Skip to main content

Protective effects of propolis and related polyphenolic/flavonoid compounds against toxicity induced by irinotecan

Abstract

Despite the excellent chemotherapeutic effect of irinotecan, its cytotoxicity and genotoxicity in normal cells remains a major problem in chemotherapy. This study was carried out to find whether propolis preparations and related flavonoids (quercetin, naringin) might enhance irinotecan-induced cytotoxicity to tumor cells in mice bearing Ehrlich ascites tumors (EAT) while protecting normal blood, liver, and kidney cells. The preparation of propolis and their flavonoids were given to mice intraperitoneally at a dose of 100 mg kg−1 body weight for three consecutive days before the ip injection of EAT cells (2 × 106). Irinotecan was administered ip at dose of 50 mg kg−1 on days 3, 4, and 5 after tumor cell inoculation. The combination treatment resulted in substantial inhibition of the growth of EAT cells as well as treatment with quercetin or irinotecan alone, whereas other treatment by itself showed little effect. However, when mice were pre-treated with test components prior to irinotecan, the frequencies of irinotecan-induced micronuclei (MN) was decreased but in mice bearing tumor QU and EEP increased number of micronucleated cells. Propolis preparation and related flavonoids were found to exhibit an important immunomodulatory effect and could decrease irinotecan-induced toxic and genotoxic effects to normal cells without effecting irinotecan cytotoxicity in EAT cells.

This is a preview of subscription content, access via your institution.

Fig. 1

References

  1. Lahouel M, Viotte G, Sumereau E, Morin JP, Fillastre JP. Haematotoxicity of doxorubicin and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and of their association in rats. Drugs Exp Clin Res. 1987;13(10):593–9.

    CAS  PubMed  Google Scholar 

  2. Fillastre JP, Viotte G, Morin JP, Moulin B. Nephrotoxicity of antitumoral agents. Adv Nephrol Necker Hosp. 1988;17:175–218. Review.

    CAS  PubMed  Google Scholar 

  3. Oršolić N, Štajcar D, Bašić I. Cytotoxicity of propolis and its polyphenolic compounds on primary culture of human urinary bladder transitional cell carcinoma. Pharmacologyonline. 2006;3:408–15.

    Google Scholar 

  4. Oršolić N, Bašić I. Cancer chemoprevention by propolis and its polyphenolic compounds in experimental animals (Phytochemistry and pharmacology III, Singh VK, Govil JN, C. Arunachalam, editors. USA: Studium Press). Recent Prog Med Plants. 2007; 17: 55-113.

  5. Benkovic V, Horvat Knezevic A, Brozovic G, Knezevic F, Đikic D, et al. Enhanced antitumor activity of irinotecan combined with propolis and its polyphenolic compounds on Ehrlich ascites tumor in mice. Biomed Pharmacother. 2007;61(5):292–7.

    CAS  PubMed  Article  Google Scholar 

  6. Grynberg NF, Carvalho MG, Velandia JR, Oliveira MC, Moreira IC. DNA topoisomerase inhibitors: biflavonoids from Ouratea species. Braz J Med Biol Res. 2002;35:819–22.

    CAS  PubMed  Article  Google Scholar 

  7. Yamashita Y, Kawada S, Fujii N, Nakano H. Induction of mammalian DNA topoisomerase II dependent DNA cleavage by antitumor antibiotic streptonigrin. Cancer Res. 1990;50:5841–4.

    CAS  PubMed  Google Scholar 

  8. López-Lázaro M, Martín-Cordero C, Toro MV, Ayuso MJ. Flavonoids as DNA topoisomerase I poisons. J Enzyme Inhibit Med Chem. 2006;233(2):255–64.

    Google Scholar 

  9. Webb MR, Ebeler SE. Comparative analysis of Topoisomerase IB inhibition and DNA intercalation by flavonoids and similar compounds: structural determinates of activity. Biochem J. 2004;384:527–41.

