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Year : 2018  |  Volume : 14  |  Issue : 3  |  Page : 671-678

Therapeutic effects of oleuropein on cisplatin-induced pancreas injury in rats

Department of Biology, Faculty of Science, Ataturk University, Erzurum, Turkey

Date of Web Publication12-Jun-2018

Correspondence Address:
Dr. Kubra Koc
Department of Biology, Faculty of Science, Ataturk University, Erzurum
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_1040_16

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 > Abstract 

Aims: Cisplatin (CIS) is an influential chemotherapeutic agent in the treatment of several types of malignant solid tumors, but its clinical use is related with ototoxicity. Oleuropein (OLE) is a natural antioxidant and scavenging free radicals. Here, we first explore the efficacy of OLE in pancreas against to the toxicity of CIS and also analyses its mechanism.
Materials and Methods: Fifty-six Sprague-Dawley rats were equally divided into eight groups, including, control group which received 7 mg/kg/day CIS intraperitoneally (i.p.) for 24 h, groups treated with doses of 50, 100, and 200 mg/kg OLE i.p. for 3 days, and groups which received same dose of CIS with three doses of OLE. After the treatments, animals were sacrificed. The oxidative DNA damage (8-hydroxy-2'-deoxyguanosine [8-OHdG]), total oxidative stress (TOS), total antioxidant status (TAS), and malondialdehyde (MDA) levels were evaluated in the pancreas. The histopathology of the pancreas was examined using three different staining methods: hematoxylin-eosin, periodic acid–Schiff, and alcian blue. Serum was provided to assess pancreatic function the lipase and amylase values.
Results: The results showed that CIS significantly increased the level of TOS, MDA, and 8-OHdG in tissue as compared to the control group. Moreover, severe tissue damages were detected in the pancreas. Whereas, OLE at high dose significantly decreased the formations of 8-OHdG, the level of MDA, and increased levels of TAS in tissue samples. In the CIS group, the levels of amylase and lipase increased compared with the control group. However, there were statistically significant differences among the CIS group and the CIS + OLE groups in the values of both amylase and lipase. In addition, histopathological findings observed in CIS group in the pancreatic tissue alleviated in CIS + OLE groups.
Conclusion: We hope that the results of this study will provide an impetus for future investigations of novel treatment strategies for OLE in pancreas due to CIS.

Keywords: Antioxidant activity, cisplatin, histopathology, oleuropein, oxidative DNA damage, pancreas

How to cite this article:
Bakir M, Geyikoglu F, Koc K, Cerig S. Therapeutic effects of oleuropein on cisplatin-induced pancreas injury in rats. J Can Res Ther 2018;14:671-8

How to cite this URL:
Bakir M, Geyikoglu F, Koc K, Cerig S. Therapeutic effects of oleuropein on cisplatin-induced pancreas injury in rats. J Can Res Ther [serial online] 2018 [cited 2022 Nov 30];14:671-8. Available from: https://www.cancerjournal.net/text.asp?2018/14/3/671/209957

 > Introduction Top

Cisplatin (CIS) is one of the important chemotherapeutic drugs having a high level and a broad spectrum of antitumor activity commonly used to treat head, neck, lung, testis, ovary, and breast cancers.[1] On the other hand, several side effects have been shown, such as nephrotoxicity, infertility, ototoxicity, and neurotoxicity.[2],[3]

Olive leaves contain a wide variety of phenolic compounds belonging to phenolic acids, phenolic alcohols, flavonoids, and secoiridoids.[4] Recently, the useful effects of olive oil have been ascribed to the content of polyphenols, which exert antioxidant, anti-inflammatory, anti-cancer, antimicrobial, antiviral, anti-atherogenic, hypoglycemic, and neuroprotective effects.[5],[6] Since the uncontrolled production of free radicals has been hypothesized as contributing to the pathogenesis of diseases, such as coronary heart disease and cancer.[7] The ability of polyphenols to scavenge free radicals could be important in explaining how polyphenols may play a role in preventing these diseases.[8] Oleuropein (OLE) is the most prevalent phenolic component in olive leaves, seed, pulp, and peel of unripe olives (up to 14% of the dry weight).[6] OLE has documented useful pharmacological effects, such as cardioprotective effect, antioxidant, anti-inflammatory, anti-cancer, anti-atherogenic activity, anti-microbial properties, and neuroprotective effect.[9],[10],[11],[12],[13],[14],[15]

The main aims of this study were (i) to determine the effects of OLE on CIS-induced pancreas toxicity in the rat. In this regard, histopathological and biochemical evaluations of the pancreas tissue were performed. (ii) To evaluate the genotoxicity of CIS and to investigate the antigenotoxic potential of OLE against CIS-induced oxidative DNA damage in rat pancreas.

