PHYTOTHERAPY RESEARCH

Phytother. Res. 23, 9991005 (2009)

Published online 12 January
PRUNUS 2009 FLESH
PERSICA in WileyEXTRACT
InterScienceAND CISPLATIN-INDUCED NEPHROTOXICITY 999
(www.interscience.wiley.com) DOI: 10.1002/ptr.2740

Extract of Prunus persica Flesh (PPFE)

Improves Chemotherapeutic Efcacy and
Protects against Nephrotoxicity in Cisplatin-
treated Mice

Chang Ki Lee1,2, Kwang-Kyun Park1,2*, Jae-Kwan Hwang3, Sang Kook Lee4 and
Won-Yoon Chung1,2*
1
Department of Oral Biology, Oral Cancer Research Institute, Oral Science Research Institute and Brain Korea 21 Project,
Yonsei University College of Dentistry, Seoul, Korea
2
Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, Korea
3
Department of Biotechnology, Yonsei University, Seoul, Korea
4
College of Pharmacy, Ewha Womans University, Seoul, Korea

Cisplatin (cis-diamminedichloroplatinum II) is one of the most effective chemotherapeutic agents used in the
treatment of a variety of human solid tumors. However, its clinical use is rather limited as a result of severe
nephrotoxicity. The principal objective of this study was to evaluate the protective effect of Prunus persica
esh extract (PPFE) against cisplatin-induced nephrotoxicity in animal models, and whether its use inuences
the therapeutic efcacy of cisplatin. The administration of PPFE alone signicantly inhibited the growth of
CT-26 colon carcinoma xenografted onto mice without adverse effects. The combination of PPFE and cisplatin
enhanced the inhibitory effect of cisplatin against tumor growth. In a xenograft model involving the repeated
administration of low-dose cisplatin for 15 days, and in an acute toxicity model involving a single administra-
tion of high-dose cisplatin over a 16 h period, the administration of PPFE in combination with and prior to the
cisplatin injection reversed the cisplatin-induced reduction in the kidney weight. PPFE blocked the increases
in the serum blood urea nitrogen and creatinine levels associated with the kidney damage. Moreover, the
administration of PPFE induced a signicant reduction in cisplatin-induced oxidative stress. These results
indicate that PPFE may promote the therapeutic efcacy of cisplatin therapy, while attenuating its inherent
nephrotoxicity. Copyright 2009 John Wiley & Sons, Ltd.

Keywords: Prunus persica esh; tumor growth; cisplatin-induced nephrotoxicity; oxidative stress.

