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Jun 6, 2015 - Laboratory of Molecular Oncology, Cheil General Hospital and Women,s Healthcare Center, Dankook University College of. Medicine, Seoul ...
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Protective Effects of Processed Ginseng and Its Active Ginsenosides on Cisplatin-Induced Nephrotoxicity: In Vitro and in Vivo Studies Jun Yeon Park,†,‡ Pilju Choi,†,§ Taejung Kim,§ Hyeonseok Ko,∥ Ho-kyong Kim,⊥ Ki Sung Kang,*,‡ and Jungyeob Ham*,§ ‡

College of Korean Medicine, Gachon University, Seongnam 461-701, South Korea KIST Gangneung Institute of Natural Products, Korea Institute of Science and Technology (KIST), Gangneung 210-340, South Korea ∥ Laboratory of Molecular Oncology, Cheil General Hospital and Women’s Healthcare Center, Dankook University College of Medicine, Seoul 100-380, South Korea ⊥ Richwood Pharmaceutical Company, Limited, Seoul 100-704, South Korea §

S Supporting Information *

ABSTRACT: Although cisplatin can dramatically improve the survival rate in cancer patients, its use is limited by its nephrotoxicity. Previous investigations showed that Panax ginseng contains components that exhibit protective activity against cisplatin-induced nephropathy. The aim of the present study is to investigate the effect of microwave-assisted processing on the protective effect of ginseng and identify ginsenosides that are active against cisplatin-induced kidney damage to evaluate the potential of using ginseng in the management of nephrotoxicity. The LLC-PK1 cell damage by cisplatin was significantly decreased by treatment with microwave-processed ginseng (MG) and ginsenosides Rg3, Rg5, and Rk1. Reduced expression of p53 and c-Jun N-terminal kinase proteins by cisplatin in LLC-PK1 cells was markedly ameliorated after Rg3 and Rg5/Rk1 treatment. Additionally, elevated expression of cleaved caspase-3 was significantly reduced by ginsenosides Rg5, Rk1, and with even greater potency, Rg3. Moreover, MG and its fraction containing active ginsenosides showed protective effects against cisplatin-induced nephropathy in mice. We found that ginsenosides Rg3, Rg5, and Rk1 generated during the heat treatment of ginseng ameliorate renal damage by regulating inflammation and apoptosis. Results of current experiments provide evidence of the renoprotective effects and therapeutic potential of MG and its active ginsenosides, both in vitro and in vivo. KEYWORDS: cisplatin, nephrotoxicity, Panax ginseng, inflammation, ginsenoside

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by sun or steamed at 95−100 °C).11,12 More than 150 different ginsenosides have been identified, exhibiting different biological effects. Ginsenosides are generally divided into protopanaxadiol and protopanaxatriol groups based on the chemical structures of aglycone moieties (Figure 1).11,13 In our recent research on the protopanaxadiol-type ginsenosides Rb1, Rb2, Rc, and Rd, the sugar moieties at carbon-20 were removed by thermal processing and the aglycones were changed into Rg3, Rg5, and Rk1 (Figure 1).13 Microwave thermal processing has been used to process a wide range of products, including foods.14 Microwave heating provides a competitive advantage compared to conventional methods, such as autoclaving, thereby leading to a highly efficient process with a shorter heating time.15 Recently, our group developed a novel ginseng extract by microwave-assisted processing. This novel extract exhibits an increased content of ginsenosides Rg3, Rg5, and Rk1.16 The aim of the present study is to investigate the protective effects of microwave-processed ginseng (MG) and its active as yet unidentified ginsenosides against cisplatin-induced nephrotoxicity in vitro and in vivo.