    CAS  PubMed  Article  Google Scholar 

  10. Constantinou A, Mehta R, Runyan C, Rao K, Vaughan A, Moon R. Flavonoids as DNA topoisomerase antagonists and poisons: structure-activity relationships. J Nat Prod. 1995;58(2):217–25.

    CAS  PubMed  Article  Google Scholar 

  11. Plowman J, Dykes DJ, Hollingshead M, Simpson-Herren L, Alley MC. Human tumor xenograft models in NCI drug development. In: Teicher B, editor. Anticancer development guide: preclinical screening, clinical trials, and approval. Totowa: Humana; 1997. p. 101–25.

    Google Scholar 

  12. Schluep T, Hwang J, Cheng J, Heidel JD, Barlett DW, et al. Preclinical efficacy of the camptothecin-polymer conjugate IT-101 in multiple cancer models. Clin Cancer Res. 2006;12(5):1606–14.

    CAS  PubMed  Article  Google Scholar 

  13. Oršolić N, Bašić I. Antitumor, hematostimulative and radioprotective action of water-soluble derivative of propolis (WSDP). Biomed Pharmacother. 2005;59(10):561–70.

    PubMed  Article  CAS  Google Scholar 

  14. Prasad KN, Cole WC, Kumar B, Prasad KC. Alpha tocopheryl succinate, retinoic acid and polar carotenoids enhanced the growth-inhibitory effect of a cholesterol-lowering drug on immortalized and transformed nerve cells in culture. J Am Coll Nutr. 2001;20(6):628–36. Review.

    PubMed  Google Scholar 

  15. Lee R, KimYJ Lee YJ, Chung HW. The selective effect of genistein on the toxicity of bleomycin in normal lymphocytes and HL-60 cells. Toxicology. 2004;195(23):87–95.

    CAS  PubMed  Article  Google Scholar 

  16. Borek C. Dietary antioxidants and human cancer. Integr Cancer Ther. 2004;3(4):333–41. Review.

    CAS  PubMed  Article  Google Scholar 

  17. Orsolic N, Kosalec I, Basic I. Synergystic antitumor effect of polyphenolic components of water soluble derivative of propolis against Ehrlich ascites tumour. Biol Pharml Bull. 2005;28(4):694–700.

    CAS  Article  Google Scholar 

  18. Popova M, Bankova V, Butovska D, Petkov V, Nikolova-Damyanova B, et al. Validated methods for the quantification of biologically active constituents of poplar-type propolis. Phytochem Anal. 2004;15:235–40.

    CAS  PubMed  Article  Google Scholar 

  19. Yang Chang CC, MH Yang, Wen HM, Chern JC. Estimation of total flavonoid content in propolis by two complementary colorimetric methods. J Food Drug Anal. 2002;10:178–82.

    Google Scholar 

  20. Ch Chen, Weng M, Ch Wu, Lin J. Comparison of radical scavenging activity, cytotoxic effects and apoptosis induction in human melanoma cells by Taiwanese propolis from different sources. Evid Based Complement Alternat Med. 2004;1(2):175–85.

    Article  Google Scholar 

  21. Kosalec I, Bakmaz M, Pepeljnjak S. Analysis of propolis from the continental and Adriatic regions of Croatia. Acta Pharm. 2003;53(4):275–85.

    CAS  PubMed  Google Scholar 

  22. Kosalec I, Bakmaz M, Pepelnjak S, Knežević S. Quantitative analysis of the flavonoids in raw propolis from northern Croatia. Acta Pharm. 2004;54:65–72.

    CAS  PubMed  Google Scholar 

  23. Bergman RA, Afifi AK, Heidger PM. Histology. Philadelphia: Saunders; 1995.

    Google Scholar 

  24. Fecchio D, Sirois P, Russo M, Jancar S. Studies on inflammatory response induced by Ehrlich tumor in mice peritoneal cavity. Inflammation. 1990;14:125–32.

    CAS  PubMed  Article  Google Scholar 

  25. Rabinovitch M, Manejias RE, Russo M, Abbey EE. Increased spreading of macrophages from mice treated with interferon inducers. Cell Immunol. 1977;29:86–95.

