cytoprotectors which interfere in these pathways are sum-

marized in Table1.

Intrinsic or mitochondrial apoptotic pathway

Mitochondrial injury in RTEC leads to the release of

apoptogenic factors, including cytochrome c, Smac/DIA-

BLO, Omi/HtrA2, and apoptosis-inducing factor or AIF

(Daugas et al.2000a; Servais et al.2008). The migration of

cytochrome c to cytosol is a key event in caspases acti-

vation, and the following sequence of events has been

described: formation of Apaf-1/cytochrome capoptosome,

caspase-9 activation, and ultimately the activation of the

executioner caspase-3 (Lee et al. 2001; Park et al. 2002;

Cullen et al.2007). Smac/DIABLO and Omi/HtrA2 inhibit

the suppressors of apoptosis, IAPs (inhibitor of apoptosis

proteins), which interfere in the cytochrome c/Apaf-1/

caspase-9 activating pathway. Omi/HtrA2 can also pro-

mote apoptosis through its serine protease activity, a

mechanism independent of caspases (Du et al. 2000; Cil-

enti et al. 2005). AIF is a protein that translocates to the

nucleus and promotes apoptosis without the activation of

caspases (Daugas et al. 2000a).

Fig. 1 Multiple pathways

involved in cisplatin-induced

nephrotoxicity

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Table 1 Nephroprotective agents, targeted pathways, molecular mechanisms, and experimental models used in studies

Target/class Agents Mechanisms of action

and experimental model

References

Cisplatin

transport and

accumulation

Imatinib Reduced the toxicity and platinum

concentration in OCT2-

expressing HEK293 cells and rat

kidneys

Tanihara et al. (2009)

Cimetidine* Competitive inhibition of cisplatin

transport at OCT2 in vitro and in

rats

Katsuda et al. (2010)

Acivicin Inhibition of GGT in mice and rats Hanigan et al. (1994), Townsend

and Hanigan (2002)

Amino oxyacetic acid Inhibition of CS lyase in mice Townsend and Hanigan (2002)

BNP7787* Formation of inactive adducts,

inhibition of GGT, inhibition of

AP-N, inhibition of CS lyase in

vitro and in mice

Hausheer et al. (2010), Hausheer et al.

(2011a,b)

Saline, saline plus mannitol,

and saline plus furosemide

Hydration/diuresis, increases the

rate of cisplatin elimination in

humans

Gonzales-Vitale et al. (1977), Hayes et al.

(1977), Frick et al. (1979), Santoso et al.

(2003)

Oxidative stress(antioxidants)

Vitamin C ROS scavenging and/or ironchelating, decreasing oxidative

stress, and avoiding activation of

apoptosis in vitro and rodent

models

Tarladacalisir et al. (2008)Vitamin E Ajith et al. (2009)

Vitamin A Dillioglugil et al. (2005)

Resveratrol Do Amaral et al. (2008)

Quercetin Francescato et al. (2004)

Caffeic acid phenethyl ester

(CAPE)

Ozen et al. (2004)

Naringenin Badary et al. (2005)

Lycopene Atessahin et al. (2005)

DMTU Santos et al. (2008)

DMSO Jones et al. (1991)

Carvedilol Rodrigues et al. (2010,2011)

Captopril El-Sayed el et al. (2008)Allopurinol plus ebselem Lynch et al. (2005)

Edaravone Satoh et al. (2003), Iguchi et al. (2004)

Desferrioxamine (DFO) Kadikoylu et al. (2004)

Oxidative stress

(antioxidants

thiols)

Diethyldithiocarbamate

(DDTC), GSH, D-methionine,

sodium thiosulphate (STS)

Restoration of thiol enzymes

function, free radical scavenging,

formation of non-toxic adducts,

reduction of cisplatin uptake by

renal cells in vitro

Cvitkovic (1998), Wu et al. (2005),

Bae et al. (2009)

N-acetylcysteine (NAC) Blockade of intrinsic and extrinsic

apoptotic pathways induced by

cisplatin in SCLC, SKOV3, and

U87MG human tumor cell lines

Wu et al. (2005)

Alpha-lipoic acid Maintenance of activities of NOand ET systems and inhibition of

the development of apoptosis in

rats

Bae et al. (2009)

Amifostine (WR 2721)** Scavenger of ROS tested in vitro,

in rodents and humans

Cvitkovic (1998)

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Cisplatin can trigger the mitochondrial apoptotic path-

way through different stimuli such as increased ROS

generation and the activation of pro-apoptotic proteins

(Hanigan and Devarajan 2003), which permeabilize the

outer mitochondrial membrane and induce the release of

cytochrome c (Lee et al.2001; Park et al.2002), AIF (Seth

et al. 2005) and Omi/HtrA2 (Cilenti et al.2005).

Mitochondrial dysfunction is considered a key event in

cisplatin-induced renal damage. Decline in membrane

electrochemical potential, disturbance in calcium homeo-

stasis, reduced ATP synthesis, and impaired mitochondrial

respiration have been demonstrated in kidneys of rats

treated with cisplatin (Santos et al. 2007; Rodrigues et al.

2010).