INTRODUCTION Cisplatin is a platinum-containing chemotherapy drug and can dramatically improve the survival rate in cancer patients. Cisplatin is the front-line therapy for a number of tumors, including ovarian, testicular, cervical, lung, and penile cancers.1,2 Despite adverse side effects of cisplatin, particularly renal damage, it has still been widely used in cancer therapy for many years.3−5 Abnormal production of oxidative stress and inflammation have been proposed to play a vital role in the etiology of cisplatin-induced nephrotoxicity.6,7 Previous investigations showed that Panax ginseng contains components that exhibit protective activity against cisplatininduced nephropathy in renal tubular epithelial cells.8,9 Ginsenosides Rh4 and Rk3 significantly ameliorated renal cell damage by cisplatin in LLC-PK1 cells.8 Maillard reaction products from a ginsenoside Re and serine also reduced renal epithelial cell damage by cisplatin.9 Notably, the amounts of active components that protect kidney cells from cisplatin-induced damage were increased by heat processing of ginseng.8,9 Ginsenosides, the unique constituents of Panax plants, are the biologically active components of ginseng.10 Several methods for increasing the biological activities of ginseng by conversion of ginsenosides using thermal processing have been developed by us and others.11,12 There are various commercial ginseng products available, such as white, red, sun, and black ginseng (dehydrated © XXXX American Chemical Society

Received: February 10, 2015 Revised: June 6, 2015 Accepted: June 6, 2015

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DOI: 10.1021/acs.jafc.5b00782 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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Journal of Agricultural and Food Chemistry

Figure 1. Structures of ginsenosides: −Glc, D-glucopyranosyl; −Rha, L -rhamnopyranosyl; −Ara(f), L -arabinofuranosyl; and −Ara(p): L-arabinopyranosyl.

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MATERIALS AND METHODS

Figure 2. Structural changes in ginsenosides present in ginseng extract induced by microwave irradiation. (A) HPLC chromatogram presenting peaks corresponding to ginsenosides (Re, Rb1, Rc, Rb2, and Rd) present in raw ginseng. (B) HPLC chromatogram presenting peaks corresponding to ginsenosides [20(S)-Rg3, 20(R)-Rg3, Rk1, and Rg5] present in microwave-processed ginseng.

Chemicals and Reagents. Standard ginsenosides, including Rb1, Rb2, Rc, Rd, Re, Rg3, Rk1, and Rg5 (purity of 98−100%) were purchased from Ambo Institute (South Korea). Dulbecco’s modified Eagle’s medium (DMEM) and fetal bovine serum (FBS) were purchased from Invitrogen Co. (Grand Island, NY). Primary antibodies for c-Jun N-terminal kinase (JNK), phospho-JNK, p53, and cleaved caspase-3 as well as all secondary antibodies were obtained from Cell Signaling Technology, Inc. (Danvers, MA). The EZ-Cytox cell viability assay kit was purchased from ITSBIO (Seoul, South Korea). Acetonitrile and water used were of high-performance liquid chromatography (HPLC) grade, obtained from Fisher Scientific (Pittsburgh, PA), and glacial acetic acid was of analytical grade, purchased from Sigma-Aldrich (St. Louis, MO). Preparation of Processed Ginseng Using Microwave Irradiation. White ginseng (WG) was processed using microwave irradiation as reported previously.16 In brief, aliquots (200 mg) of the dry extract of WG were added to 1 mL of water in a 10 mL container of a microwave irradiator (model 908005) manufactured by CEM Company. WG was irradiated with microwaves in the sealed container at a temperature of 150 °C and power of 100 W (2455 MHz frequency) for 60 min. Microwave-irradiated dry extracts of ginseng (MG) were freeze-dried to obtain microwave-irradiated process products. Microwave irradiation was performed at a pressure of 20 atm. Vessel pressure was automatically controlled by the microwave irradiator. Purification of Ginsenoside-Containing Fractions. MG extract (50 g) was subjected to open-column chromatography on a Diaion HP-20 (Mitsubishi Chemical Co., Ltd., Tokyo, Japan) and eluted stepwise with 5 L of distilled water and MeOH. The respective fractions were evaporated to yield the water eluate (MG−H2O, 38 g) and the MeOH eluate (MG−MeOH, 10 g). Analysis of Ginsenosides. Ginsenosides were identified and quantified using a previously reported method.13 An analytical reversedphase HPLC system comprised of a solvent degasser (Agilent, G1322A), binary pump (Agilent, G1312C), and model 380 evaporative light