    CAS  PubMed  Article  Google Scholar 

  26. Rabinovitch M, DeStefano MJ. Macrophage spreading in vitro. I. Inducers of spreading. Exp Cell Res. 1973;77:323–34.

    CAS  PubMed  Article  Google Scholar 

  27. Suzuki I, Hayashi I, Takaki T, Groveman DS, Fujimiya Y. Antitumor and anticytopenic effects of aqueous extracts of propolis in combination with chemotherapeutic agents. Cancer Biother Radiopharm. 2002;17(5):553–62.

    CAS  PubMed  Article  Google Scholar 

  28. Holden HE, Majeska JB, Studwell D. A direct comparison of mouse and rat bone marrow and blood as target tissues in the micronucleus assay. Mutat Res. 1997;391(1–2):87–9.

    CAS  PubMed  Google Scholar 

  29. Hayashi M, Hashimoto S, Sakamoto Y, Hamada C, Sofuni T, Yoshimura I. Statistical analysis of data in mutagenicity assays: rodent micronucleus assay. Environ Health Perspect. 1994;102(1):49–52.

    PubMed  Google Scholar 

  30. Orsolic N, Brbot Saranovic A, Basic I. Direct and indirect mechanism(s) of antitumor activity of propolis and its polyphenolic compounds. Planta Med. 2005;72:14–9.

    Google Scholar 

  31. Kohno H, Tanaka T, Kawabata K, Hirose Y, Sugie Y, et al. Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane-induced colon carcinogenesis in male F344 rats. Int J Cancer. 2002;101:461–8.

    CAS  PubMed  Article  Google Scholar 

  32. Hertog MG, Feskens EJ, Hollman PC, Katan MB, et al. Dietary antioxidant flavonoids and risk of coronary heart disease. The Zutphen elderly study. Lancet. 1993;342:1007–11.

    CAS  PubMed  Article  Google Scholar 

  33. Potter SM, Baum JA, Teng H, Stillman RJ, Shay NF, et al. Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women. Am J Clin Nutr. 1998;68:1375S–9S.

    CAS  PubMed  Google Scholar 

  34. Joel SP, Shah R, Slevin ML. Etoposide dosage and pharmacodynamics. Cancer Chemother Pharmacol. 1994;34:S69–75.

    PubMed  Article  Google Scholar 

  35. Kobayashi K, Ratain MJ. Pharmacodynamics and long-term toxicity of etoposide. Cancer Chemother Pharmacol. 1994;34:S64–8.

    PubMed  Article  Google Scholar 

  36. Watson RW. Redox regulation of neutrophil apoptosis. Antioxid Redox Signal. 2002;4:97–104.

    CAS  PubMed  Article  Google Scholar 

  37. Hande KR. Etoposide pharmacology. Semin Oncol. 1992;19(6 Suppl 13):3–9. Review.

    CAS  PubMed  Google Scholar 

  38. Lamson DW, Brignall MS. Antioxidants and cancer therapy II: quick reference guide. Altern Med Rev. 2000;5:152–63.

    CAS  PubMed  Google Scholar 

  39. Conklin KA. Cancer chemotherapy and antioxidants. J Nutr. 2004;134:3201S–4S.

    CAS  PubMed  Google Scholar 

  40. Hogland HC. Hematologic complications of cancer chemotherapy. Semin Oncol. 1982;9(1):95–102.

    Google Scholar 

  41. Lahouel M, Boulkour S, Segueni N, Fillastre JP. Protective effect of flavonoids against the toxicity of vinblastine, cyclophosphamide and paracetamol by inhibition of lipid-peroxidation and increase of liver glutathion. Haema. 2004;7:59–67.

    CAS  Google Scholar 

  42. Fitzpatrick LR, Wang J, Le T. Caffeic acid phenethyl ester, an inhibitor of nuclear factor-kappaB, attenuates bacterial peptidoglycan polysaccharide-induced colitis in rats. J Pharmacol Exp Ther. 2001;299(3):915–20.