It is known that cisplatin can damage complexes I, II,

III, and IV of the mitochondrial respiratory chain,

increasing the generation of superoxide anions at com-

plexes I, II, and III. Superoxide anions might originate

Table 1 continued

Target/class Agents Mechanisms of action

and experimental model

References

Apoptosis TNFR1-deficient mice Avoid TNF activation of apoptosis

when ROS production is

increased in mice models

Tsuruya et al. (2003)

TNF-a-deficient mice Ramesh and Reeves (2002)

TNFR2-deficient mice Ramesh and Reeves (2003)

Trichostatin A (TSA) Inhibition of p53 activation inRTPC cell line

Dong et al. (2009)

Suberoylanilide hydroxamic

acid (SAHA)

Inhibition of p53 activation and

reduction of Bax translocation

and cytochrome c release in

RTPC and HCT116 colon cancer

cells

Dong et al. (2009)

Pituitary adenylate cyclase-

activating polypeptide

(PACAP38)

Inhibition of p53 expression,

inhibition of caspase-7 cleavage

in HK-2 cells and mice

Li et al. (2010,2011)

Erythropoietin (EPO) Up-regulation of anti-apoptotic

proteins expression, down-

regulation of pro-apoptotic

proteins and reduction of

caspase-3 activity in rats

Rjiba-Touati et al. (2012)

Rottlerin Inhibition of PKC delta in mice Pabla et al. (2011)

Inflammation Salicylate Anti-inflammatory action in rats Li et al. (2002)

GM6001 and pentoxifylline Inhibition of TNF-a with

antagonists and blunted the up-

regulation of cytokines such as

TGF-b, RANTES, MIP-2, MCP-

1, and IL-1b in mice

Ramesh and Reeves (2002)

Pituitary adenylate cyclase-

activating polypeptide

(PACAP38)

Reduction of TNF-a levels in HK-

2 cells and mice

Li et al. (2010,2011)

Quercetin* Inhibition of TNF-a and NO

production through attenuation

of NF-kB activity in rats

Sanchez-Gonzalez et al. (2011a,b)

Celecoxib Inhibition of COX-2 Jia et al. (2011)

Abnormal

hemodynamics

Captopril Inhibition of renin-angiotensin

system, prostaglandins, and

endothelin-1 in rats

El-Sayed el et al. (2008), Saleh et al.

(2009)

Losartan Blockage of angiotensin II

receptor in rats

Saleh et al. (2009)

Aminophylline Competitive antagonist of

adenosine in rats

Heidemann et al. (1989)

BN-52063 Platelet-activating factor (PAF)

antagonist in rats

dos Santos et al. (1991), Dos Santos et al.

(1991)

* Does not change cisplatin-antitumor action in the experimental model

** Approved to be used in humans

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hydroxyl radicals by partial reduction catalyzed by transi-

tion metals, mainly iron (Fenton reaction) (Kruidering et al.

1994, 1997; Turrens 2003; Yao et al. 2007). Hydroxyl

radicals are very strong oxidants, and their induction has

been demonstrated in kidneys of rats treated with cisplatin

(Matsushima et al.1998; Santos et al.2008). The oxidative

damage induced by cisplatin has been associated with

depletion of the non-enzymatic (GSH and NADPH) and theenzymatic antioxidant defense system (superoxide dismu-

tase, catalase, glutathione peroxidase, glutathione trans-

ferase, and glutathione reductase) in rat kidneys

(Hannemann et al. 1991; Sadzuka et al. 1992; Antunes

et al. 2000; Kadikoylu et al. 2004). Lipoperoxidation,

oxidation of cardiolipin, oxidation of sulfhydryl protein,

increased carbonylated proteins levels, decreased activity

of aconitase, cytochrome c release, increased activity of

caspase-9, and caspase-3 have also been associated with

the renal damage induced by cisplatin (Kaushal et al.2001;

Park et al. 2002; Santos et al. 2007). Cytochrome c is

attached to the inner mitochondrial membrane (IMM), andits release occurs due to the loss of the mitochondrial

membrane integrity. The mitochondrial membrane is a

target of the oxidative species that attack proteins and

lipids, particularly the anionic phospholipid cardiolipin,

located in IMM. As cardiolipin holds cytochrome

cattached to IMM, its oxidation contributes to cytochrome

c release to cytosol (Petrosillo et al. 2003). Cardiolipin is

also a target of caspase-2 and Bid, a pro-apoptotic protein

from the Bcl2 family, which promotes a link between the

extrinsic and intrinsic apoptotic pathways, since it is acti-

vated by caspase-8 (extrinsic pathway) and acts on mito-

chondria promoting the apoptotic intrinsic pathway

(Enoksson et al. 2004; Campbell et al. 2008; El Sabbahy

and Vaidya2011). Besides increasing mitochondrial ROS

generation, cisplatin activates the pro-apoptotic proteins

Bax and Bak, upstream mitochondrial injury. These pro-

teins induce the permeabilization of the outer mitochon-

drial membrane and therefore, cytochrome c release and

caspases activation (Lee et al. 2001; Park et al. 2002;

Cullen et al.2007). The nephrotoxicity induced by cisplatin

is attenuated in Bax/Bak-knockout cells and in Bax-defi-

cient mice (Jiang et al. 2006; Wei et al. 2007a). Erythro-

poietin (EPO), a renal cytokine which regulates

hematopoiesis, has been shown to reduce apoptosis during

cisplatin nephrotoxicity by the up-regulation of anti-apop-

totic proteins expression, down-regulation of pro-apoptotic

protein levels, and reduction of caspase-3 activity (Rjiba-

Touati et al. 2012).

