Cancer Chemotherapy and Pharmacology

, Volume 56, Issue 1, pp 63–69 | Cite as

American ginseng berry extract and ginsenoside Re attenuate cisplatin-induced kaolin intake in rats

  • Sangeeta Mehendale
  • Han Aung
  • Anbao Wang
  • Jun-Jie Yin
  • Chong-Zhi Wang
  • Jing-Tian Xie
  • Chun-Su Yuan
Original Article
First Online:
Received:
Accepted:

Abstract

Purpose

Cisplatin, a chemotherapeutic agent, causes significant nausea and vomiting. It is postulated that cisplatin-induced oxidant stress may be responsible for these symptoms. We tested whether pretreatment with American ginseng berry extract (AGBE), an herb with potent antioxidant capacity, and one of its active antioxidant constituents, ginsenoside Re, could counter cisplatin-induced emesis using a rat pica model.

Methods

In rats, exposure to emetic stimuli such as cisplatin causes significant kaolin intake, a phenomenon called pica. We therefore measured cisplatin-induced kaolin intake as an indicator of the emetic response. Rats were pretreated with vehicle, AGBE (dose range 50–150 mg/kg, IP) or ginsenoside Re (2 and 5 mg/kg, IP). Rats were treated with cisplatin (3 mg/kg, IP) 30 min later. Kaolin intake, food intake, and body weight were measured every 24 h for 120 h. Additionally, the free radical scavenging activity of AGBE was measured in vitro using ESR spectroscopy.

Results

A significant dose-response relationship was observed between increasing doses of pretreatment with AGBE and reduction in cisplatin-induced pica. Kaolin intake was maximally attenuated by AGBE at a dose of 100 mg/kg. Food intake also improved significantly at this dose (P<0.05). Pretreatment with ginsenoside Re (5 mg/kg) also decreased kaolin intake (P<0.05). In vitro studies demonstrated a concentration-response relationship between AGBE and its ability to scavenge superoxide and hydroxyl radicals.

Conclusion

Pretreatment with AGBE and its major constituent, Re, attenuated cisplatin-induced pica, and demonstrated potential for the treatment of chemotherapy-induced nausea and vomiting. Significant recovery of food intake further strengthens the conclusion that AGBE may exert an antinausea/antiemetic effect.

Keywords

American ginseng Berry Ginsenoside Re Herbal medicine Cisplatin 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgements

This work was supported in part by NIH grants P30 CA14599, R01 CA79042, AT00563 and AT002176.

