Saffron Aqueous Extract Inhibits the Chemically-induced Gastric Cancer Progression in the Wistar Albino Rat

Document Type : Original Article


1 Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

2 1Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran Department of Biology, Faculty of Sciences, Zabol University, Zabol, Iran

3 The Cancer Institute, Imam Khomeini University Hospital, Tehran University of Medical Sciences, Tehran, Iran

4 Department of Medical Physics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

5 Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran


Objective(s): Gastric cancer is the first and second leading cause of cancer related death in Iranian men and women, respectively. Gastric cancer management is based on the surgery, radiotherapy and chemotherapy. In the present study, for the first time, the beneficial effect of saffron (Crocus sativus L.) aqueous extract (SAE) on the 1-Methyl-3-nitro-1-nitrosoguanidine (MNNG)-induced gastric cancer in rat was investigated.
Materials and Methods: MNNG was used to induce gastric cancer and then, different concentrations of SAE were administered to rats. After sacrificing, the stomach tissue was investigated by both pathologist and flow cytometry, and several biochemical parameters was determined in the plasma (or serum) and stomach of rats.
Results: Pathologic data indicated the induction of cancer at different stages from hyperplasia to adenoma in rats; and the inhibition of cancer progression in the gastric tissue by SAE administration; so that, 20% of cancerous rats treated with higher doses of SAE was completely normal at the end of experiment and there was no rat with adenoma in the SAE treated groups. In addition, the results of the flow cytometry/ propidium iodide staining showed that the apoptosis/proliferation ratio was increased due to the SAE treatment of cancerous rats. Moreover, the significantly increased serum LDH and decreased plasma antioxidant activity due to cancer induction fell backwards after treatment of rats with SAE. But changes in the other parameters (Ca2+, tyrosine kinase activity and carcino-embryonic antigen) were not significant.
Conclusion: SAE inhibits the progression of gastric cancer in rats, in a dose dependent manner.


  1. Matysiak-Bundnik T, Megraud F. Helicobacter pylori infectionand gastric cancer. Eur J Cancer 2006; 42:708-716.

  2. Macdonald JS. Gastric cancer-new Therapeutic toptions. N Eng J Med 2006; 355:76-77.

  3. John C, Layke PPL. Gastric cancer: diagnosis and treatment options. Am Fam Physician 2004; 69:1133-1140.
  4. NCCN (National Comprehensive Cancer Network). Clinical Practice Guidelines in Oncology. New York: Gastric Cancer; 2006.
  5. Sadjadi A, Nouraie M, Mohagheghi MA, Mousavi-Jarrahi A, Malekzadeh R, Parkin DM. Cancer occurrence in Iran in 2002, an international perspective. Asian Pac J Cancer Perv  2005; 6:359-363.
  6. Caldas C, Carneiro F, Lynch HT, Yokota J, Wiesner GL, Powell SM, et al. Familial gastric cancer: overview and guidelines for management.. J Med Genet  1999; 36:873-880.
  7. Fitzgerald RC, Caldas C. Familial gastric cancer - clinical management. Best Pract Res Clin Gastroenterol  2006; 20:735-743.
  8. Komatsu S, Masuda T, Hisamichi S. Effect of calcium on rat gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine. Tohoku J Exp Med 1991; 165:291-297.
  9.  Hu PJ, Yu J, Zeng ZR, Leung WK, Lin HL, Tang BD, et al. Chemoprevention of gastric cancer by celecoxib in rats. Gut  2004; 53:195-200.

10. Scartozzi M, Galizia E, Freddari F, Berardi R, Cellerino R, Cascinu S. Molecular biology of sporadic gastric cancer: prognostic indicators and novel therapeutic approaches. Cancer Treat Rev 2004; 30:451-459.

11. Kim JR, Lee K, Jung WT, Lee OJ, Kim TH, Kim HJ, et al. Validity of serum pepsinogen levels and quininium resin test combined for gastric cancer screening. Cancer Detect Prev 2005; 29:570-575.

12. Bast  C Robert KWD, Pollock l E Raphae,  Weichselbaum  R Ralph ,  Holland  F James,  Frei Emil, editor. Holland-Frei Cancer Medicine. 5th ed. BC Decker; 2000.

