Arch Toxicol (2012) 86:12331250

DOI 10.1007/s00204-012-0821-7

REVIEW ARTICLE

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 inherent
nephrotoxicity. 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 targets for nephroprotection, and many new potentially protective 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 accumulated 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

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: acsantos@fcfrp.usp.br

whose anticancer activity was accidentally discovered by

the physicistbiologist Barnett Rosenberg, during his
studies addressing the effect of a platinum electrode-generated electric field on the division processes of Escherichia coli. He observed that the cellular division was
inhibited and a filamentous growth was induced by electrolysis products that were afterward identified as platinum
compounds. Based on this observation, he and his colleagues investigated the antitumor activity of platinum
compounds in leukemia L1210- and Sarcoma 180-bearing
mice. The antitumor efficacy of cisplatin was then discovered (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 combined 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, malignant 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 resistance and severe side effects such as nephrotoxicity,
neurotoxicity, ototoxicity, and emetogenicity (Wang and
Lippard 2005; Pabla and Dong 2008). Among these factors,
nephrotoxicity has been reported as the major limiter in
cisplatin therapy (Arany and Safirstein 2003).

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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 nontoxic 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 (Rosenberg 1985; Bajorin et al. 1986; Gordon and
Gattone 1986; Kuhlmann et al. 1997; Schenellmann 2001).
The nephrotoxicity induced by cisplatin is dose-dependent
and therefore limits the increase of doses, compromising
the efficacy of the therapy (Hanigan and Devarajan 2003).
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 function 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 concentrations as well as reduced serum magnesium and potassium
levels are frequent in patients treated with cisplatin (Ries
and Klastersky 1986; Kintzel 2001; Han et al. 2009).
The high concentration of cisplatin in kidneys favors its
cellular uptake by passive diffusion (Gale et al. 1973;
Gately and Howell 1993), and this was once considered the
main process through which cisplatin entered and accumulated 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 associated 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 (Sharp 2003),
it was first associated with cisplatin uptake by non-renal
cells and only recently a study associated Ctr1 with cisplatin 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

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

Additionally, it was reported that the concomitant administration of imatinib, a cationic anticancer agent, with cisplatin prevented cisplatin-induced nephrotoxicity by
inhibiting the OCT2-mediated renal accumulation of cisplatin (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 nephrotoxicity was observed. The nephroprotective action of
cimetidine has been attributed to (i) a competitive inhibition 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). Another
strategy to blockade cisplatin uptake in renal cells is the
inhibition of Ctr1. In fact, it has been reported that CTR1deficient 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-intrastrand 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 eventually apoptosis (Jamieson and Lippard 1999; Wong and
Giandomenico 1999; Cohen and Lippard 2001; Wang and

Arch Toxicol (2012) 86:12331250

Lippard 2005). 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 formation (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 cisplatin 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-dividing; 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 have
been associated with the toxic effects of cisplatin on
healthy renal cells. Oxidative damage and inflammatory
events might explain the effects on other cellular constituents and have been associated with cisplatin-induced
nephrotoxicity (Cvitkovic 1998; Ali and Al Moundhri
2006; Yao et al. 2007; Pabla and Dong 2008). 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 Lippard 2005; 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 gammaglutamyl 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 macromolecules leading eventually to renal cell death (Ward
1975; Wainford et al. 2008). The interference in this biotransformation 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

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enzymes such as aminopeptidase N (AP-N), renal dipeptidase (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 then
reabsorbed into proximal tubular cells and finally metabolized by CS lyase to toxic reactive thiols resulting in
nephrotoxicity (Hanigan et al. 1994; Townsend and Hanigan 2002; Townsend et al. 2003; Zhang and Hanigan 2003).
The inhibition of CS lyase with amino oxyacetic acid was
protective in mice treated with 15 mg/kg cisplatin (Townsend and Hanigan 2002); however, opposing data have been
reported. According to a more recent study, AP-N, RDP,
and CS-lyase inhibition were non-protective against nephrotoxicity 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 drug
named BNP7787 (disodium 2,2-dithio-bis-ethane sulfonate, 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 formation of this inactive adduct with cisplatin, other mechanisms 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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Arch Toxicol (2012) 86:12331250