Besides the apoptosis dependent of caspases activation,

cisplatin can also trigger a mitochondrial mediated and

caspase-independent apoptotic pathway through the apop-

tosis-inducing factor (AIF), a protein located in the mito-

chondrial intermembrane space and present in renal

epithelium. When the outer mitochondrial membrane is

damaged, AIF translocates to the nucleus inducing chro-

matin condensation and large-scale DNA fragmentation.

The anti-apoptotic Bcl-2 protein preserves the mitochon-

drial membrane integrity, preventing both the release of

cytochrome c and translocation of AIF to the nucleus

(Daugas et al. 2000b; Adams and Cory2001). The release

of AIF has been reported to be dependent on caspase-2,which is activated by PIDD, a p53-induced protein with

death domain. Caspase-2 permeabilizes the outer mito-

chondrial membrane and damages anionic phospholipids,

causing release of pro-apoptotic factors such as cyto-

chromec and AIF. Inhibition of caspase-2 and inhibition of

AIF have been reported as protective against cisplatin-

induced renal damage (Daugas et al.2000b; Enoksson et al.

2004; Seth et al.2005; Jiang and Dong2008; Servais et al.

2008).

The transcriptional factor p53 activates pro-apoptotic

genes encoding Bax, Bak, PUMA-a, PIDD, and the ER-

iPLA2 (Ca2?-independent phospholipase A2) and down-regulates the anti-apoptotic proteins Bcl-2 and Bcl-xL,

leading to the mitochondrial apoptotic pathway (Seth et al.

2005; Jiang et al.2006; Jiang and Dong2008; Servais et al.

2008). The involvement of ROS, particularly hydroxyl

radicals, in p53 activation during cisplatin nephrotoxicity

has been suggested (Jiang et al.2007), and the crucial role

of hydroxyl radicals in cisplatin nephrotoxicity has been

demonstrated (Santos et al. 2008).

Due to the importance of ROS and oxidative stress in the

induction of apoptotic cell death, particularly of the

intrinsic pathway, one of the most studied approaches to

protect against cisplatin nephrotoxicity is the use of natural

and synthetic antioxidants. Experimental studies have

reported the protective effects of natural compounds such

as vitamins C (Tarladacalisir et al. 2008), E (Ajith et al.

2009), and A (Dillioglugil et al. 2005); resveratrol (Do

Amaral et al. 2008), quercetin (Francescato et al. 2004),

and caffeic acid phenethyl ester (Ozen et al. 2004);

naringenin (Badary et al. 2005) and lycopene (Atessahin

et al. 2005), as well as synthetic compounds such as

DMTU (Santos et al. 2008), DMSO (Jones et al. 1991),

carvedilol (Rodrigues et al.2010), allopurinol plus ebselem

(Lynch et al. 2005), edaravone (Satoh et al. 2003; Iguchi

et al. 2004), desferrioxamine (DFO) (Kadikoylu et al.

2004), and many others. Antioxidants protect kidneys from

cisplatin damage mainly by free radical scavenging or iron

chelation (Koyner et al.2008). As ROS plays a role in the

inflammatory pathway, antioxidants may also interfere

positively in the inflammatory process. The nephroprotec-

tive effect of quercetin, for example, seems to be related

with its antioxidant activity as well as with its capacity to

inhibit renal inflammation and tubular cell apoptosis.

Quercetin has been shown to inhibit lipopolysaccharide-

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induced TNF-aand NO production through attenuation of

NF-kB activity in macrophages, microglia cells, and mast

cells. Quercetin prevents the renal damage of cisplatin

without affecting the antitumor activity of cisplatin in

tumor-bearing rats (Sanchez-Gonzalez et al.2011b).

Some of the antioxidants which successfully protected

against cisplatin nephrotoxicity in experimental studies

cannot be clinically applied due to their intrinsic toxicity.One example is DMTU, an interesting small and highly

diffusible molecule, which effectively scavenges hydroxyl

radicals and prevents oxidative injury in different biologi-

cal systems, but has been associated with fetotoxicity and

lung damage (Milner et al. 1993; Beehler et al. 1994;

Santos et al. 2008). The importance of these kinds of

compounds is that (a) they help to delineate mechanisms

and specific events involved in the toxicity/protection and

(b) might be used as models for the development of new

protective drugs with less intrinsic toxicity. In this context,

compounds which have been proved safe in a different

clinical application and also possess antioxidant properties,such as the antihypertensive carvedilol (Rodrigues et al.

2010) and the antihyperuricemic allopurinol (Lynch et al.

2005), might be interesting alternatives.