References

  1. 1.
    Schnell FM (2003) Chemotherapy-induced nausea and vomiting: the importance of acute antiemetic control. Oncologist 8:187–198Google Scholar
  2. 2.
    Spitzer TR, Friedman CJ, Bushnell W, Frankel SR, Raschko J (2000) Double-blind, randomized, parallel-group study on the efficacy and safety of oral granisetron and oral ondansetron in the prophylaxis of nausea and vomiting in patients receiving hyperfractionated total body irradiation. Bone Marrow Transplant 26:203–210CrossRefPubMedGoogle Scholar
  3. 3.
    The Italian Group for Antiemetic Research in Radiotherapy (1999) Radiation-induced emesis: a prospective observational multicenter Italian trial: the Italian Group for Antiemetic Research in Radiotherapy. Int J Radiat Oncol Biol Phys 44:619–625Google Scholar
  4. 4.
    Matsuki N (1996) Mechanisms of cytotoxic drug-induced emesis and its prevention. Yakugaku Zasshi 116:710–718Google Scholar
  5. 5.
    Torii Y, Mutoh M, Saito H, Matsuki N (1993) Involvement of free radicals in cisplatin-induced emesis in Suncus murinus. Eur J Pharmacol 248:131–135Google Scholar
  6. 6.
    Scarantino CW, Ornitz RD, Hoffman LG, Anderson RF Jr (1994) On the mechanism of radiation-induced emesis: the role of serotonin. Int J Radiat Oncol Biol Phys 30:825–830Google Scholar
  7. 7.
    Cubeddu LX (1992) Mechanisms by which cancer chemotherapeutic drugs induce emesis. Semin Oncol 19:2–13Google Scholar
  8. 8.
    Fukui H, Yamamoto M, Ando T, Sasaki S, Sato S (1993) Increase in serotonin levels in the dog ileum and blood by cisplatin as measured by microdialysis. Neuropharmacology 32:959–968Google Scholar
  9. 9.
    Simpson K, Spencer CM, McClellan KJ (2000) Tropisetron: an update of its use in the prevention of chemotherapy-induced nausea and vomiting. Drugs 59:1297–1315Google Scholar
  10. 10.
    Nitta Y, Nishibori M, Iwagaki H, Yoshino T, Mori S, Sawada K, Nakaya N, Saeki K, Tanaka N (2001) Changes in serotonin dynamics in the gastrointestinal tract of colon-26 tumour-bearing mice: effects of cisplatin treatment. Naunyn Schmiedebergs Arch Pharmacol 364:329–334Google Scholar
  11. 11.
    Mitchell D, Wells C, Hoch N, Lind K, Woods SC, Mitchell LK (1976) Poison induced pica in rats. Physiol Behav 17:691–697Google Scholar
  12. 12.
    Mitchell D, Krusemark ML, Hafner D (1977) Pica: a species relevant behavioral assay of motion sickness in the rat. Physiol Behav 18:125–130Google Scholar
  13. 13.
    Takeda N, Hasegawa S, Morita M, Matsunaga T (1993) Pica in rats is analogous to emesis: an animal model in emesis research. Pharmacol Biochem Behav 45:817–821Google Scholar
  14. 14.
    Rudd JA, Yamamoto K, Yamatodani A, Takeda N (2002) Differential action of ondansetron and dexamethasone to modify cisplatin-induced acute and delayed kaolin consumption (“pica”) in rats. Eur J Pharmacol 454:47–52Google Scholar
  15. 15.
    Takeda N, Hasegawa S, Morita M, Horii A, Uno A, Yamatodani A, Matsunaga T (1995) Neuropharmacological mechanisms of emesis. II. Effects of antiemetic drugs on cisplatin-induced pica in rats. Methods Find Exp Clin Pharmacol 17:647–652Google Scholar
  16. 16.
    Ozaki A, Sukamoto T (1999) Improvement of cisplatin-induced emesis and delayed gastric emptying by KB-R6933, a novel 5-HT3 receptor antagonist. Gen Pharmacol 33:283–288Google Scholar
  17. 17.
    Foss JF, Yuan CS, Roizen MF, Goldberg LI (1998) Prevention of apomorphine- or cisplatin-induced emesis in the dog by a combination of methylnaltrexone and morphine. Cancer Chemother Pharmacol 42:287–291Google Scholar
  18. 18.
    Shao ZH, Xie JT, Van den Hoek TL, Mehendale S, Aung H, Li CQ, Qin Y, Schumacker PT, Becker LB, Yuan CS (2004) Antioxidant effects of American ginseng berry extract in cardiomyocytes exposed to acute oxidant stress. Biochim Biophys Acta 1670:165–171Google Scholar