chondrial vacuolization (Jones et al., 1985). Cisplatin-

INTRODUCTION
Cisplatin (cis-diamminedichloroplatinum II) is a plati-
num coordinated complex which is utilized widely
as an antineoplastic agent for the treatment of many
solid tumors, including cancers of the ovary, testis, lung,
bladder, head and neck, cervix, and endometrium
(Rosenberg, 1985). Despite its excellent chemother-
apeutic activity, the clinical use of cisplatin is limited
by its undesirable side effects, which include severe
nephrotoxicity and hepatotoxicity (Von Hoff et al., 1979;
Cersosimo, 1993). Cisplatin-induced nephrotoxicity in
rats is associated with increased renal vascular resist-
ance and morphological damage to the intracellular
organelles, including cellular necrosis, loss of microvilli,
changes in the number and size of lysosomes, and mito-
* Correspondence to: Dr Won-Yoon Chung, Department of Oral Biology,
Yonsei University College of Dentistry, 134 Shinchon-Dong, Seodaemoon-
Ku, Seoul 120-752, Korea.
E-mail: wychung@yuhs.ac
Dr Kwang-Kyun Park, Department of Oral Biology, Yonsei University
College of Dentistry, 134 Shinchon-Dong, Seodaemoon-Ku, Seoul 120-
752, Korea.
E-mail: biochelab@yuhs.ac
Contract/grant sponsor: BioGreen 21 Program, Rural Development Ad-
ministration, Republic of Korea; contract/grant number: 20050401-034-
763, 20080401-034-071.
Copyright 2009 John Wiley & Sons, Ltd.
Copyright 2009 John Wiley & Sons, Ltd.
induced alterations in rat kidney functions also include
the inhibition of protein synthesis, the depletion of re-
duced glutathione (GSH), lipid peroxidation, mitochondrial
damage and changes in urine volume, body weight and
creatinine clearance (Kersten et al., 1998; Matsushima
et al., 1998).
Although the precise mechanism underlying this
cisplatin-induced nephrotoxicity remains poorly under-
stood, cisplatin is taken up preferentially and accumu-
lates in human kidney cells (Stewart et al., 1982),
resulting in an enhanced production of reactive oxygen
species (ROS) and a reduction in the levels of anti-
oxidant enzymes (Kim et al., 1997; Mora et al., 2003).
Therefore, antioxidant enzymes and compounds such
as superoxide dismutase, glutathione peroxidase, gluta-
thione and avonoids have been assessed for their po-
tential protection against cisplatin-induced nephrotoxicity
in rats (Husain et al., 1998; Behling et al., 2006). Moreover,
a recent study has demonstrated that supplementation
with antioxidant micronutrients, such as vitamin C,
vitamin E and selenium, can protect against cisplatin-
induced nephrotoxicity in cancer patients (Weijl et al.,
2004).
The consumption of fruits and vegetables is associ-
ated closely with a reduced risk of chronic diseases such
as cancer and cardiovascular disease. Several natural
Received
Phytother. Res. 26 May(2009)
23, 9991005 2008
RevisedDOI:
7 October 2008
10.1002/ptr
Accepted 16 October 2008
1000 C. K. LEE ET AL.
products have been used to protect against the toxicities
induced by certain drugs and carcinogenic xenobiotics.
It was demonstrated recently that the ethanol extract
of Prunus persica esh (PPFE) protects against the
hepatotoxicity induced by the repeated administration
of low-dose cisplatin, as well as the acute hepatotoxicity
induced by a single administration of high-dose cisplatin
in mice (Lee et al., 2008).
It is very important to nd nontoxic agents that can
be used for protection against chemotherapy-induced
nephrotoxicity because the kidneys are profoundly
involved in the maintenance of body homeostasis. The
principal objective of this study was to further assess
whether PPFE has the potential to function as a bene-
cial supplement augmenting the therapeutic efcacy
of cisplatin chemotherapy, and helping to maintain
patient health during cisplatin treatment. The inhibi-
tory effects of PPFE alone and in combination with
cisplatin on the growth of xenografted mouse colon
carcinoma cells were evaluated, as well as its protective
effects against cisplatin-induced nephrotoxicity in mice.
MATERIALS AND METHODS
Chemicals. Cisplatin, sodium dodecyl sulfate, 1,1,3,3-
tetramethoxypropane, sulfanilamide, sodium nitrite, thio-
barbituric acid (TBA), potassium chloride, acetic acid,
n-butanol and pyridine were purchased from Sigma-
Aldrich Chemical. Dulbeccos Modied Eagle Medium
(DMEM), fetal bovine serum (FBS) and phosphate-
buffered saline (PBS) were obtained from Gibco BRL.
All reagents used in this study were of analytical grade.
Preparation of PPFE. The fruits of P. persica L. Batsch
(peaches) were purchased at the Kyeonggi Dong-Boo
Fruit Agricultural Cooperative (Icheon, Korea), where
a voucher specimen (PE20060801) has been deposited.
The fruits were washed with tap water, and its pericarp
and seed were removed. The collected esh (100 g) was