scattering detector (ELSD, Agilent) was used in the analysis. The standard solutions containing 1−100 μg of each ginsenoside were injected onto the HPLC column, with all calibration curves showing good linearity (R2 > 0.995). The analysis was repeated 2 times for the assessment of repeatability. Protective Effect against Oxidative Damage in Kidney Cells. The protective effect against oxidative nephrotoxicity was evaluated in LLC-PK1 cells.17 LLC-PK1 (pig kidney epithelium, CL-101) cells were cultured in DMEM supplemented with 10% FBS, 1% penicillin/ streptomycin, and 4 mM L-glutamine at 37 °C with 5% CO2 in air. Cells were seeded in 96-well culture plates at 1 × 104 cells/well and allowed to adhere for 24 h. Thereafter, test samples with or without cisplatin (25 μM) were added to the culture medium. Epigallocatechin gallate (EGCG) was used as a positive control. After 24 h of incubation, the cell viability was evaluated using the EZ-Cytox cell viability assay kit. Protective Effect against Cisplatin-Induced Nephrotoxicity in Mice. All procedures involving the use of live animals as described in this study were approved in May 2013 by the Institutional Animal Care and Use Committee of the Korea Institute of Science and Technology and strictly followed the National Institutes of Health (NIH) guidelines for humane treatment of animals. Male C57/BL6 mice, 9−10 weeks of age, were obtained from Orient Bio Co., Ltd. (Seongnam, South Korea). They were kept on a 12 h light/dark cycle and given free access to water and a normal diet. The mice were subsequently divided into 6 groups that were similar in their initial body weights and assigned to the following treatment groups: group 1, vehicle-treated mice received water alone (no ginseng treatment; n = 4); group 2, cisplatin-treated mice received water alone (no ginseng treatment; n = 4); group 3, cisplatin-treated mice received WG extract (100 mg/kg) in aqueous B

DOI: 10.1021/acs.jafc.5b00782 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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Journal of Agricultural and Food Chemistry

Figure 3. Comparison of the protective effects of WG, MG, MG−MeOH, MG−H2O, Rg3, Rg5/Rk1, and EGCG against cisplatin-induced cytotoxicity in LLC-PK1 cells. (∗) p < 0.05 compared to the cisplatin-treated control value. Western Blotting Analysis. Whole-cell extracts were then prepared according to the instructions of the manufacturer using RIPA buffer (Cell Signaling Technology, Danvers, MA) supplemented with 1× protease inhibitor cocktail and 1 mM phenylmethylsulfonyl fluoride. Proteins were separated by electrophoresis, blotted onto polyvinylidene fluoride (PVDF) transfer membrane, and analyzed with epitope-specific primary and secondary antibodies. Statistical Analysis. Statistical significance was determined through the one-way analysis of variance (ANOVA), followed by a multiplecomparison test with Bonferroni adjustment. p values lower than 0.05 were considered statistically significant (SPSS 11.5 software).

solution orally for 10 days (cisplatin + WG; n = 4); group 4, cisplatintreated mice received MG extract (100 mg/kg) in aqueous solution orally for 10 days (cisplatin + MG; n = 4); group 5, cisplatin-treated mice received MG−MeOH (25 mg/kg) in aqueous solution orally for 10 days (cisplatin + MG−MeOH; n = 4); and group 6, cisplatin-treated mice received NAC (100 mg/kg) in aqueous solution orally for 10 days (cisplatin + NAC; n = 4). Samples were orally administered daily, while vehicle-treated rats were given water. After 10 days, mice in the five treatment groups (cisplatin, cisplatin + WG, cisplatin + MG, cisplatin + MG−MeOH, and cisplatin + NAC) were intraperitoneally administered a single dose of cisplatin (16 mg/kg of body weight) in 0.9% saline. Mice were sacrificed 3 days after cisplatin administration under light ether anesthesia. Blood samples were collected in tubes containing 0.18 M ethylenediaminetetraacetic acid (EDTA) from the abdominal aorta. Analyses of Plasma Biomarkers. Blood samples were centrifuged at 3000g for 10 min at 4 °C. The plasma creatinine levels were measured by a rate-blanked kinetic Jaffe method.