Fig. 1 Multiple pathways

involved in cisplatin-induced
nephrotoxicity

et al. 1996). More recently, several studies have demonstrated that both the mechanisms of cell death are induced
by cisplatin in vivo (Baek et al. 2003; Tsuruya et al. 2003;
Wang and Lippard 2005). 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 alterations resulting from therapeutic doses (Lieberthal et al.
1998; Ueda et al. 2000; Hanigan and Devarajan 2003;
Wang and Lippard 2005).
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 Reeves 2002). 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

123

cisplatin are summarized in Fig. 1, and the potential

cytoprotectors which interfere in these pathways are summarized in Table 1.

Intrinsic or mitochondrial apoptotic pathway

Mitochondrial injury in RTEC leads to the release of
apoptogenic factors, including cytochrome c, Smac/DIABLO, 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 activation, and the following sequence of events has been
described: formation of Apaf-1/cytochrome c apoptosome,
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 promote apoptosis through its serine protease activity, a
mechanism independent of caspases (Du et al. 2000; Cilenti et al. 2005). AIF is a protein that translocates to the
nucleus and promotes apoptosis without the activation of
caspases (Daugas et al. 2000a).

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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 OCT2expressing HEK293 cells and rat
kidneys

Tanihara et al. (2009)

Cimetidine*

Competitive inhibition of cisplatin

transport at OCT2 in vitro and in
rats
Inhibition of GGT in mice and rats

Katsuda et al. (2010)

Acivicin

Oxidative stress
(antioxidants)

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)

Vitamin C
Vitamin E

ROS scavenging and/or iron

chelating, decreasing oxidative
stress, and avoiding activation of
apoptosis in vitro and rodent
models

Tarladacalisir et al. (2008)

Ajith et al. (2009)

Vitamin A
Resveratrol

Dillioglugil et al. (2005)

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

Edaravone

Lynch et al. (2005)

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

Desferrioxamine (DFO)
Oxidative stress
(antioxidants
thiols)

Hanigan et al. (1994), Townsend

and Hanigan (2002)

Kadikoylu et al. (2004)

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 NO
and 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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Table 1 continued
Target/class

Apoptosis

Agents

Mechanisms of action
and experimental model

TNFR1-deficient mice

Avoid TNF activation of apoptosis

when ROS production is
increased in mice models

TNF-a-deficient mice
TNFR2-deficient mice
Trichostatin A (TSA)

Inflammation

Abnormal
hemodynamics

References

Tsuruya et al. (2003)

Ramesh and Reeves (2002)
Ramesh and Reeves (2003)
Dong et al. (2009)

Suberoylanilide hydroxamic
acid (SAHA)

Inhibition of p53 activation in

RTPC cell line
Inhibition of p53 activation and
reduction of Bax translocation
and cytochrome c release in
RTPC and HCT116 colon cancer
cells

Pituitary adenylate cyclaseactivating 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, downregulation of pro-apoptotic
proteins and reduction of
caspase-3 activity in rats

Rjiba-Touati et al. (2012)

Dong et al. (2009)

Rottlerin

Inhibition of PKC delta in mice

Pabla et al. (2011)

Salicylate
GM6001 and pentoxifylline

Anti-inflammatory action in rats

Inhibition of TNF-a with
antagonists and blunted the upregulation of cytokines such as
TGF-b, RANTES, MIP-2, MCP1, and IL-1b in mice

Li et al. (2002)
Ramesh and Reeves (2002)

Pituitary adenylate cyclaseactivating polypeptide

(PACAP38)

Reduction of TNF-a levels in HK2 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)

Captopril

Inhibition of renin-angiotensin
system, prostaglandins, and
endothelin-1 in rats
Blockage of angiotensin II
receptor in rats

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

Losartan

Saleh et al. (2009)

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

** Approved to be used in humans

Cisplatin can trigger the mitochondrial apoptotic pathway 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

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electrochemical potential, disturbance in calcium homeostasis, 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 complexes I, II, and III. Superoxide anions might originate