The dietary antioxidants such as vitamins A, C, and E

and some flavonoids might act as pro-oxidants under some

specific conditions; vitamin C and quercetin, for example,

induce free radical production in the presence of transition

metals (Laughton et al. 1989; Tirosh et al. 1996; Schmal-

hausen et al.2007; Santos2012). Some studies have shown

that the pro-oxidant activity of some flavonoids potentiate

the antitumor activity of cisplatin. The flavonoids, 20,50-

dihydroxychalcone (20,50-DHC, 20lM), and chrysin

(20 lM) potentiated the cytotoxicity of cisplatin in human

lung adenocarcinoma (A549) cells and the mechanism of

action was attributed to GSH depletion (Kachadourian

et al. 2007). Cytotoxicity of quercetin in human leukemia

cells HL-60 has been attributed to its pro-oxidant action

(Sergediene et al. 1999). Additionally, it has been dem-

onstrated that quercetin increases the efficacy of cisplatin

in nude mice implanted with human tumor xenografts

(Hofmann et al.1990), in human non-small cell lung car-

cinoma H-520 cells (Kuhar et al. 2006), and in human head

and neck cancer (Sharma et al. 2005). Therefore, while

antioxidants have been shown to effectively prevent the

nephrotoxicity of cisplatin, some of them might also be

pro-oxidant and exacerbate the oxidative damage to heal-

thy tissues or on the hand, interfere positively, sensitizing

tumor cells to the action of cisplatin. The delicate balance

among these effects determines the final outcome of the

adjuvant therapy with antioxidants during cisplatin che-

motherapy. Besides that, although the antitumor and toxic

mechanisms induced by cisplatin seem to be distinct, there

is a general concern that the antioxidant therapy might

interfere in the antitumor efficacy. Further clinical studies

are needed to establish the real role of antioxidants in

cisplatin chemotherapy.

Sulfhydryl compounds constitute a particular group of

antioxidants that have also been reported to decrease the

toxicity of platinum compounds. Their action includes

restoration of thiol enzymes function, free radical scav-

enging, formation of non-toxic adducts, reduction in cis-platin uptake by renal cells, and increase in the urinary

excretion of cisplatin (Santos2012). The nephroprotective

effect of diethyldithiocarbamate (DDTC), GSH, D-methi-

onine, amifostine, sodium thiosulphate (STS), N-acetyl-

cysteine (NAC), and lipoic acid has been demonstrated

(Cvitkovic 1998; Wu et al. 2005; Bae et al. 2009); how-

ever, studies indicate that the thiol moiety react with

cisplatin resulting in the formation of an inactive platinum

thiol conjugate (Hausheer et al. 1998). Different from the

antioxidants that act as reducing agents, GSH, NAC, and

STS are nucleophiles, and therefore can covalently bind to

the electrophilic intermediates of cisplatin reducing theantitumor efficacy (Conklin2004). A recent in vitro study

demonstrated that tumor growth was statistically signifi-

cantly increased when STS were administered simulta-

neously with cisplatin or 4-hours after cisplatin (Yee et al.

2008). It was also demonstrated that STS, GSH, and NAC

can prevent, and moreover, revert (only NAC and STS) the

formation of cisplatinDNA adducts in whole blood

(Brouwers et al.2008). In order to overcome the interaction

between sulfhydryl agents and cisplatin, the administration

by two different routes, for example, intravenous and

intraperitoneal, respectively, has been proposed (Guastalla

et al. 1994).

Like other antioxidants, thiols might also have pro-

oxidant action. It has been reported that thiols produce

superoxide radicals causing low-density lipoproteins

(LDL) oxidation (Heinecke et al. 1993; Tirosh et al.1996).

The thiophosphate amifostine (WR 2721) is approved

by the FDA for minimizing renal toxicity in patients

receiving cisplatin. It is a pro-drug which is converted to

the active free thiol WR 1065, a scavenger of ROS

(Cvitkovic 1998). The limitation factors of the use of

amifostine include: high costs, side effects, and concerns

that it might interfere in the antitumor efficacy of cisplatin

(Koyner et al.2008), although some studies suggest it does

not. An in vitro study demonstrated that amifostine inhibits

DNA platination and is also able to reverse part of the

cisplatinDNA adducts formed, but different from the

other thiols tested (DDTC and STS), and amifostine does

not interfere in the antitumor efficacy of cisplatin. Addi-

tionally, clinical studies with amifostine have not provide

the evidence of impairment of antitumor activity (Block

and Gyllenhaal 2005). The relative success of amifostine

has been attributed to the selective formation, uptake, and

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accumulation of the active metabolite WR1065 in normal

tissues (Treskes et al. 1992; Block and Gyllenhaal 2005).

There are also reports of ineffectiveness of amifostine.

Severe nephrotoxicity, among other toxicities, has been

reported in some patients treated with cisplatin despite the

use of the drug (Sastry and Kellie2005; Katzenstein et al.

2009). The side effects of amifostine might be serious and

include severe hypotension, ototoxicity, nausea, dizziness,vomiting, transient decrease in serum calcium levels,

infusion-related flushing, and skin reactions (Gandara et al.

1990; Kemp et al. 1996; Block and Gyllenhaal 2005;

Hausheer et al.2011b). Subcutaneous administration seems

to reduce its toxicity (Block and Gyllenhaal 2005).