 > Materials and Methods Top

This study was carried out in the Experimental Animals Research Centre of Atatürk University. The experiments were approved by the Local Ethics Committee for Experiments on Animals of Atatürk University (protocol number: B.30.2.ATA.0.23.85-11). All experiments were carried out in accordance with the Guide for the Care and Use of Laboratory Animals published by the Institute of Laboratory Animal Resources Commission on Life Sciences.[16]


Fifty-six adult male Spraque-Dawley rats (weighing 200–250 g) obtained from Medical Experimental Application and Research Center, Atatürk University were used. Animals were housed inside polycarbonate cages in an air-conditioned room (22 ± 2°C) with 12 h light-dark cycle. Standard rat feed and water were provided ad libitum. The rats were allowed to acclimatize to the laboratory environment for 7 days before the start of the experiment.

Experimental design

The fifty-six rats were randomly assigned into eight groups (seven rats each). In Group 1 (control), rats received 1 mL of distillated water as vehicle. In Group 2 (CIS), rats received 7 mg CIS/kg body weight, diluted in distillated water (1 mL). In Groups 3, 4, and 5 (OLE), rats received 1 mL of OLE solution (50, 100, and 200 mg/kg/day). In Groups 6, 7, and 8 (CIS + OLE), the animals received 1 mL of preparations of OLE following CIS administration. The injections of CIS were given using a single dose, through intraperitoneal (i.p.) route for 24 h. The OLE and CIS + OLE groups received i.p. injections with a single daily dose for a total period of 3 days. On day 4 after injections, the rats were anesthetized with isoflurane. Blood samples were collected for biochemical studies. At the end of this application, rats were immediately sacrificed by cervical decapitation. After cervical dislocation under anesthesia, the pancreas specimens were gathered for further analyses.

Preparation of pancreas tissue homogenates

Fresh pancreas tissues were rinsed with ice-cold saline and immediately stored at −80°C. The tissue specimens were weighed and then homogenized in a 50-mM phosphate buffered saline at pH 7.0. Homogenized pancreas tissues were then centrifuged at 10.000 rpm at 4°C over 15 min to isolate the supernatant for subsequent analysis.

Amylase and lipase measurement for pancreatic function assessment

Blood samples were taken immediately before rats were killed for measurement amylase and lipase values. Serum amylase and lipase levels were determined spectrophotometrically using an automated analyzer (Olympus AU 600, Diamond Diagnostic, Holliston, USA). All chemicals were obtained from Sigma (Sigma, St Louis MO, USA).

Determination of 8-hydroxy-2'-deoxyguanosine level

8-hydroxy-2'-deoxyguanosine (8-OHdG) assay kits were purchased from Cayman Chemical for determining 8-OHdG levels in the pancreas samples. Since it is a competitive assay that can be used for the quantification of 8-OHdG in homogenates and recognizes both free 8-OHdG and DNA-incorporated 8-OHdG, many types of research are being performed to use this protocol. This assay depends on the competition between 8-OHdG and 8-OHdG-acetylcholinesterase conjugate for a limited amount of 8-OHdG monoclonal antibody.[17] All procedures were carried out in accordance with the provider manual.

Determination of lipid peroxidation

Quantitative measurement of malondialdehyde (MDA) was performed following the thiobarbituric acid (TBA) test.[18] Pancreas homogenate (2 mL) was mixed with 1 mL of 20% (v/v) TCA and 1 mL of 0.67% (v/v) TBA and then boiled for 10 min. After cooling, the mixture was filtered through Whatman filter paper and reading of the filtrate was done at 530 nm. The amount of MDA formed was quantitated with TBA and used as an index of lipid peroxidation. The results were expressed as nanomoles of MDA per milligram of protein using molar extinction coefficient (1.56 × 105 cm 2/mmol).

Measurement of total antioxidant capacity and total oxidant status

Total antioxidant status (TAS) and total oxidative stress (TOS) levels were measured using a colorimetric method that was introduced by Erel.[19] The results were expressed as millimolar Trolox equivalent per liter (mmol Trolox equivalent/g protein) for TAS and micromolar hydrogen peroxide equivalent per liter (μmol H2O2 equivalent/g protein) for TOS. The ratio of TOS to TAS was accepted as the OSI. For the calculation, the resulting unit of TAS was converted to μmol/g protein, and the OSI value was calculated according to the following formula.[20]

OSI (arbitrary unit) = (TOS [μmol H2O2 equivalent/g protein]/TAS [μmol Trolox equivalent/g protein]) × 100.