Arch Toxicol (2012) 86:12331250

hydroxyl radicals by partial reduction catalyzed by transition 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 the
enzymatic antioxidant defense system (superoxide dismutase, catalase, glutathione peroxidase, glutathione transferase, 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), and
its 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
c attached 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 activated by caspase-8 (extrinsic pathway) and acts on mitochondria promoting the apoptotic intrinsic pathway
(Enoksson et al. 2004; Campbell et al. 2008; El Sabbahy
and Vaidya 2011). Besides increasing mitochondrial ROS
generation, cisplatin activates the pro-apoptotic proteins
Bax and Bak, upstream mitochondrial injury. These proteins induce the permeabilization of the outer mitochondrial 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-deficient mice (Jiang et al. 2006; Wei et al. 2007a). Erythropoietin (EPO), a renal cytokine which regulates
hematopoiesis, has been shown to reduce apoptosis during
cisplatin nephrotoxicity by the up-regulation of anti-apoptotic proteins expression, down-regulation of pro-apoptotic
protein levels, and reduction of caspase-3 activity (RjibaTouati et al. 2012).
Besides the apoptosis dependent of caspases activation,
cisplatin can also trigger a mitochondrial mediated and
caspase-independent apoptotic pathway through the apoptosis-inducing factor (AIF), a protein located in the mitochondrial intermembrane space and present in renal

1239

epithelium. When the outer mitochondrial membrane is

damaged, AIF translocates to the nucleus inducing chromatin condensation and large-scale DNA fragmentation.
The anti-apoptotic Bcl-2 protein preserves the mitochondrial membrane integrity, preventing both the release of
cytochrome c and translocation of AIF to the nucleus
(Daugas et al. 2000b; Adams and Cory 2001). 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 mitochondrial membrane and damages anionic phospholipids,
causing release of pro-apoptotic factors such as cytochrome c and AIF. Inhibition of caspase-2 and inhibition of
AIF have been reported as protective against cisplatininduced renal damage (Daugas et al. 2000b; Enoksson et al.
2004; Seth et al. 2005; Jiang and Dong 2008; Servais et al.
2008).
The transcriptional factor p53 activates pro-apoptotic
genes encoding Bax, Bak, PUMA-a, PIDD, and the ERiPLA2 (Ca2?-independent phospholipase A2) and downregulates 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 Dong 2008; 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 nephroprotective 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-a and 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 biological 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; Schmalhausen et al. 2007; Santos 2012). 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, 20 lM), 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 demonstrated 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 carcinoma 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 healthy 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 chemotherapy. 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

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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 scavenging, formation of non-toxic adducts, reduction in cisplatin uptake by renal cells, and increase in the urinary
excretion of cisplatin (Santos 2012). The nephroprotective
effect of diethyldithiocarbamate (DDTC), GSH, D-methionine, amifostine, sodium thiosulphate (STS), N-acetylcysteine (NAC), and lipoic acid has been demonstrated
(Cvitkovic 1998; Wu et al. 2005; Bae et al. 2009); however, 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 the
antitumor efficacy (Conklin 2004). A recent in vitro study
demonstrated that tumor growth was statistically significantly increased when STS were administered simultaneously 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 prooxidant 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. Additionally, 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

Arch Toxicol (2012) 86:12331250

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 Kellie 2005; 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 turn
activates the effector caspase-3 (Strasser et al. 2000).
Cisplatin up-regulates the expression of the pro-inflammatory cytokine TNF-a, whose activities are mainly mediated 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
induce apoptosis and 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-adeficient mice (Ramesh and Reeves 2002), and in TNFR2deficient 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 proteins, 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
Devarajan 2003). 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

1241

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, inhibition
of 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
c release induced by cisplatin (Dong et al. 2009).
A death receptors pathway mediated by TRAIL (tumor
necrosis factor-related apoptosis-inducing ligand) is also
activated by cisplatin; this pathway selectively induces
apoptosis in several cancer cells but not in normal cells
(Wang and El-Deiry 2003). 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 localization, 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 cisplatin has been suggested as a strategy to overcome many
solid cancers resistance (Wu and Kakehi 2009). TRAIL signaling 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 endoplasmic reticulum (ER) apoptotic pathway in RTEC, resulting