Extrinsic pathway, dependent on caspase-8

The extrinsic apoptotic pathway is activated when a ligand

binds to death receptors on the cytoplasmic membrane of

cells, recruiting, and activating caspase-8, which in turnactivates the effector caspase-3 (Strasser et al. 2000).

Cisplatin up-regulates the expression of the pro-inflam-

matory cytokine TNF-a, whose activities are mainly medi-

ated by the death receptors TNFR1 and TNFR2, which are

also up-regulated by cisplatin. While TNFR1 seems to

directly induce the extrinsic apoptotic pathway, TNFR2 has

been mainly associated with the inflammatory response,

which amplifies TNFR1 effects. TNFR2 seems to indirectly

induceapoptosisand necrosis in RTEC,since unlike TNFR1,

TNFR2 does not have the death domain to directly trigger

apoptosis (Ramesh and Reeves 2003; Sanchez-Gonzalez

et al.2011a). Cisplatin also up-regulates Fas ligand/receptor

system. Both Fas and TNFR1 interact with Fas-associated

death domain protein (FADD), which leads to caspase-8

activation, caspase-3 activation, and cell death (Tsuruya

et al.2003). Attenuation of cisplatin-induced nephrotoxicity

in TNFR1-deficient mice (Tsuruya et al.2003), in TNF-a-

deficient mice (Ramesh and Reeves2002), and in TNFR2-

deficient mice (Ramesh and Reeves 2003) has been reported.

It has also been suggested that increased generation of ROS

in mitochondria plays a role in TNF-mediated apoptosis and

in Fas-L expression (Beyaert and Fiers 1994; Bauer et al.

1998; Tsuruya et al.2003).

Besides activating the expression of pro-apoptotic pro-

teins, which converge to mitochondria, the transcriptional

factor p53 also activates genes encoding Fas, therefore

playing a role in the extrinsic apoptotic pathway via Fas/

FADD signaling (Burns and El-Deiry 1999; Hanigan and

Devarajan2003). Additionally, a p53-dependent increased

production of executioner caspases-6 and -7 has been

demonstrated both in RTEC and in the kidney cortex of

mice treated with cisplatin (Yang et al.2008). Moreover, it

has been reported that p53-deficient mice treated with

cisplatin have lower degree of apoptosis in renal tubular

cells, decreased renal tissue damage, and improved renal

function as compared to wild-type animals treated with

cisplatin (Wei et al. 2007b). The pituitary adenylate

cyclase-activating polypeptide (PACAP38) has been

reported to ameliorate cisplatin-induced acute kidney

injury and to increase tubular regeneration. It has been

associated with the inhibition of p53 expression, inhibitionof caspase-7 cleavage, and therefore the inhibition of

apoptosis. PACAP38 has also been shown to interfere in

the inflammatory pathway of cisplatin nephrotoxicity by

reducing TNF-a levels (Li et al. 2010, 2011). Inhibitors

of histone deacetylases (HDACs), like suberoylanilide

hydroxamic acid (SAHA) and trichostatin A (TSA) can also

protect against cisplatin nephrotoxicity by inhibiting p53

activation. SAHA may also interfere in the mitochondrial

pathway, by reducing Bax translocation and cytochrome

crelease induced by cisplatin (Dong et al.2009).

A death receptors pathway mediated by TRAIL (tumor

necrosis factor-related apoptosis-inducing ligand) is alsoactivated by cisplatin; this pathway selectively induces

apoptosis in several cancer cells but not in normal cells

(Wang and El-Deiry2003). There are five types of TRAIL

receptors; however, most cancer cells activate signals

through DR4 (TRAIL-R1) and DR5 (TRAIL-R2). The

activation of death domains at TRAIL receptors leads to

pro-caspase-8 activation and subsequently to caspase-3

activation. In some types of cells, the amount of caspase-8

activated by this pathway is not enough to activate the

downstream caspases but sufficient to cleave Bid, which then

triggers the mitochondrial pathway (Johnson et al. 2007;

Vondalova Blanarova et al. 2011). Cisplatin has been

reported to increase DR5 expression and lipid raft localiza-

tion, therefore potentiating TRAIL-induced apoptosis in

human prostate and colon cancer cells(Vondalova Blanarova

et al.2011). It has also been reported to enhance cell death

induced by TRAIL in human renal cell carcinoma (ACHN),

bladder cancer (T24), lung cancer (MAC10), and cervical

cancer (Hela) cell lines. Combination of TRAIL with cis-

platin has been suggested as a strategy to overcome many

solid cancers resistance (Wu and Kakehi2009). TRAIL sig-

naling had been associated with the antitumor activity of

cisplatin, not with its nephrotoxic action. The selectivity of

TRAIL for cancer cells has been attributed to higher

expression of decoy receptors (DcRs) in normal cells. These

receptors are unable to signal apoptosis and therefore

compete for TRAIL binding, inhibiting TRAIL signaling in

normal cells (Sheridan et al.1997).