then extracted three times in ve volumes (w/v) of 80%
ethanol for 48 h at room temperature. The extract was
ltered, concentrated in a rotary vacuum evaporator,
and freeze-dried. The dried extract (PPFE, 30.4 g) was
stored at 20 C until needed.
Animals. The ICR male mice (30 5 g, 5 weeks of age)
and BALB/c male mice (30 5 g, 5 weeks of age) were
purchased from Central Lab Animal Inc. (Seoul, Korea),
and were provided free access to a standard chow diet
(Daejong Inc., Seoul, Korea) and water ad libitum. All
the mice were allowed 1 week to acclimatize prior to
the experiments, and were maintained at 25 2 C, with
a relative humidity of 55 5% and a 12 h light-dark
cycle. The animal studies were conducted in accordance
with the rules and regulations established by the
Institutional Animal Ethics Committee of the Yonsei
University College of Dentistry.
In vivo xenograft model with low-dose cisplatin. The
inhibitory effect of PPFE on tumorigenicity, as well
as its protective effect against nephrotoxicity induced
by the repeated administration of low-dose cisplatin,
was evaluated by dividing the mice into the following
ve groups, each group containing eight mice: PBS-
Copyright 2009 John Wiley & Sons, Ltd.
treated group, CT-26 cell-inoculated group, CT-
26-inoculated group with cisplatin, CT-26-inoculated
group with PPFE, and CT-26-inoculated group with
cisplatin plus PPFE. The following procedure was used
to establish the CT-26 tumors in the BALB/c male mice.
CT-26 mouse colon cancer cells were cultured in
DMEM with 10% FBS, harvested using trypsin-EDTA,
and resuspended in PBS. The CT-26 cells (2 106 cells
in 0.1 mL PBS) were injected subcutaneously into the
right anks of the mice. Then 24 h later, the BALB/c
mice were dosed with PPFE [500 mg/kg body weight
(BW)] in PBS by oral gavage. Two hours after treat-
ment with PPFE, cisplatin (5 mg/kg BW) in PBS was
injected intraperitoneally. PPFE and cisplatin were
administered once daily for 15 days. The control group
received PBS instead of PPFE and/or cisplatin. On
day 15, the tumor size was measured using calipers and
the tumor volumes were calculated by the following
formula: (length width2)/2. The mice were killed
under anesthesia 16 h after the nal cisplatin injection,
and the individual body weights were measured. The
kidneys were excised immediately after the blood
had been collected from each mouse, weighed and
homogenized for subsequent experiments.
Induction of acute nephrotoxicity by high-dose cisplatin.
In order to assess the protective effect of PPFE against
high-dose cisplatin-induced acute nephrotoxicity, the
ICR mice were divided into the following three groups,
each containing eight mice: PBS-treated group, cisplatin-
treated group and the cisplatin plus PPFE-treated group.
The ICR mice were dosed orally with PPFE (500 mg/
kg BW) in PBS for 7 days. Cisplatin (45 mg/kg BW)
in PBS, at a dose reported to induce nephrotoxicity
in mice without lethality, was injected i.p. 3 h after
the nal PPFE treatment. The control group received
PBS instead of PPFE and/or cisplatin. Then 16 h later,
the mice were killed under anesthesia and the body
weight of each mouse was measured. The kidneys were
excised immediately after collecting blood from each
mouse, then weighed and homogenized for subsequent
experiments.
Determination of the serum biochemical parameters.
The blood samples were left to stand at room tempera-
ture for 1 h, and then centrifuged for 10 min at 300 g
to obtain the serum. The serum blood urea nitrogen
(BUN) and creatinine levels were measured as indicators
of kidney function. All biochemical assays were per-
formed spectrophotometrically, using commercially
available kits (Asan Pharmaceutical, Seoul, Korea).
Nitric oxide (NO) determination. It is quite difcult to
measure NO concentrations in biological specimens.
Thus, the serum nitrite and nitrate levels were estimated
as an index of NO production. The detection of the
serum nitrite and nitrate levels was based on the Griess
reaction (Cortas and Wakid, 1990). The total nitrite
was spectrophotometrically measured at a wavelength
of 540 nm after converting nitrate to nitrite. The nitrite
concentration was calculated using a standard curve for
sodium nitrite.
Preparation of the homogenates from the kidney tissues.
The kidney tissues were immediately perfused with
ice-cold saline (0.9% KCl) to remove the blood. The
Phytother. Res. 23, 9991005 (2009)
DOI: 10.1002/ptr
 PRUNUS PERSICA FLESH EXTRACT AND CISPLATIN-INDUCED NEPHROTOXICITY
tissues were cut into small pieces with scissors on ice,
then homogenized in 10 volumes of ice-cold 1.15% KCl.
The homogenate was centrifuged for 30 min at 800 g
at 4 C. Aliquots of the supernatant were collected and