Histopathological examination

The pancreas tissues of rats were fixed in buffered 10% formalin solution for 24 h and embedded in a paraffin wax. Tissues were then sectioned at 5-μm, stained with hematoxylin-eosin (H and E), periodic acid–Schiff (PAS) and alcian blue methods. A semiquantitative evaluation of pancreas tissue was accomplished by scoring the degree of severity according to the formerly published criteria.[21] For each pancreas section, whole slide was examined for dilated acini, fibrosis, focal necrosis of  Islets of Langerhans More Details, degeneration of Langerhans, infiltration, and congestion were observed under bright field using an Olympus BX60 microscope equipped with a digital CCD. In addition, high-resolution pictures (×200) of samples were taken under the same microscope. The pancreas damage was scored with a maximum score of 18. The maximum score for the other pathological findings was 3.

Statistical analysis

For statistical analysis, we used SPSS for Windows 13.0 (SPSS Inc., Chicago, IL, USA). The experimental data were analyzed using one-way analysis of variance followed by Tukey post hoc test for multiple comparisons. Results are presented as mean ± standard error and values of P < 0.05 were considered statistically significant.

 > Results Top

8-OHdG was used as a marker of oxidative DNA damage. As presented in [Table 1], in control group and OLE treated groups, the levels of 8-OHdG was similar. On the other hand, the levels of 8-OHdG in rat pancreas were markedly increased after CIS administration. A dose-dependent a decrease in 8-OHdG was observed in the CIS + OLE groups and levels of 8-OH-dG increased by CIS were normalized in the pancreas by a dose of 200 mg/kg OLE.
Table 1: The effects of OLE on pancreas 8-OHdG levels after treated with cisplatin

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[Table 2] shows the effect of CIS administration on TAS, TOS, and MDA levels in pancreatic tissues of rats. TOS and MDA levels in the pancreases of CIS group were higher than those of the control group while TAS level was significantly lower than those of the control group (P < 0.05). In only OLE treated groups, the levels of biochemical parameters were similar compared with control group. The supplementation of rats with OLE resulted in a reversal of biochemical parameters when compared with the CIS groups. Moreover, these effects were associated with the increasing doses of OLE therapy.
Table 2: The effects of OLE on pancreas MDA, TAS and TOS levels after treated with cisplatin

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Pancreatic amylase and lipase values were found to be significantly increased in the CIS group compared with the control group (P < 0.05). Pancreatic amylase and lipase values in the CIS + OLE groups were found to be significantly decreased compared to the CIS group (P < 0.05). In addition, i.p. injection of OLE alone, the amylase and lipase levels were not changed [Table 3].
Table 3: The effects of OLE on pancreas serum amylase and lipase levels after treated with cisplatin

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In control group, the normal architecture of tissue in sections stained with H and E [Figure 1] and [Figure 2], PAS [Figure 3], alcian blue [Figure 4] are shown. In sections stained with H and E, CIS group showed significant pancreatic changes as compared with control group; dilated acini, fibrosis, infiltration, focal necrosis of islets of Langerhans, congestion, degeneration of Langerhans [Figure 1] and [Figure 2]. However, the treatment of OLE was able to reduce the pancreas damage. Moreover, this positive impact was notably correlated with increased OLE doses. In 50 and 100 mg/kg CIS + OLE groups, above mentioned pathological findings were alleviated. There were more congestion, infiltration, dilated acini, and fibrosis in 50 mg/kg CIS + OLE group than in 100 mg/kg CIS + OLE group. Moreover, in 200 mg/kg CIS + OLE group, pancreas tissue showed a normal structure and orderly arrangement and resembled those of control rats [Figure 2]. Histopathological scores of the groups are summarized in [Table 4]. Moreover, the analysis of histopathological data demonstrated significant differences between the groups (P < 0.05).
Figure 1: The pancreas histology in control and cisplatin groups rats; (a) Control group, Langerhans islet (l). (b-g) The pancreas degenerations in 7 mg/kg cisplatin group (b) Dilated acini (arrows) (c) Fibrosis (f) (d) Infiltration (i) (e) Focal necrosis of islets of Langerhans (arrow), (f) Congestion (c) and (g) Degeneration of islet cells (arrow) (H and E, ×200)