Endoplasmic reticulum (ER) pathway

Cisplatin has also been reported to activate the endoplas-

mic reticulum (ER) apoptotic pathway in RTEC, resulting

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in the activation of pro-caspase 12, which is highly

expressed at the cytosolic side of the ER in RTEC.

Increased expression of markers of ER stress (XBP1 tran-

scription factor) and ER-mediated apoptosis (m-calpain

and caspase12 cleavage products) have been found in

kidneys of rats treated with cisplatin (Peyrou et al. 2007).

The activation of caspase-12 leads to the activation of

caspase 9 in a mechanism, which does not depend oncytochromec release; activation of caspase-9 then activates

the effector caspase-3. The ER stress pathway also involves

the activation of Ca2?-independent phospholipase A2 (ER-

iPLA-2), which seems to act downstream p53 nuclear

localization and upstream caspase-3 activation, in a

mechanism independent of mitochondrial dysfunction. In

fact, it has been proposed that in the absence of mito-

chondrial dysfunction, ER might be the connector between

p53 and caspase 3 activation (Cummings et al. 2004). The

mechanism by which cisplatin disrupts ER probably

involves increased ROS generation in ER cytochrome

P450, particularly CYP2E1 (Nakagawa et al. 2000; Liu andBaliga 2005; Peyrou et al. 2007; Pabla and Dong 2008).

CYP2E1 is an effective generator of ROS, which is highly

present in the liver, but is also found in small amounts in

other tissues, including kidneys (Caro and Cederbaum

2004). Liu and Baliga demonstrated that the microsomal

CYP2E1 is a site and a source of ROS generation in cis-

platin-induced apoptosis and that pro-caspase 12 is acti-

vated in the kidneys of cisplatin-treated CYP2E1 wild-type

mice, but not in the CYP2E1 null mice. Therefore, the

authors suggested that the oxidative stress induced by

cisplatin in ER CYP2E1 leads to the activation of pro-

caspase 12, resulting in renal cell apoptosis (Liu et al.

2002; Liu and Baliga 2003,2005).

Role of inflammation in cisplatin nephrotoxicity

The inflammatory events induced by cisplatin in kidneys

have been mainly attributed to enhanced expression of

TNF-a (Ramesh and Reeves 2002, 2003, 2005), a multi-

functional cytokine with important roles in inflammation

and immunity (Old1988). The TNF-a/TNFR signaling has

been implicated in two different pathways during cisplatin

nephrotoxicity, namely (i) the extrinsic pathway via cas-

pase-8 activation, discussed previously in this review; and

(ii) the inflammatory response, in which TNF-a activates

pro-inflammatory cytokines and chemokines and recruit

leukocytes, therefore causing oxidative stress and ampli-

fying the renal damage (Szlosarek and Balkwill 2003). In

fact, TNF-a is both an inducer of ROS and induced by

ROS, particularly by the hydroxyl radicals generated by

cisplatin (Goossens et al.1995; Ramesh and Reeves2002).

ROS activates the transcription factor NF-kB, which in turn

induce the production of pro-inflammatory cytokines, such

as TNF-a (Sanchez-Gonzalez et al. 2011b). Besides the

direct oxidative damage to lipids and proteins (Santos et al.

2008), the hydroxyl radicals generated by cisplatin have

also been implicated in the phosphorylation of p38 MAPK,

which mediates the synthesis of TNF-a. Accordingly,

dimethylthiourea, a classical hydroxyl radical scavenger,

has been demonstrated to prevent the activation of p38MAPK and the increase of mRNA levels of TNF-a in the

kidneys of mice treated with cisplatin. Moreover, inhibition

of p38 MAPK reduces TNF-a production and protects

against cisplatin-induced renal damage in vivo (Ramesh

and Reeves2005).

The activation of protein kinase C (PKC) leads to the

activation of MAPKs, and it has been associated with

cisplatin nephrotoxicity (Ikeda et al.1999). Recently, PKC

delta, a member of PKC family, has been implicated in

cisplatin nephrotoxicity. This pathway involves the acti-

vation of PKC delta by cisplatin, which in turn activates

MAPKs to induce tubular cell injury and death. Pharma-cological inhibition of PKC delta with rottlerin and genetic

inhibition of PKC delta attenuate renal apoptosis and tissue

damage, preserving renal function during cisplatin treat-

ment. Inhibition of PKC delta may also intensify the

antitumor effect of cisplatin (Pabla et al. 2011).

The events downstream p-38 MAPK activation that

leads to TNF-a synthesis during the renal inflammation

induced by cisplatin have not been delineated, but it has

been demonstrated that in lipopolysaccharide-stimulated

neutrophils as well as in vascular smooth muscle cells,

activation of p38 MAPK leads to the degradation of IjB

(inhibitor of NF-jB), therefore promoting activation and

migration of NF-jB to nucleus and consequently, the

production of pro-inflammatory cytokines including TNF-a

(Nick et al. 1999; Yamakawa et al. 1999; Mishima et al.

2006). On the other hand, some of these inflammatory

mediators, including TNF-a, promote an amplifying loop,

inducing themselves phosphorylation and degradation of

the inhibitory protein IjBa, translocation of the nuclear

factor-jB (NF-jB), and transcription of genes that encode

inflammatory mediators (Barnes1997; Lee et al.2006).