stored at 80 C to measure the malondialdehyde
(MDA) levels.
Determination of lipid peroxidation. The MDA con-
tent in kidney tissues, as an index of the extent of lipid
peroxidation, was assessed in the form of thiobarbituric
acid reactive substances (TBARS), using the method
modied by Ohkawa et al. (1979). MDA reacts with
TBA to form a colored complex with a maximum
absorbance at 532 nm. The reaction mixture consisted
of 0.2 mL of 8.1% sodium dodecyl sulfate, 1.5 mL of
20% acetic acid (pH 3.5), 1.5 mL of 0.8% TBA, 0.2 mL
of the homogenate and 0.6 mL of distilled water. The
mixture was then incubated for 1 h at 95 C, cooled
for 5 min with tap water, mixed vigorously with 5 mL
of a n-butanolpyridine (151, v/v) mixture, and centri-
fuged for 10 min at 1200 g. The absorbance of the
organic layer (upper n-butanol phase) was measured
at 532 nm. 1,1,3,3-Tetramethoxypropane was used to
establish a standard curve, and the nal MDA concen-
tration was expressed as nmol MDA/mg protein. The
total protein concentration was determined using a BCA
protein assay kit (Pierce Biotechnology).
Statistical analysis. The results are expressed as the
mean SE. All analyses were conducted using the SPSS
statistical program. (version 10.0, SPSS Inc. Chicago,
IL, USA). The effect of treatment was determined by
analysing the data using one-way ANOVA repeated
measures followed by Dunnetts t-test. Values of p <
0.05 were considered signicant.
RESULTS
Antitumor activity of PPFE alone and
in combination with cisplatin
The effects of PPFE (500 mg/kg BW), low-dose cisplatin
(5 mg/kg BW) and PPFE together with low-dose cispla-
tin on tumorigenicity were rst assessed in order to
determine whether the administration of PPFE inuences
the antineoplastic capacity of cisplatin. In a xenograft
model in which murine colon carcinoma CT-26 cells
were inoculated into BALB/c mice, PPFE administered
orally and cisplatin administered i.p. for 15 days were
shown to inhibit the growth of the tumors by 48%
and 57%, respectively (Fig. 1). The mice receiving both
PPFE and cisplatin for 15 days evidenced a 68% reduc-
tion in tumor growth.
Protective activity of PPFE on cisplatin-induced
nephrotoxicity
The protective effect of PPFE against cisplatin-induced
nephrotoxicity was assessed by measuring the kidney
weight as a percentage of the total body weight (Fig. 2),
and the BUN and creatinine levels in the serum (Fig. 3).
Cisplatin administration induced signicant damage
to the renal functions in mice treated with low-dose
Copyright 2009 John Wiley & Sons, Ltd.
1001
Figure 1. Effect of PPFE on the growth of CT-26 colon carci-
noma cells inoculated into the BALB/c mice. CT-26 tumors were
established in BALB/c male mice (n = 8) by injecting the CT-26
cells (2 106 cells in 0.1 mL PBS) subcutaneously into the right
flanks of the mice on day 0. PPFE (500 mg/kg BW, p.o.) and/or
cisplatin (5 mg/kg BW, i.p.) were administered to the BALB/c
mice once daily for 15 days. The control group (n = 8) received
PBS instead of PPFE and cisplatin. On day 15, the tumor volumes
were calculated using the following formula: (length width2)/2.
* p < 0.005 versus CT-26 cell alone-treated group.
cisplatin (5 mg/kg BW) for 15 days in a xenograft model
and in mice treated with high-dose cisplatin (45 mg/kg
BW) for 16 h. This damage was characterized by a
reduction in the kidney weight and increases in serum
BUN and creatinine levels. Treatment with PPFE plus
low-dose cisplatin for 15 days signicantly blocked
the cisplatin-induced reduction in the kidney weight
and the cisplatin-induced increases in serum BUN and
creatinine levels. The mice treated with PPFE alone
evidenced no kidney dysfunction. In addition, 7 days
of oral PPFE administration prior to treatment with
high-dose cisplatin also noticeably mitigated the cisplatin-
induced nephrotoxicity.
Inhibitory activity of PPFE on cisplatin-induced
oxidative stress
The serum nitrite level as an indicator of NO production
and the tissue MDA level as a measure of lipid peroxida-
tion were both signicantly higher in the mice treated
with low-dose cisplatin for 15 days in the xenograft
model and in the mice treated with high-dose cisplatin
over a 16 h period. The cisplatin-mediated increases
in serum nitric oxide (Fig. 4) and tissue MDA levels
(Fig. 5) were prevented by treatment with PPFE plus
cisplatin as well as by pretreatment with PPFE prior
to the induction of acute cisplatin-mediated toxicity.
Treatment with PPFE alone did not affect serum nitric
oxide and tissue MDA levels.
DISCUSSION
The majority of anticancer agents cause toxicity in vari-
ous organs via a disruption of the oxidant/antioxidant
balance (Fadillioglu and Erdogan, 2003). Cisplatin is one
Phytother. Res. 23, 9991005 (2009)
DOI: 10.1002/ptr
1002 C. K. LEE ET AL.