  19. 19.
    Xie JT, Mehendale SR, Wang A, Han AH, Wu JA, Osinski J, Yuan CS (2004) American ginseng leaf: ginsenoside analysis and hypoglycemic activity. Pharmacol Res 49:113–117Google Scholar
  20. 20.
    Aung HH, Dey L, Mehendale S, Xie JT, Wu JA, Yuan CS (2003) Scutellaria baicalensis extract decreases cisplatin-induced pica in rats. Cancer Chemother Pharmacol 52:453–458Google Scholar
  21. 21.
    Zhao H, Joseph J, Zhang H, Karoui H, Kalyanaraman B (2001) Synthesis and biochemical applications of a solid cyclic nitrone spin trap: a relatively superior trap for detecting superoxide anions and glutathiyl radicals. Free Radic Biol Med 31:599–606Google Scholar
  22. 22.
    Yasuko N, Masahiro K, Akitane M, Packer L (1999) Automated electron spin resonance free radical detector assays for antioxidant activity in natural extracts. Methods Enzymol 299:28–34Google Scholar
  23. 23.
    Ueno S, Matsuki N, Saito H (1987) Suncus murinus: a new experimental model in emesis research. Life Sci 41:513–518CrossRefGoogle Scholar
  24. 24.
    Milano S, Blower P, Romain D, Grelot L (1995) The piglet as a suitable animal model for studying the delayed phase of cisplatin-induced emesis. J Pharmacol Exp Ther 274:951–961PubMedGoogle Scholar
  25. 25.
    King GL, Rabin BM, Weatherspoon JK (1999) 5-HT3 receptor antagonists ameliorate emesis in the ferret evoked by neutron or proton radiation. Aviat Space Environ Med 70:485–492Google Scholar
  26. 26.
    King GL (1990) Animal models in the study of vomiting. Can J Physiol Pharmacol 68:260–268Google Scholar
  27. 27.
    Andrews PL, Sanger GJ (2002) Abdominal vagal afferent neurones: an important target for the treatment of gastrointestinal dysfunction. Curr Opin Pharmacol 2:650–656Google Scholar
  28. 28.
    Morita M, Takeda N, Kubo T, Matsunaga T (1988) Pica as an index of motion sickness in rats. ORL J Otorhinolaryngol Relat Spec 50:188–192Google Scholar
  29. 29.
    Mitchell D, Laycock JD, Stephens WF (1977) Motion sickness-induced pica in the rat. Am J Clin Nutr 30:147–150Google Scholar
  30. 30.
    Aung HH, Mehendale SR, Xie JT, Moss J, Yuan CS (2004) Methylnaltrexone prevents morphine-induced kaolin intake in the rat. Life Sci 74:2685–2691Google Scholar
  31. 31.
    Yamamoto K, Takeda N, Yamatodani A (2002) Establishment of an animal model for radiation-induced vomiting in rats using pica. J Radiat Res (Tokyo) 43:135–141Google Scholar
  32. 32.
    Stankiewicz A, Skrzydlewska E, Makiela AM (2002) Effects of amifostine on liver oxidative stress caused by cyclophosphamide administration to rats. Drug Metabol Drug Interact 19:67–82Google Scholar
  33. 33.
    Duncan M, Grant G (2003) Oral and intestinal mucositis—causes and possible treatments. Aliment Pharmacol Ther 18(9):853–874Google Scholar
  34. 34.
    Minami M, Ogawa T, Endo T, Hamaue N, Hirafuji M, Yoshioka M, Blower PR, Andrews PL (1997) Cyclophosphamide increases 5-hydroxytryptamine release from the isolated ileum of the rat. Res Commun Mol Pathol Pharmacol 97:13–24Google Scholar
  35. 35.
    Minami M, Endo T, Hirafuji M, Hamaue N, Liu Y, Hiroshige T, Nemoto M, Saito H, Yoshioka M (2003) Pharmacological aspects of anticancer drug-induced emesis with emphasis on serotonin release and vagal nerve activity. Pharmacol Ther 99:149–165CrossRefPubMedGoogle Scholar
  36. 36.
    Hesketh PJ, Van Belle S, Aapro M, Tattersall FD, Naylor RJ, Hargreaves R, Carides AD, Evans JK, Horgan KJ (2003) Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur J Cancer 39:1074–1080Google Scholar
  37. 37.
    Kris MG, Roila F, De Mulder PH, Marty M (1998) Delayed emesis following anticancer chemotherapy. Support Care Cancer 6:228–232Google Scholar
  38. 38.