Cytokines like transcribing growth factor-b (TGF-b),

monocyte chemoattractant protein-1 (MCP-1), intercellular

adhesion molecule (ICAM), and hemeoxygenase-1 have

been implicated in cisplatin-induced nephrotoxicity (Yao

et al. 2007). Significant up-regulation of TNF-a, TGF-b,

RANTES, MIP-2, MCP-1, TCA3, IL-1b, and ICAM-1 was

found in kidneys from cisplatin-treated animals (Ramesh

and Reeves2002).

The increase of interleukin 1b (IL-1b) has been asso-

ciated with the pro-inflammatory caspase-1 (interleukin

1b-converting enzyme or ICE). Caspase-1 activation seems

not to occur in cultured LLC-PK1 cells exposed to cisplatin

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(Lau1999; Kaushal et al.2001), but it was demonstrated in

mice (Faubel et al. 2004). Besides activating IL-1b, cas-

pase-1 also activates other cytokines, such as IL-18 and IL-

6, and promotes neutrophil infiltration. Inhibition of IL-1b,

IL-18, and IL-6 or neutrophil infiltration in the kidney is

not sufficient to prevent cisplatin-induced renal injury;

however, caspase-1-deficient mice are protected against

cisplatin-induced apoptosis and acute tubular necrosis. Thismight be due to the participation of caspase-1 in the

apoptotic pathway. Besides participating in the inflamma-

tory process, caspase-1 may also activate the effector

caspase-3, inducing apoptosis in renal tissue (Faubel et al.

2004,2007).

Strategies to reduce the inflammatory events in cisplatin

nephrotoxicity have been reported. The use of the anti-

inflammatory salicylate reduced cisplatin nephrotoxicity

without affecting the antitumor activity in rats implanted

with MTLn3 breast cancer cells (Li et al.2002). Inhibition

of TNF-awith antagonists like GM6001 and pentoxifylline

blunted the up-regulation of cytokines such as TGF-b,RANTES, MIP-2, MCP-1, and IL-1b and attenuated the

renal damage in mice treated with cisplatin (Ramesh and

Reeves2002).

Activation of COX-2/mPGES-1 (cyclooxygenase/

microsomal prostaglandin E synthase-1) pathway and

particularly the pro-inflammatory PGE2 probably plays a

role in mediating cisplatin-induced renal injury. Celecoxib,

a COX-2 inhibitor, ameliorated the renal dysfunction and

structural damage in mice treated with cisplatin. Addi-

tionally, TNF-a, IL-1b, subunits of NADPH oxidase,

thiobarbituric acid-reactive substances, and Prostaglandin

E2 (PGE2), which are induced by cisplatin, were all

diminished in mPGES-1 null mice (Jia et al.2011).

Renal hemodynamic changes induced by cisplatin

Cisplatin causes damage and dysfunction in the renal

vascular endothelium, persistent vasoconstriction, and

renal vascular resistance (Winston and Safirstein 1985).

The microvascular damage caused by cisplatin may lead to

thrombotic microangiopathy (Jackson et al.1984), reduced

renal blood flow, reduced glomerular filtration rate, and

tubular cells hypoxia (Winston and Safirstein1985; Togna

et al. 2000). A pro-inflammatory state, with over-expres-

sion of endothelial cell adhesion molecules, leukocytes

infiltration, and vascular congestion was found in kidneys

of cisplatin-treated rats (Luke et al. 1992). Cisplatin alters

the response of arterioles to vasoactive substances, causing

abnormal autoregulation of the renal blood flow and aug-

mented vascular tone. Increased responsiveness to vaso-

constrictors as well as increased response to renal nerve

stimulation and decreased production of vasodilatory

prostaglandins have been implicated in the abnormal renal

vascular autoregulation related to cisplatin administration.

(Schrier et al. 2004; Khan et al. 2007; Bae et al. 2009;

Sanchez-Gonzalez et al. 2011a). Mediators like platelet-

activating factor or PAF (Pirotzky et al. 1990), adenosine

(Heidemann et al.1989), angiotensin II (Saleh et al. 2009),

and endothelin-1 (Masereeuw et al. 2000; El-Sayed el et al.

2008) have been associated with the renal hemodynamicchanges caused by cisplatin. The oxidative stress induced

by cisplatin has been implicated in the increase of these

renal vasoconstrictors. Captopril, an angiotensin-convert-

ing enzyme (ACE) inhibitor containing sulfhydryl (-SH)

group was protective against cisplatin-induced nephrotox-

icity in rats. Its protection was associated with its antiox-

idant properties, inhibition of renin-angiotensin system,

prostaglandins, and endothelin-1 (El-Sayed el et al. 2008;

Saleh et al. 2009). The angiotensin II receptor blocker

Losartan was also shown to protect against cisplatin-

induced nephrotoxicity, and its mechanism of nephropro-

tection was attributed to the inhibition of renin-angiotensinsystem as well as antioxidant action (Saleh et al. 2009).