Figure 2. Effect of PPFE on the kidney weight in the mice with cisplatin-induced nephrotoxicity. The kidney weight, as a percentage
of the total body weight, was measured in the mice (n = 8) treated with PPFE and/or low-dose cisplatin (5 mg/kg BW) for 15 days in
a xenograft model (A) and in mice (n = 8) treated with high-dose (45 mg/kg BW) for 16 h after the oral administration of PPFE or no
treatment for 7 days (B). (A) # p < 0.01 versus CT-26 cell alone-treated group, * p < 0.05 versus CT-26 cells plus cisplatin-treated group;
(B) # p < 0.005 versus control group, * p < 0.01 versus cisplatin-treated group.

Figure 3. Effect of PPFE on the serum BUN and creatinine levels in the mice with cisplatin-induced nephrotoxicity. The serum BUN
and creatinine levels were measured using commercially available kits, in the mice (n = 8) treated with PPFE and/or low-dose
cisplatin (5 mg/kg BW) for 15 days in a xenograft model (A) and in the mice (n = 8) treated with high-dose (45 mg/kg BW) for 16 h
following the oral administration of PPFE extract or no treatment for 7 days (B). (A) # p < 0.005 versus CT-26 cell alone-treated group,
* p < 0.05 versus CT-26 cells plus cisplatin-treated group; (B) # p < 0.001 versus control group, * p < 0.005 versus cisplatin-treated
group.

of the most active cytotoxic agents in the treatment of
cancer, and its therapeutic activity is dose-dependent.
However, its use is limited principally by its nephro-
toxicity (Cvitkovic, 1998). Cisplatin induces mitochondrial
dysfunctions, particularly via the inhibition of the electron
transfer system, resulting in the enhanced production
of superoxide anions, hydrogen peroxide and hydroxyl
Copyright 2009 John Wiley & Sons, Ltd.
radicals (Baliga et al., 1999; Baek et al., 2003). There is
evidence to suggest that cisplatin-induced renal damage
is closely associated with increases in lipid peroxidation
and glutathione depletion due to these reactive oxygen
species (ROS), and a reduction in the levels of antioxi-
dant enzymes (Sadzuka et al., 1992; Husain et al., 1998;
Ajith et al., 2007). Therefore, antioxidants have been
Phytother. Res. 23, 9991005 (2009)
DOI: 10.1002/ptr
 PRUNUS PERSICA FLESH EXTRACT AND CISPLATIN-INDUCED NEPHROTOXICITY 1003

Figure 4. Effect of PPFE on the serum NO levels in mice with cisplatin-induced nephrotoxicity. The serum nitrite levels, as an indicator
of NO production, were measured using Griess reagent, in the mice (n = 8) treated with PPFE extract and/or low-dose cisplatin
(5 mg/kg BW) for 15 days in a xenograft model (A) and in mice (n = 8) treated with high-dose (45 mg/kg BW) for 16 h after the
oral administration of PPFE or no treatment for 7 days (B). (A) # p < 0.001 versus CT-26 cell alone-treated group, * p < 0.005 versus
CT-26 cells plus cisplatin-treated group; (B) # p < 0.001 versus control group, * p < 0.05 versus cisplatin-treated group.

Figure 5. Effect of PPFE on the lipid peroxidation in the kidney tissues of mice with cisplatin-induced nephrotoxicity. The MDA levels
in the tissue were measured in the mice (n = 8) treated with PPFE and/or low-dose cisplatin (5 mg/kg BW) for 15 days in a xenograft
model (A) and in mice (n = 8) treated with high-dose (45 mg/kg BW) for 16 h following the oral administration of PPFE or no treatment
for 7 days (B). Kidney tissues were immediately perfused with ice-cold saline (0.9% KCl) to remove the blood. The tissues were
cut into small pieces on ice and homogenized in 10 volumes of ice-cold 1.15% KCl. The homogenate was centrifuged for 30 min
at 800 g at 4 C. Aliquots of the supernatant were collected. The MDA was reacted with TBA, and absorbance was measured at
532 nm. (A) # p < 0.005 versus CT-26 cell alone-treated group, * p < 0.05 versus CT-26 cells plus cisplatin-treated group; (B) # p < 0.001
versus control group, * p < 0.005 versus cisplatin-treated group.