3. RESULTS AND DISCUSSION The chromatograms for each of the prepared ginseng extracts are shown in panels A and B of Figure 2. The processing conditions for microwave treatment of ginseng extracts were optimized,16 C

DOI: 10.1021/acs.jafc.5b00782 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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Journal of Agricultural and Food Chemistry and conditions resulting in the highest amounts of ginsenosides Rg3, Rg5, and Rk1 were selected. Ginsenosides were identified and quantified as reported previously.13,16 As shown in panels A and B of Figure 2, each of the ginsenosides Re (114 μg), Rb1 (158 μg), Rc (94 μg), Rb2 (74 μg), and Rd (8 μg) content was decreased in WG, while the ginsenosides Rg3 (105 μg), Rk1 (151 μg), and Rg5 (275 μg) content increased in MG by microwave irradiation at 150 °C for 60 min. Ginsenosides 20(S)-Rg3 and 20(R)-Rg3 are produced by the elimination of the glycosyl residue at carbon-20 of protopanaxadiol-type saponins, such as ginsenosides Rb1, Rb2, Rc, and Rd during the steaming process.11,18,19 Ginsenoside Rg3 is converted to Rg5 and Rk1 by further dehydration at the carbon-20 position by high pressure and temperature.13,19 Using LLC-PK1 renal epithelial cells as the in vitro model, we compared the protective activities of WG, MG, MG−MeOH, MG−H2O, ginsenoside Rg3 epimers, and ginsenoside Rg5/Rk1 against cisplatin-induced oxidative renal damage. The ginsenoside stereoisomers were used as mixtures because of the difficulty in preparing a single ingredient with high purity. On the basis of previously collected data, 25 μM cisplatin, which results in approximately 60% cell death, was selected for further study. Loss of cell viability was noted after 24 h incubations of samples at a range of ginsenoside concentrations (0, 50, 100, and 250 μg/mL) with cisplatin (25 μM). The renoprotective effect of MG was observed to be stronger than that of WG (panels A and B of Figure 3). Additionally, we have assessed the renoprotective effects of the water and MeOH elution fractions of MG (MG−H2O and MG−MeOH) to identify the main active components. On the basis of our observations, the MeOH fraction increased cell viability at a concentration of 50 μg/mL, while no amelioration in cell viability was observed following treatment with MG−H2O (panels C and D of Figure 3). High concentrations of ginsenosides-20(S)-protopanaxadiol (ginsenosides Rb1, Rb2, Rc, Rd, Rg3, Rg5, and Rk1) and 20(S)-protopanaxatriol (ginsenosides Re and Rg1) are already known to be eluted in the MeOH fraction,11 suggesting that the observed renoprotective activity of the MeOH elute is likely due to ginsenosides. Consequently, we investigated the renoprotective effects using ginsenosides Rg3 and Rg5/Rk1, the content of which was increased by microwave processing. Ginsenosides Rg3 and Rg5/Rk1 were found to significantly ameliorate cisplatin-induced reduction in cell viability in a dose-dependent manner (panels E and F of Figure 3). This protective effect was stronger than that of EGCG (Figure 3). We have also confirmed that MG and its active components did not affect the anticancer activity of cisplatin (see Figure S1 of the Supporting Information). Figure 4 presents the protein expression levels of P-JNK, JNK, p53, and cleaved caspase-3 in the control and treated (WG, MG, and MG−MeOH) cells. The blocking of JNK−p53−caspase-3 signaling cascade plays a vital role in mediating the protective effect of renoprotectants against oxidative cytotoxicity in cultured LLC-PK1 cells.20−22 Cisplatin-induced nephrotoxicity was previously correlated with the formation of oxidative stress, which can activate JNK.23,24 Treatments with antioxidants and caspase inhibitors were shown to ameliorate cisplatin-related nephrotoxicity.25 The important roles of JNK activation have emphasized the regulation of apoptosis pathways as well as inflammation.26−28 In LLC-PK1 cells, p53 is activated by cisplatin, and p53 inhibition by pharmacological and molecular approaches reduces cisplatin-induced apoptosis.29,30 Expression of JNK and p53 proteins in LLC-PK1 cells recovered markedly after treatments with MG and MG−MeOH but not with WG

Figure 4. Comparison of the effects of WG, MG, and MG−MeOH on the expression of proteins P-JNK (46 and 54 kDa), JNK (46 and 54 kDa), p53 (53 kDa), and cleaved caspase-3 (17 and 19 kDa) in LLC-PK1 cells. Western blot assays were performed in triplicate for each protein and were repeated at least 3 times. The presence or absence of samples is indicated by a plus or minus sign, respectively.