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Figure 2: The pancreas histology in cisplatin + oleuropein group rats; (a-c) cisplatin + 50 mg/kg oleuropein group, Infiltration (i), Congestion (c), Arrows: Dilated acini, Fibrosis (f) (d) cisplatin + 100 mg/kg oleuropein group, Dilated acini (arrows), (e) Congestion (c), Infiltration (arrow) and (f) cisplatin + 200 mg/kg oleuropein group (H and E, ×200)

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Figure 3: The pancreas histology in control, cisplatin, and cisplatin + oleuropein group rats, (a) Control group, (b) The decreased glycogen content in pancreas of cisplatin group compared with control group, (c and d) The increased glycogen content in pancreas of cisplatin + 50 mg/kg and cisplatin + 100 mg/kg oleuropein groups, (e) The glycogen content in pancreas of cisplatin + 200 mg/kg oleuropein group similar to control (PAS, ×200)

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Figure 4: (a) Control group, (b) cisplatin group and (c) cisplatin + 200 mg/kg oleuropein group, Ductal mucin (arrows), (Alcian Blue, ×200)

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Table 4: Histopathological scores of pancreas pathology in cerulein-induced AP

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PAS staining clearly revealed depletion of glycogen in CIS group compared with control group [Figure 3]a and [Figure 3]b. Treatment with OLE for 7 days revealed a dose-dependent increase of glycogen of pancreas [Figure 3]c and [Figure 3]d. In OLE 200 mg/kg group, pancreas glycogen content was similar with the control group [Figure 3]e. In sections stained with alcian blue method, there were not any change in mucin content of ductal walls in studied all groups [Figure 4].

 > Discussion Top

CIS is a chemotherapeutic agent that is widely used in cancer treatment. Numerous side effects have been detected. CIS has many side effects, including bone marrow toxicity, renal toxicity, gastrointestinal toxicity, peripheral neuropathy, and ototoxicity.[22] In this study, we established whether the pharmacological treatment with OLE provides a protective effect against CIS damage in the pancreas of rats. CIS chemotherapy is limited due to the development of myelosuppression and genotoxicity which may lead to secondary cancer.[23] Moreover, it has been revealed that significant dose-dependent increase in genotoxicity with respect to DNA damage as a result of CIS treatment.[24] As a cytotoxic agent, CIS interferes with DNA synthesis and causes DNA cross-linking that modulates cell cycle progression, thus ultimately inducing tumor cell apoptosis.[25]

8-OHdG is the most common marker of DNA oxidation produced by oxidation of DNA bases.[26] In CIS therapy, the 8-OHdG levels are elevated, therefore in previous studies, it has frequently been utilized as a reliable biomarker of oxidative stress-related DNA damage.[27] There was no scoring system for the report of the intensity of CIS-induced 8-OHdGs in the pancreas. For the first time, we here demonstrate that 7 mg/kg/day CIS administration induced significant DNA damages to pancreas cells. According to our results, 8-OHdG score is a good predictor for detecting the protective role of OLE against CIS-induced toxicity in rats. In this study, i.p. injection of CIS resulted in an apparent increase in 8-OHdG formations; however, OLE was observed to protect pancreas cells of rats from CIS-induced DNA damage. This study is the first to demonstrate a vital role of OLE in the suppression of 8-OHdG formations in pancreas cells.

It is established that the products of lipid peroxidation, especially the cytotoxic aldehydes like MDA, are important because they can also induce damage DNA and the highly active hydroxyl radicals can break the DNA threads creating (8-OHdG).[28] The previous studies showed that CIS-induced an excessive production of MDA.[29],[30],[31],[32],[33] In this study, CIS increased MDA (a secondary product of lipid peroxidation) and decreased antioxidant content in the pancreas homogenates. We detected that the application of OLE significantly ameliorates endogenous antioxidant activity in studied tissues by decreasing MDA. MDA level was lower in the 50 and 100 mg/kg OLE groups as compared to the CIS group. A significant inhibition of lipid peroxidation in pancreas cells was obtained in the presence of 200 mg/kg OLE (P < 0.05).