administered prior to cisplatin treatment in order to
protect against nephrotoxicity (Husain et al., 1998).
Recent studies have reported that supplementation with
dietary antioxidants, including selenium as an essential
trace element (Fujieda et al., 2006), vitamin C (Greggi
Antunes et al., 2000; De Martinis and Bianchi, 2001),
vitamin E (Naziroglu et al., 2004), capsaicin from hot red
peppers (Shimeda et al., 2005) and caffeic acid phenethyl
ester from honeybee propolis (Iraz et al., 2006), can
attenuate cisplatin-induced nephrotoxicity. In addition,
it has been suggested that some foods, including black
grapes and Brassica rapa, may exert a signicant nephro-
protective effect (Cojocel and Thomson, 2004; Kim et al.,
2006).
The current study was designed to estimate the pro-
tective potential of PPFE, which contains a variety of
antioxidants, against cisplatin-induced nephrotoxicity
without any loss of chemotherapeutic efcacy in animal
models. This is, to the best of our knowledge, the rst
report concerning the inhibitory activities of PPFE
Copyright 2009 John Wiley & Sons, Ltd.
against tumorigenicity and cisplatin-induced nephrotoxi-
city in animal models.
The study assessed the effects of PPFE on the tumori-
genicity and therapeutic efcacy of cisplatin in CT-26
cell-inoculated BALB/c mice. Interestingly, the admin-
istration of PPFE alone resulted in a signicant inhibi-
tion against the growth of tumors without the attendant
adverse effects. The combination of PPFE and cisplatin
improved the inhibitory effects of cisplatin on tumor
growth.
The results showed that the single administration of
high-dose cisplatin (45 mg/kg BW) over a 16 h period
in the acute toxicity model, as well as the repeated
administration of low-dose cisplatin (5 mg/kg BW)
for 15 days in a xenograft model, caused signicant
renal dysfunction. Cisplatin-induced kidney damage
was characterized by a reduction in kidney weight as a
percentage of the total body weight, and increases in
the serum creatinine and BUN levels. The repeated
oral administration of PPFE in combination with and
Phytother. Res. 23, 9991005 (2009)
DOI: 10.1002/ptr
1004 C. K. LEE ET AL.
prior to the cisplatin injection repaired these functional
indices in the kidney to control levels.
The effect of PPFE on cisplatin-induced oxidative
stress was also evaluated by determining the levels
of serum nitric oxide and the lipid peroxidation in the
kidney tissues. The data demonstrated that the serum
nitric oxide level increased signicantly in mice con-
secutively administered with low-dose cisplatin for 15
days and in mice administered with a single high-dose
cisplatin over a 16 h period. In addition, a marked
increase in renal tissue MDA level was noted, con-
sidered to be a reliable marker of lipid peroxidation
by ROS in all mice given cisplatin treatment. It was
reported that cisplatin treatment induces a signicant
increase in the activity of the calcium-independent
nitric oxide synthase (NOS) in the rat kidney and liver,
thereby resulting in an increase in NO formation
(Srivastava et al., 1996). Peroxynitrite, which is gener-
ated by the reaction between nitric oxide and superoxide
anion, oxidizes biomolecules such as DNA, proteins
and lipids, and has the potential to impair the adhesion
properties of renal tubular cells (Wangsiripaisan et al.,
1999). In this study, the repeated oral administration
of PPFE in combination with and prior to cisplatin
treatment prevented the cisplatin-mediated increases
in serum nitric oxide and tissue MDA levels.
The impact of antioxidant supplementation on chemo-
therapeutic efcacy remains a matter of some contro-
versy. Some have argued that antioxidants scavenge the
ROS integral to the activity of certain chemotherapy
drugs, thereby diminishing therapeutic efcacy. A re-
cent study has demonstrated that dietary curcumin with