(Figure 4). To further investigate the ability of MG and MG− MeOH to prevent apoptosis, the renal expression of cleaved caspase-3 was measured. In these experiments, MG significantly reduced the expression of cleaved caspase-3 (Figure 4). Figure 5 presents the expression of proteins P-JNK, JNK, p53,

Figure 5. Comparison of the effect of ginsenosides Rg3 (50 and 100 μg/mL) and Rg5/Rk1 (50 and 100 μg/mL) on the expression of proteins P-JNK (46 and 54 kDa), JNK (46 and 54 kDa), p53 (53 kDa), and cleaved caspase-3 (17 and 19 kDa) in LLC-PK1 cells. Western blot assays were performed in triplicate for each protein and were repeated at least 3 times. The presence or absence of samples is indicated by a plus or minus sign, respectively.

and cleaved caspase-3 in control and experimental cells treated with ginsenoside Rg3 (at 50 and 100 μg/mL) or Rg5/Rk1 (50 and 100 μg/mL). Expression of JNK and p53 proteins in LLC-PK1 cells was markedly increased following treatment with Rg3 and Rg5/Rk1. Additionally, the elevated expression of cleaved caspase-3 following cisplatin treatment was significantly attenuated by ginsenosides Rg5/Rk1 and, more potently, by ginsenoside Rg3 co-treatments (Figure 5). To determine whether MG and its ginsenoside fraction elicit renoprotective effects in vivo, we used cisplatin-induced renal D

DOI: 10.1021/acs.jafc.5b00782 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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Journal of Agricultural and Food Chemistry Author Contributions †

Jun Yeon Park and Pilju Choi contributed equally to this work.

Funding

This work was supported by the Korea Institute of Science and Technology Institutional Program (2Z04390) and Industrial Infrastructure Program for Fundamental Technologies (N0000885), which is funded by the Ministry of Trade, Industry and Energy (MOTIE, South Korea). Notes

The authors declare no competing financial interest.