CIS can generate reactive oxygen species such as superoxide and hydroxyl radicals.[30],[33],[34] It has been reported that chemotherapy with CIS creates a reduce the plasma concentrations of various antioxidants.[35] This decrease can cause a failure of the antioxidant defence mechanisms against organ damage. Previous studies have shown that the administration of antioxidants can reduce the side effects associated with CIS.[36],[37],[38],[39],[40]

OLE derived from numerous plants, particularly from the olive tree, Olea europaea L. (Oleaceae), is a biophenol with many biological activities.[41] Some studies have shown that OLE possesses a wide range of pharmacologic and health-promoting properties including antiarrhythmic, immune-stimulant, cardioprotective, anti-inflammatory, and antioxidant, effects.[10],[42],[43] Many of these properties have been defined as resulting from the antioxidant feature of OLE.[44]

We investigated on pancreas the effects of TAS and TOS in relation to our pathological study. According to our findings, the measurements of TAS in biological tissues will allow to understand if the protective effect displayed by antioxidants reflect an improvement in endogenous antioxidant defenses and a reduction of chemotherapy risk. We established that OLE administration dose-dependently increased antioxidant capacity (50 and 100 mg/kg). Especially, 200 mg/kg OLE exhibited powerful antioxidant activity in pancreas against CIS exposure. According to our findings, OLE could protect tissue from harmful effects of CIS by increasing the level of reduced TAS. OLE increased the cells antioxidant capacity by stimulating the synthesis of antioxidant enzymes and helped maintain their activity during oxidative stress.

CIS has been widely and effectively used for chemotherapy against a number of tumor types; however, the drug induces a series of side effects in various organs.[45] It is reported that CIS may generate oxygen free radicals in the body. Moreover, the free radicals may cause changes in cell structure and function, thereby affecting tissue and organ function.[46] In this context, our results revealed that CIS treatment resulted in significant attenuation of pancreas dysfunction (decreased amylase and lipase levels). Similarly, the finding was reported after transcatheter arterial infusion with CIS for advanced hepatocellular carcinoma.[47] On the contrary, elevated levels of amylase and lipase in pancreas cells were normalized by OLE treatment in this study. At this point, we proposed that the antioxidant role of OLE could be a therapeutic agent for protection from CIS toxicity in enzyme-secreting cells, as well as in other cell types.

In this study, pathological changes in pancreas induced by CIS and the treatment of pancreas with OLE were used as a reference. Our histopathological findings in CIS-treated rats were dilated acini, fibrosis, focal necrosis of islets of Langerhans, degeneration of Langerhans, infiltration, congestion, and decreased glycogen. Pancreatic fibrosis is defined by the overgrowth and excess deposition of extracellular matrix components, including collagen.[48] Tissue collagen is investigated as a free radical-induced fibrosis marker, and as an effect of chemotherapy, it is increased substantially in all tissues.[49] Our histopathological scoring system indicates that 7 mg/kg/day CIS application remarkable increases collagen content and other pathological findings in the pancreas. Results of this study show that the 200 mg/kg dose of OLE, by its antioxidant properties, alleviates oxidative injury, and fibrosis-induced by CIS in the pancreas. Hence, this study might be the first report on the effect of OLE on pancreas fibrosis in an experimental model. Olive polyphenols have been claimed to play a significant protective role in cancer and other inflammation-related diseases. Both inflammatory and cancer cell models have demonstrated that olive leaf polyphenols are anti-inflammatory and protect against DNA damage initiated by free radicals.[50] Our study's results show that OLE decreases CIS-induced lymphocyte infiltration in the pancreas. From the pathological score, we can see that 200 mg/kg OLE are much more effective against CIS toxicity than 100 mg/kg OLE.

In this study, CIS reduced activities of gluconeogenesis enzymes in the pancreas. However, OLE resulted in the entire development of glycogenesis as evident by higher of glycogen deposits as compared to CIS group. Moreover, consistent with the detections of the present study, in the pancreas of the animals treated with CIS was recorded diffuse degenerative changes and necrosis. However, high dose of OLE could reduce the degree of necrosis. There were no significant changes in mucin content between OLE and CIS groups.

The results of the current study indicated that treatment with OLEextract at 200 mg/kg significantly reduced the histopathological findings in the treatment group. Moreover, administration of OLE at 100 and 50 mg/kg in treatment group alleviated the histopathological findings.

 > Conclusion Top

In summary, OLE can decrease CIS-induced pancreas toxicity by inhibiting lipid peroxidation and ROS; and this method has good clinical applicability. This means that OLE combined with CIS may be applied to tumor patients to improve chemotherapy efficiency in the near future. On the basis of long-term experience and extensive clinical data, OLE may represent a candidate for the management of CIS-induced DNA damages, pathological lesions, and functional disorders in the pancreas.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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