123

1242

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 transcription 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 on
cytochrome c release; activation of caspase-9 then activates
the effector caspase-3. The ER stress pathway also involves
the activation of Ca2?-independent phospholipase A2 (ERiPLA-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 mitochondrial 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 and
Baliga 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 cisplatin-induced apoptosis and that pro-caspase 12 is activated 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 procaspase 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 multifunctional cytokine with important roles in inflammation
and immunity (Old 1988). The TNF-a/TNFR signaling has
been implicated in two different pathways during cisplatin
nephrotoxicity, namely (i) the extrinsic pathway via caspase-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 amplifying 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 Reeves 2002).
ROS activates the transcription factor NF-kB, which in turn

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Arch Toxicol (2012) 86:12331250

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 p38
MAPK 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 Reeves 2005).
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 activation of PKC delta by cisplatin, which in turn activates
MAPKs to induce tubular cell injury and death. Pharmacological inhibition of PKC delta with rottlerin and genetic
inhibition of PKC delta attenuate renal apoptosis and tissue
damage, preserving renal function during cisplatin treatment. 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 (Barnes 1997; 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 Reeves 2002).
The increase of interleukin 1b (IL-1b) has been associated 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

Arch Toxicol (2012) 86:12331250

(Lau 1999; Kaushal et al. 2001), but it was demonstrated in

mice (Faubel et al. 2004). Besides activating IL-1b, caspase-1 also activates other cytokines, such as IL-18 and IL6, 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. This
might be due to the participation of caspase-1 in the
apoptotic pathway. Besides participating in the inflammatory 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 antiinflammatory salicylate reduced cisplatin nephrotoxicity
without affecting the antitumor activity in rats implanted
with MTLn3 breast cancer cells (Li et al. 2002). Inhibition
of TNF-a with 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
Reeves 2002).
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. Additionally, 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 Safirstein 1985; Togna
et al. 2000). A pro-inflammatory state, with over-expression 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 augmented vascular tone. Increased responsiveness to vasoconstrictors as well as increased response to renal nerve
stimulation and decreased production of vasodilatory

1243

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 plateletactivating 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 hemodynamic
changes caused by cisplatin. The oxidative stress induced
by cisplatin has been implicated in the increase of these
renal vasoconstrictors. Captopril, an angiotensin-converting enzyme (ACE) inhibitor containing sulfhydryl (-SH)
group was protective against cisplatin-induced nephrotoxicity in rats. Its protection was associated with its antioxidant 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 cisplatininduced nephrotoxicity, and its mechanism of nephroprotection was attributed to the inhibition of renin-angiotensin
system as well as antioxidant action (Saleh et al. 2009).
Adenosine, a renal vasoconstrictor formed by the degradation 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 synthesis of PAF induced by cisplatin in kidneys results from
the disturbances in the oxidative metabolism and in calcium homeostasis caused by the drug. The increase in
cytosolic calcium promoted by cisplatin activates calciumdependent 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 mediated by a1-adrenoceptors, the major subtype of a-adrenoceptors 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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1244

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 (LaunayVacher 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-containing
chemotherapy (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 Gyllenhaal 2005).
The first attempt to reduce cisplatin nephrotoxicity was
the mannitol-induced diuresis. Mannitol promotes an
osmotic diuresis, increasing the rate of cisplatin elimination, 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 reported
similar 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 demonstrated that apart from the first cycle of treatment, hydration plus mannitol protection was not effective as
compared to hydration alone (Cornelison and Reed 1993).
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 cisplatinrelated nephrotoxicity (Santoso et al. 2003). The beneficial
effect of furosemide is also controversial (Cornelison and
Reed 1993). High doses of furosemide cause nephrotoxicity, 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).

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Arch Toxicol (2012) 86:12331250

Conclusion
Given the importance of cisplatin chemotherapy and the
unsatisfactory results of the conventional protection measures, many studies have focused on protective strategies
targeting the main molecular mechanisms of cisplatin toxicity, which have been delineated so far. Encouraging results
have been found in vitro and in animal models, but the lack of
data regarding the effects of the cytoprotectors on the antitumor activity of cisplatin allied with the lack 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 the
structure 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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