13. Correa P, Haenszel W, Cuello C. A model for gastric cancer epidemiology. Lancet 1972 ;2:58-60.

14. Lynch HT, Grady W, Suriano G, Huntsman D. Gastric cancer: new genetic developments. J Surg Oncol  2005; 90:114-133; discussion 33.

15. Gwen Harison  PI. Management of oesophageal and gastric cancer. First ed. Edinburgh: Scottish Intercollegiate Guidlines Network; 2006. p. 1-74.

16. Fuchs CS, Meyer RJ. Gastric Carcinoma.N Eng J Med  1995; 333:32-41.

17. Buttar NS, Wiersema MJ, Wang KK, Demars CJ,Prasad GA, Lutzke LS. Rodent endosonography to monitor esophageal cancer. Int J Gastrointest Cancer  2006; 37:84-90.

18. Hernandez LV, Bhutani MS. Emerging applications of endoscopic ultrasound in gastrointestinal cancers. Gastrointest Cancer Res 2008; 2:198-202.

19. Pungpapong S, Noh KW, Wallace MB. Endoscopic ultrasonography in the diagnosis and management of cancer. Expert Rev Mol Diagn 2005; 5:585-597.

20. Waxman I, Dye CE. Interventional endosonography. Cancer J  2002; 1:S113-123.

21. Miri HR, Bathaie SZ, Mohagheghi MA, Mokhtari-Dizaji M, Shahbazfar AA. A non-invasive method for early detection of MNNG-induced gastric cancer of male Wistar rat:Ultrasonic study. Ultrasound Med Biol 2011; 37:780-787.

22. Abdullaev FI. Cancer chemopreventive and tumoricidal properties of saffron (Crocus sativus L.). Exp Biol Med (Maywood) 2002; 227:20-25.

23. Nair S, Kurumboor S, Hasegawa J. Saffron chemoprevention in biology and medicine: a review. Cancer Biother 1995; 10:257-264.

24. Abdullaev FI, Riveron-Negrete L, Caballero-Ortega H, Manuel Hernandez J, Perez-Lopez I, Pereda-Miranda R, et al. Use of in vitro assays to assess the potential antigenotoxic and cytotoxic effects of saffron (Crocus sativus L.). Toxicol       In Vitro  2003; 17:731-736.

25. Li C-Y, Wu T-S. Constituents of the stigmas of crocus sativus and their tyrosinase inhibitory activity. J Nat Prod  2002; 65:1452-1456.

26. Salomi MJ, Nair SC, Panikkar KR. Inhibitory effects of Nigella sativa and saffron (Crocus sativus) on chemical carcinogenesis in mice. Nutr Cancer 1991; 16:67-72.

27. Abdullaev FI, Ferenkel GD. The effect of saffron on intracellular DNA, RNA and protein synthesis in malignant and non-malignant human cells. Biofactors  1992; 4:43-45.

28. Abdullaev FI, Frenkel GD. Effect of saffron on cell colony formation and cellular nucleic acid and protein synthesis. Biofactors  1992; 3:201-204.

29. Escribano J, Alonso GL, Coca-Prados M, Fernandez JA. Crocin, safranal and picrocrocin from saffron (Crocus sativus L.) inhibit the growth of human cancer cells in vitro. Cancer Lett 1996; 100:23-30.

30. Bathaie SZ, Mousavi SZ. New applications and mechanisms of action of saffron and its important ingredients. Crit Rev Food Sci Nutr 2010 ; 50:761-86.

31. Bolhasani A, Bathaie SZ, Moosavi-Movahedi A.A, Ghaffari M. The Study of the Interaction ofMonoterpene aldehydes from Iranian Saffron withDNA. Modarres J Med Sci 2003, 6:33-42.

32. Bolhasani-sanjani A, Bathaie SZ, Yavari I, Moosavi-movahedi A, Ghaffari M. Separation and purification of some components of Iranian saffron. Asian J Chem  2005; 17:725-729.