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(1) Noori, S.; Mahboob, T. Antioxidant effect of carnosine pretreatment on cisplatin-induced renal oxidative stress in rats. Indian J. Clin. Biochem. 2010, 25, 86−91. (2) Li, J.; Jiang, K.; Qiu, X.; Li, M.; Hao, Q.; Wei, L.; Zhang, W.; Chen, B.; Xin, X. Overexpression of CXCR4 is significantly associated with cisplatin-based chemotherapy resistance and can be a prognostic factor in epithelial ovarian cancer. BMB Rep. 2014, 47, 33−38. (3) Rosenberg, B.; Vancamp, L.; Krigas, T. Inhibition of cell division in escherichia coli by electrolysis products from a platinum electrod. Nature 1965, 205, 698−699. (4) Siddik, Z. H. Cisplatin: Mode of cytotoxic action and molecular basis of resistance. Oncogene 2003, 22, 7265−7279. (5) Wang, D.; Lippard, S. J. Cellular processing of platinum anticancer drugs. Nat. Rev. Drug Discovery 2005, 4, 307−320. (6) Forbes, J. M.; Coughlan, M. T.; Cooper, M. E. Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes 2008, 57, 1446− 1454. (7) Heyman, S. N.; Rosen, S.; Rosenberger, C. A role for oxidative stress. Contrib. Nephrol. 2011, 174, 138−148. (8) Baek, S. H.; Piao, X. L.; Lee, U. J.; Kim, H. Y.; Park, J. H. Reduction of cisplatin-induced nephrotoxicity by ginsenosides isolated from processed ginseng in cultured renal tubular cells. Biol. Pharm. Bull. 2006, 29, 2051−2055. (9) Lee, J. H.; Lee, W.; Lee, S.; Jung, Y.; Park, S. H.; Choi, P.; Kim, S. N.; Ham, J.; Kang, K. S. Important role of Maillard reaction in the protective effect of heat-processed ginsenoside Re-serine mixture against cisplatin-induced nephrotoxicity in LLC-PK1 cells. Bioorg. Med. Chem. Lett. 2012, 22, 5475−5479. (10) Huang, Y. C.; Chen, C. T.; Chen, S. C.; Lai, P. H.; Liang, H. C.; Chang, Y.; Yu, L. C.; Sung, H. W. A natural compound (ginsenoside Re) isolated from Panax ginseng as a novel angiogenic agent for tissue regeneration. Pharm. Res. 2005, 22, 636−646. (11) Kang, K. S.; Ham, J.; Kim, Y. J.; Park, J. H.; Cho, E. J.; Yamabe, N. Heat-processed Panax ginseng and diabetic renal damage: Active components and action mechanism. J. Ginseng Res. 2013, 37, 379−388. (12) Park, E. H.; Kim, Y. J.; Yamabe, N.; Park, S. H.; Kim, H. K.; Jang, H. J.; Kim, J. H.; Cheon, G. J.; Ham, J.; Kang, K. S. Stereospecific anticancer effects of ginsenoside Rg3 epimers isolated from heatprocessed American ginseng on human gastric cancer cell. J. Ginseng Res. 2014, 38, 22−27. (13) Kim, Y. J.; Yamabe, N.; Choi, P.; Lee, J. W.; Ham, J.; Kang, K. S. Efficient thermal deglycosylation of ginsenoside Rd and its contribution to the improved anticancer activity of ginseng. J. Agric. Food Chem. 2013, 61, 9185−9191. (14) Zhu, J.; Kuznetsov, A. V.; Sandeep, K. P. Numerical simulation of forced convection in a duct subjected to microwave heating. Heat Mass Transfer 2007, 43, 255−264. (15) Cuccurullo, G.; Giordano, L.; Viccione, G. An analytical approximation for continuous flow microwave heating of liquids. Adv. Mech. Eng. 2015, 5, 929236. (16) Choi, P.; Park, J. Y.; Kim, T.; Park, S. H.; Kim, H.; Kang, K. S.; Ham, J. Improved anticancer effect of ginseng extract by microwaveassisted processing through the generation of ginsenosides Rg3, Rg5 and Rk1. J. Funct. Foods 2015, 14, 613−622.

Figure 6. Protective effects of microwave-processed ginseng extract against cisplatin-induced renal damage in mice. (∗) p < 0.05 compared to the cisplatin-treated control value.

oxidative-damaged mice as an in vivo model. Cisplatin-injected mice exhibited increased serum levels of creatinine compared to the vehicle-treated animals (Figure 6). Serum creatinine is a tried and true marker of kidney injury.31,32 Elevated serum creatinine levels in cisplatin-treated mice were slightly attenuated by cotreatment with WG. In particular, increased serum creatinine levels were significantly reduced by administration of MG and, more potently, MG−MeOH, which contains ginsenosides Rg3, Rg5, and Rk1 (Figure 6). The renoprotective effect of MG−MeOH was as strong as that of NAC, which has been found to be effective in attenuating nephrotoxicity induced by cisplatin.33 Therefore, cotreatment with MG and its active ginsenosides afforded significant protection against cisplatin-induced nephrotoxicity in mice. In summary, we demonstrated that MG and its active ginsenosides Rg3, Rg5, and Rk1 showed a protective effect against cisplatin-induced nephrotoxicity in cultured kidney cells and mice. We found that ginsenosides Rg3, Rg5, and Rk1, generated during the heat treatment of ginseng, ameliorate renal damage by regulating inflammation and apoptosis. The experimental results provide convincing evidence for kidney protection effects of MG and its active ginsenosides, both in vitro and in vivo, supporting its therapeutic potential. Future studies will focus on the effect of MG and its active ginsenosides on unexplored areas, such as diabetic nephropathy.

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ASSOCIATED CONTENT

S Supporting Information *

Effects of MG and its active components on the anti-proliferative effect of cisplatin in PC3 prostate cancer cells (Figure S1) (PDF). The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jafc.5b00782.

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REFERENCES

AUTHOR INFORMATION

Corresponding Authors

*Telephone: 82-31-750-5402. Fax: 82-31-750-5416. E-mail: [email protected]. *Telephone: 82-33-650-3502. Fax: 82-33-650-3508. E-mail: [email protected]. E

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