antioxidative and chemopreventive activities reduced
REFERENCES
Ajith TA, Usha S, Nivitha V. 2007. Ascorbic acid and alpha-
tocopherol protect anticancer drug cisplatin induced
nephrotoxicity in mice: a comparative study. Clin Chim Acta
375: 8286.
Baek SM, Kwon CH, Kim JH, Woo JS, Jung JS, Kim YK. 2003.
Differential roles of hydrogen peroxide and hydroxyl radi-
cal in cisplatin-induced cell death in renal proximal tubular
epithelial cells. J Lab Clin Med 142: 178 186.
Baliga R, Ueda N, Walker PD, Shah SV. 1999. Oxidant mecha-
nisms in toxic acute renal failure. Drug Metab Rev 31: 971
997.
Behling EB, Sendo MC, Francescato HD, Antunes LM, Costa
RS, Bianchi Mde L. 2006. Comparative study of multiple
dosage of quercetin against cisplatin-induced nephrotoxicity
and oxidative stress in rat kidneys. Pharmacol Rep 58: 526
532.
Cersosimo RJ. 1993. Hepatotoxicity associated with cisplatin
chemotherapy. Ann Pharmacother 27: 438441.
Chirino YI, Hernandez-Pando R, Pedraza-Chaveri J. 2004. Peroxy-
nitrite decomposition catalyst ameliorates renal damage and
protein nitration in cisplatin-induced nephrotoxicity in rats.
BMC Pharmacol 4: 2029.
Cojocel C, Thomson MS. 2004. Protective effect of resveratrol
against 6-hydroxydopamine-induced impairment of renal
p-aminohippurate transport. Arch Toxicol 78: 525532.
Cortas NK, Wakid NW. 1990. Determination of inorganic nitrate
in serum and urine by a kinetic cadmium-reduction method.
Clin Chem 36: 14401443.
Cvitkovic E. 1998. Cumulative toxicities from cisplatin therapy
and current cytoprotective measures. Cancer Treat Rev 24:
265281.
De Martinis BS, Bianchi MD. 2001. Effect of vitamin C supple-
mentation against cisplatin-induced toxicity and oxidative
DNA damage in rats. Pharmacol Res 44: 317320.
Copyright 2009 John Wiley & Sons, Ltd.
camptothecin-, mechlorethamine- and doxorubicin-
induced apoptosis in human breast cancer cells through
inhibition of ROS generation and signicantly inhib-
ited cyclophosphamide-induced tumor regression in an
in vivo model of human breast cancer (Somasundaram
et al., 2002). By way of contrast, several studies have
suggested that antioxidant supplementation resulted
in increased survival times and tumor responses, as
well as lower toxicity compared with the controls
(Sarkar and Li, 2006). In this study, PPFE was shown
to promote the therapeutic efcacy of cisplatin and to
reduce its toxicity via a blockage of oxidative stress.
The various antioxidants in PPFE, including kaempferol,
quercetin and ascorbic acid, may contribute to its anti-
tumor activity and nephroprotective effects. Further
studies to determine the active compounds and to
control the quality of the extracts are required for clini-
cal application.
In conclusion, the oral administration of PPFE in-
hibited tumor growth and increased the chemother-
apeutic efcacy of cisplatin in a CT-26 colon cancer
xenograft model. PPFE attenuated cisplatin-induced
nephrotoxicity and oxidative stress in animal models.
These results indicate that PPFE supplementation may
be one effective method to increase the therapeutic
efcacy of cisplatin and ameliorate its side effects in
cancer patients.
Acknowledgements
This work was supported by grants (20050401-034-763 and 20080401-
034-071) from BioGreen 21 Program, Rural Development Adminis-
tration, Republic of Korea.
Fadillioglu E, Erdogan H. 2003. Effects of erdosteine treatment
against doxorubicin-induced toxicity through erythrocyte
and plasma oxidant/antioxidant status in rats. Pharmacol
Res 47: 317322.
Fujieda M, Naruse K, Hamauzu T et al. 2006. Effect of selenium
on cisplatin-induced nephrotoxicity in rats. Nephron Exp
Nephrol 104: e112e122.
Greggi Antunes LM, Darin JD, Bianchi MD. 2000. Protective
effects of vitamin C against cisplatin-induced nephrotoxicity
and lipid peroxidation in adult rats: a dose-dependent study.