    CAS  PubMed  Google Scholar 

  43. Ballester I, Camuesco D, Galvez J, Sanchez de Medina F, Zarzuelo A. Inhibition of pro-inflammatory markers in primary bone marrow-derived mouse macrophages by naturally occurring flavonoids: analysis of the structure-activity relationship. Biochem Pharmacol. 2006;72(8):1010–21.

    PubMed  Article  CAS  Google Scholar 

  44. Oršolić N, Horvat-Knežević A, Benković V, Bašić I. Benefits of use of propolis and related flavonoids against the toxicity of chemotherapeutic agents. Scientific evidence of the use of propolis in ethnomedicine. In: Oršolić N, Bašić I, editors. Ethnopharmacology—review book. India: Research Signpost; 2008. p. 195–222.

  45. da Silva J, Herrmann SM, Heuser V, Peres W, Possa Marroni N, et al. Evaluation of the genotoxic effect of rutin and quercetin by comet assay and micronucleus test. Food Chem Toxicol. 2002;40(7):941–7.

    CAS  PubMed  Article  Google Scholar 

  46. Yen GC, Duh PD, Tsai HL, Huang SL. Pro-oxidative properties of flavonoids in human lymphocytes. Biosci Biotechnol Biochem. 2003;67(6):1215–22.

    CAS  PubMed  Article  Google Scholar 

  47. Rajkapoor B, Murugesh N, Chodon D, Sakthisekaran D. Chemoprevention of N-nitrosodiethylamine induced phenobarbitol promoted liver tumors in rat by extract of Indigofera aspalathoides. Biol Pharm Bull. 2005;28(2):364–6.

    CAS  PubMed  Article  Google Scholar 

  48. Boutet I, Meistertzheim A, Tanguy A, Thébault MT, Moraga D. Molecular characterization and expression of the gene encoding aspartate aminotransferase from the Pacific oyster Crassostrea gigas exposed to environmental stressors. Comp Biochem Physiol C Toxicol Pharmacol. 2005;140(1):69–78.

    PubMed  Article  CAS  Google Scholar 

  49. Mc Intyre N, Rosalki S. Biochemical investigations in the management of liver disease. In: Prieto J, Rodes J, Shafriz DA, editors. Hepatobiliary diseases. `: Springer; 1992. p. 39–71.

    Google Scholar 

  50. Sforcin JM. Propolis and the immune system: a review. J Ethnopharmacol. 2007;113(1):1–14. Review.

    CAS  PubMed  Article  Google Scholar 

  51. Chopra S, Pillai KK, Husain SZ, Giri DK. Propolis protects against doxorubicin-induced myocardiopathy in rats. Exp Mol Pathol. 1995;62(3):190–8.

    CAS  PubMed  Article  Google Scholar 

  52. Sanz MJ, Ferrandiz MI, Cejudo M, Terencio MC, Gil B, et al. Influence of a series of natural flavonoids on free radical generating systems and oxidative stress. Xenobiotica. 1994;24(7):689–99.

    CAS  PubMed  Article  Google Scholar 

  53. Padmavathi R, Senthilnathan P, Sakthisekaran D. Therapeutic effect of propolis and paclitaxel on hepatic phase I and II enzymes and marker enzymes in dimethylbenz(a)anthracene-induced breast cancer in female rats. Comp Biochem Physiol C Toxicol Pharmacol. 2006;143(3):349–54.

    PubMed  Article  CAS  Google Scholar 

  54. Kolankaya D, Selmanoglu G, Sorkun K, Salih B. Protective effects of Turkish propolis on alcohol-induced serum lipid changes and liver injury in male rats. Food Chem. 2002;78:13–217.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nada Oršolić.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Oršolić, N., Benković, V., Lisičić, D. et al. Protective effects of propolis and related polyphenolic/flavonoid compounds against toxicity induced by irinotecan. Med Oncol 27, 1346–1358 (2010). https://doi.org/10.1007/s12032-009-9387-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12032-009-9387-5

Keywords

  • Propolis preparations
  • Quercetin
  • Naringin
  • Irinotecan
  • Ehrlich ascites tumors
  • Chemoprevention
  • Immunomodulatory effect