    Liu ZQ, Luo XY, Liu GZ, Chen YP, Wang ZC, Sun YX (2003) In vitro study of the relationship between the structure of ginsenoside and its antioxidative or prooxidative activity in free radical induced hemolysis of human erythrocytes. J Agric Food Chem 51:2555–2558Google Scholar
  39. 39.
    Zheng W, Wang SY (2003) Oxygen radical absorbing capacity of phenolics in blueberries, cranberries, chokeberries, and lingonberries. J Agric Food Chem 51:502–509Google Scholar
  40. 40.
    Kitts D, Hu C (2000) Efficacy and safety of ginseng. Public Health Nutr 3:473–485Google Scholar
  41. 41.
    Shao ZH, Van den Hoek TL, Li CQ, Schumacker PT, Becker LB, Chan KC, Qin Y, Yin JJ, Yuan CS (2004) Synergistic effect of Scutellaria baicalensis and grape seed proanthocyanidins on scavenging reactive oxygen species in vitro. Am J Chin Med 32:89–95Google Scholar
  42. 42.
    Dehne N, Lautermann J, Petrat F, Rauen U, de Groot H (2001) Cisplatin ototoxicity: involvement of iron and enhanced formation of superoxide anion radicals. Toxicol Appl Pharmacol 174:27–34Google Scholar
  43. 43.
    Davis CA, Nick HS, Agarwal A (2001) Manganese superoxide dismutase attenuates cisplatin-induced renal injury: importance of superoxide. J Am Soc Nephrol 12:2683–2690PubMedGoogle Scholar
  44. 44.
    Yoon SR, Nah JJ, Shin YH, Kim SK, Nam KY, Choi HS, Nah SY (1998) Ginsenosides induce differential antinociception and inhibit substance P induced-nociceptive response in mice. Life Sci 62:PL319–PL325Google Scholar
  45. 45.
    Sampson JH, Phillipson JD, Bowery NG, O’Neill MJ, Houston JG, Lewis JA (2000) Ethnomedicinally selected plants as sources of potential analgesic compounds: indication of in vitro biological activity in receptor binding assays. Phytother Res 14:24–29Google Scholar
  46. 46.
    Min KT, Koo BN, Kang JW, Bai SJ, Ko SR, Cho ZH (2003) Effect of ginseng saponins on the recombinant serotonin type 3A receptor expressed in xenopus oocytes: implication of possible application as an antiemetic. J Altern Complement Med 9:505–510Google Scholar
  47. 47.
    Deng HL, Zhang JT (1991) Anti-lipid peroxidative effect of ginsenoside Rb1 and Rg1. Chin Med J (Engl) 104:395–398Google Scholar
  48. 48.
    Lamson DW, Brignall MS (1999) Antioxidants in cancer therapy; their actions and interactions with oncologic therapies. Altern Med Rev 4:304–329PubMedGoogle Scholar
  49. 49.
    Lee SJ, Sung JH, Moon CK, Lee BH (1999) Antitumor activity of a novel ginseng saponin metabolite in human pulmonary adenocarcinoma cells resistant to cisplatin. Cancer Lett 144:39–43Google Scholar
  50. 50.
    Mochizuki M, Yoo YC, Matsuzawa K, Sato K, Saiki I, Tono-oka S, Samukawa K, Azuma I (1995) Inhibitory effect of tumor metastasis in mice by saponins, ginsenoside-Rb2, 20(R)- and 20(S)-ginsenoside-Rg3, of red ginseng. Biol Pharm Bull 18:1197–1202PubMedGoogle Scholar
  51. 51.
    Yokozawa T, Liu ZW (2000) The role of ginsenoside-Rd in cisplatin-induced acute renal failure. Renal Fail 22:115–127Google Scholar
  52. 52.
    Rybak LP, Kelly T (2003) Ototoxicity: bioprotective mechanisms. Curr Opin Otolaryngol Head Neck Surg 11:328–333Google Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Sangeeta Mehendale
    • 1
    • 2
  • Han Aung
    • 1
    • 2
  • Anbao Wang
    • 1
    • 2
  • Jun-Jie Yin
    • 4
  • Chong-Zhi Wang
    • 1
    • 2
  • Jing-Tian Xie
    • 1
    • 2
  • Chun-Su Yuan
    • 1
    • 2
    • 3
  1. 1.Tang Center for Herbal Medicine Research, The Pritzker School of MedicineUniversity of ChicagoChicagoUSA
  2. 2.Departments of Anesthesia and Critical Care, The Pritzker School of MedicineUniversity of ChicagoChicagoUSA
  3. 3.Committee on Clinical Pharmacology and Pharmacogenomics, The Pritzker School of MedicineUniversity of ChicagoChicagoUSA
  4. 4.Center for Food Safety and Applied NutritionFDACollege ParkUSA20740

Personalised recommendations