Adenosine, a renal vasoconstrictor formed by the degra-

dation of ATP, decreases glomerular filtration rate and is

thought to be involved in various forms of acute renal

failure, including that induced by cisplatin. It is possible

that the decrease in phosphorylative oxidation induced by

cisplatin results in increased adenosine generation. The

competitive antagonist of adenosine, aminophylline, was

shown to improve kidney function when administered

during the maintenance phase of cisplatin-induced acute

renal failure (Heidemann et al. 1989). The increased syn-

thesis of PAF induced by cisplatin in kidneys results from

the disturbances in the oxidative metabolism and in cal-

cium homeostasis caused by the drug. The increase in

cytosolic calcium promoted by cisplatin activates calcium-

dependent membrane phospholipase A2, which participates

in PAF synthesis (Lopez-Novoa 1999). Treatment with

platelet-activating factor antagonist, BN-52063 (dos Santos

et al.1991a; Dos Santos et al.1991b) completely prevented

the acute renal damage induced by cisplatin.

Additionally, it has been proposed that augmented

adrenergic response can play a role in the hemodynamic

changes and enhanced vascular resistance induced by

cisplatin in kidneys. Moreover, this response might be med-

iated by a1-adrenoceptors, the major subtype ofa-adreno-

ceptors in renal vasculature (Hye Khan et al. 2007).

Current measures of nephroprotection during cisplatin

chemotherapy

The main protective measures currently employed in

clinical practice are based on avoiding the excessive

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exposure of kidneys, basically by hydration/diuresis,

monitoring of renal function by creatinine clearance (e.g.,

calculated by the Cockcroft-Gault equation), and reducing

cisplatin doses when the renal function is altered (Launay-

Vacher et al. 2008; Losonczy et al. 2010). However, the

conventional measures of hydration and osmotic diuresis are

not enough to prevent a significant decrease in glomerular

filtration rate after a single cycle of cisplatin-containingchemotherapy (Benoehr et al. 2005). The cytoprotectant

amifostine is also used to reduce nephrotoxicity when high

doses of cisplatin are used, in general when doses of cisplatin

are above 100 mg/m2 or cumulative doses are above

300 mg/m2 (Block and Gyllenhaal2005).

The first attempt to reduce cisplatin nephrotoxicity was

the mannitol-induced diuresis. Mannitol promotes an

osmotic diuresis, increasing the rate of cisplatin elimina-

tion, while decreasing the cisplatin concentration in urine.

The first study addressing the protective effect of mannitol

diuresis was published in 1977 and described the reduction

of cisplatin renal damage in dogs; some studies reportedsimilar results in humans (Gonzales-Vitale et al. 1977;

Hayes et al.1977; Frick et al.1979). However, the efficacy

of mannitol is not a consensus. A posterior study demon-

strated that apart from the first cycle of treatment, hydra-

tion plus mannitol protection was not effective as

compared to hydration alone (Cornelison and Reed1993).

Additionally, a more recent study compared the 3 types of

hydration/diuresis used in clinical practice, namely:

(i) saline, (ii) saline plus mannitol, and (iii) saline plus

furosemide and concluded that saline and saline plus

furosemide were both more effective against cisplatin

nephrotoxicity than saline plus mannitol. Moreover, the

study suggested that mannitol might contribute to cisplatin-

related nephrotoxicity (Santoso et al. 2003). The beneficial

effect of furosemide is also controversial (Cornelison and

Reed 1993). High doses of furosemide cause nephrotoxi-

city, and it has been suggested that its use with cisplatin

may aggravate the nephrotoxicity (Lehane et al. 1979).

The general recommendation is that only euvolemic

patients should receive platinum compounds. Patients

treated with high doses of cisplatin should receive normal

saline infusion (100 ml/h) prior to, during and several days

following the administration of cisplatin; however, despite

these measures, renal failure still occurs (Losonczy et al.

2010). It has been reported that the infusion of cisplatin

diluted in hypertonic saline (3%) might provide protection

against the renal toxicity (Dumas et al. 1990), but some

studies have shown that GFR remains reduced despite this

measure (Launay-Vacher et al. 2008). Moreover, there is

also the concern that the elevated concentration of chloride

ions would prevent the formation of the aquated species

responsible for the antitumor activity of cisplatin (Hanigan

et al. 2005).

Conclusion

Given the importance of cisplatin chemotherapy and the

unsatisfactory results of the conventional protection mea-

sures, many studies have focused on protective strategies

targeting the main molecular mechanisms of cisplatin tox-

icity, which have been delineated so far. Encouraging results

have been found in vitro and in animal models,but the lack ofdata regarding the effects of the cytoprotectors on the anti-

tumor activity of cisplatin alliedwith thelack of continuity of

these preliminary findings, which rarely reach clinical trials,

has prevented the clinical application of the compounds

reported as effective. Therefore, convincing evidence that

simultaneous tumor protection does not occur should be

provided and extensive clinical trials should be conducted to

confirm the beneficial effects in man. Additionally, the better

understanding of the multiple interconnected pathways of

nephrotoxicity might reveal selective modulators or events

to be targeted by the future cytoprotectors. Finally, the

design and development of improved molecules based on thestructure of the reported protective compounds will also

contribute to obtain cytoprotectors with increased safety as

well as selectiveness toward specific targets.

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