Pharmacol Res 41: 405411.
Husain K, Morris C, Whitworth C, Trammell GL, Rybak LP,
Somani SM. 1998. Protection by ebselen against cisplatin-
induced nephrotoxicity: antioxidant system. Mol Cell Biochem
178: 127133.
Iraz M, Ozerol E, Gulec M et al. 2006. Protective effect of caffeic
acid phenethyl ester (CAPE) administration on cisplatin-
induced oxidative damage to liver in rat. Cell Biochem Funct
24: 357361.
Jones TW, Chopra S, Kaufman JS, Flamenbaum W, Trump BF.
1985. Cis-diamminedichloroplatinum (II)-induced acute renal
failure in the rat. Lab Invest 52: 363374.
Kersten L, Braunlich H, Keppler BK, Gliesing C, Wendelin M,
Westphal J. 1998. Comparative nephrotoxicity of some
antitumor-active platinum and ruthenium complexes in rats.
J Appl Toxicol 18: 93 101.
Kim YH, Kim YW, Oh YJ et al. 2006. Protective effect of the
ethanol extract of the roots of Brassica rapa on cisplatin-
induced nephrotoxicity in LLC-PD1 cells and rats. Biol Pharm
Bull 29: 24362441.
Kim YK, Jung JS, Lee SH, Kim YW. 1997. Effects of antioxidants
and Ca2+ in cisplatin-induced cell injury in rabbit renal cortical
slices. Toxicol Appl Pharmacol 146: 261269.
Lee CK, Park KK, Hwang JK, Lee SK, Chung WY. 2008. The extract
Phytother. Res. 23, 9991005 (2009)
DOI: 10.1002/ptr
 PRUNUS PERSICA FLESH EXTRACT AND CISPLATIN-INDUCED NEPHROTOXICITY
of Prunus persica flesh (PPFE) attenuates chemotherapy-
induced hepatotoxicity in mice. Phytother Res 22: 223227.
Matsushima H, Yonemura K, Ohishi K, Hishida A. 1998. The
role of oxygen free radicals in cisplatin-induced acute renal
failure in rats. J Lab Clin Med 131: 518526.
Mora Lde O, Antunes LM, Francescato HD, Bianchi Mde L. 2003.
The effects of oral glutamine on cisplatin-induced nephro-
toxicity in rats. Pharmacol Res 47: 517522.
Naziroglu M, Karaoglu A, Aksoy AO. 2004. Selenium and high
dose vitamin E administration protects cisplatin-induced
oxidative damage to renal, liver and lens tissues in rats.
Toxicology 195: 221230.
Ohkawa N, Ohishi N, Yagi K. 1979. Assay of lipid peroxides in
animal tissues by thiobarbituric acid reaction. Anal Biochem
95: 351358.
Rosenberg B. 1985. Fundamental studies with cisplatin. Cancer
55: 230323l6.
Sadzuka Y, Shoji T, Takino Y. 1992. Effect of cisplatin on the
activities of enzymes which protect against lipid peroxidation.
Biochem Pharmacol 43: 18721875.
Sarkar FH, Li Y. 2006. Using chemopreventive agents to enhance
the efficacy of cancer therapy. Cancer Res 66: 33473350.
Shimeda Y, Hirotani Y, Akimoto Y et al. 2005. Protective effects
Copyright 2009 John Wiley & Sons, Ltd.
1005
of capsaicin against cisplatin-induced nephrotoxicity in rats.
Biol Pharm Bull 28: 16351638.
Somasundaram S, Edmund NA, Moore DT, Small GW, Shi YY,
Orlowski RZ. 2002. Dietary curcumin inhibits chemotherapy-
induced apoptosis in models of human breast cancer.
Cancer Res 62: 38683875.
Srivastava RC, Farookh A, Ahmad N, Misra M, Hasan SK, Husain
MM. 1996. Evidence for the involvement of nitric oxide in
cisplatin-induced toxicity in rats. Biometals 9: 139142.
Stewart DJ, Benjamin RS, Luna M. 1982. Human tissue distribu-
tion of platinum after cis-diaminedi-chloroplatinum. Cancer
Chemother Pharmacol 10: 5154.
Von Hoff DD, Schilsky R, Reichert CM et al. 1979. Toxic effects
of cis-dichlorodiammineplatinum(II) in man. Cancer Treat
Rep 63: 15271531.
Wangsiripaisan A, Gengaro PE, Nemenoff RA, Ling H, Edelstein CL,
Schrier RW. 1999. Effect of nitric oxide donors on renal tubu-
lar epithelial cell-matrix adhesion. Kidney Int 55: 22812288.
Weijl NI, Elsendoorn TJ, Lentjes EG et al. 2004. Supplementation
with antioxidant micronutrients and chemotherapy-induced
toxicity in cancer patients treated with cisplatin-based
chemotherapy: a randomized, double-blind, placebo-controlled
study. Eur J Cancer 40: 17131723.
Phytother. Res. 23, 9991005 (2009)
DOI: 10.1002/ptr