33. Ashrafi M. The in vitro studies on the interactions of the molecular component of Iranian saffron with histone H1 and H1-DNA complex. Tehran: Tarbiat Modares University; 2003.

34.Ashrafi M, Bathaie SZ, Taghikhani M, Moosavi-Movahedi AA. The effect of carotenoids obtained from saffron on histone H1 structure and H1-DNA interaction. Int J Biol Macromol 2005; 36:246-252.

35. Meng LX, Li Q, Xue YJ, Guo RD, Zhang YQ, Song XY. Identification of gastric cancer-related genes by multiple high throughput analysis and data mining. Zhonghua Wei Chang Wai Ke Za Zhi  2007; 10:169-172.

36. Meng Z, Lei D, Wang J. Expression and mutation of p53 and H-ras genes in the carcinogenesis and development of gastric adenocarcinoma induced by MNNG in rats. Zhonghua Bing Li Xue Za Zhi 1998; 27:117-119.

37. Mei Y, Wei D, Liu J. Modulation effect of tea polyphenol toward N-methyl-N'-nitro-N-nitrosoguanidine-induced precancerous gastric lesion in rats. J Nutr Biochem  2005; 16:172-177.

38. Iishi H, Tatsuta M, Baba M, Uehara H, Nakaizumi A. Protection by galanin against gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats. Cancer Res 1994 ; 54:3167-3170.

39. Gao Z, Yang J, Huang Y, Yu Y. N-methyl-N'-nitro-N-nitrosoguanidine interferes with the epidermal growth factor receptor-mediated signaling pathway. Mutat Res 2005; 570:175-184.

40. Benzie IF sJ. The ferric reducing ability of plasma (FRAP) as a measure of antioxidant power: the FRAP assay. Anal Biochem  1996; 239:70-76.

41. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72:248-254.

42. Lauren P. The two histological main types of gastric carcinoma:diffuse and so-called intestinal- type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 1965;64:31-49.

43. Yamane T, Takahashi T, Kuwata K, Oya K, Inagake M, Kitao Y, et al. Inhibition of N-methyl-N'-nitro-N-nitrosoguanidine-inducedcarcinogenesis by (-)-epigallocatechin gallate in the rat glandular stomach. Cancer Res 1995; 55:2081-2084.

44. Hirose M, Fukushima S, Kurata Y, Tsuda H, Tatematsu M, Ito N. Modification of N-methyl-N'-nitro-N-nitrosoguanidine-induced forestomach and glandular stomach carcinogenesis by phenolic antioxidants in rats. Cancer Res 1988; 48:5310-5315.

45. Abdullaev F. Crocus sativus against cancer. Arch Med Res 2003; 34:354.

46. Abdullaev FI, Ferenkel GD. Effect of saffron on cell colony formation and cellular nucleic acid and protein synthesis. Biofactors 1992; 3:201-204.

47.Abdullaev FI, Espinosa-Aguirre JJ. Biomedical properties of saffron and its potential use in cancer therapy and chemoprevention trials. Cancer Detect Prev  2004; 28:426-432.

48. Nair S, Panikkar B, Panikkar K. Antitumor activity of saffron (Crocus sativus). Cancer Lett 1991; 57:109-114.

49. Chitsazan A, Bathaie SZ, Mohagheghi MA, Banasadegh S. Rat mammary tumor induced by NMU and the effect of natural carotenoids. XXX1st Symposium on Hormone and Regulation: Cancer and Cell Signalling. Monte Saint Odile, France: 2006.

50. Bai H, Gu L, Zhou J, Deng D. p16 hypermethylation during gastric carcinogenesis of Wistar rats by N-methyl-N'-nitro-N-nitrosoguanidine. Mutat Res 2003; 535:73-78.

51. Sugimura T, Fujimura S. Tumour production in glandular stomach of rat by N-methyl-N'-nitro-N-nitrosoguanidine. Nature 1967; 216:943-944.

52. Zhang RF. The influence of castration on the induction of gastric adenocarcinoma by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in Wistar rats. Zhonghua Bing Li Xue Za Zhi 1989; 18:128-130.

53. Kobori O, Gedigk P, Totovic V. Adenomatous changes and adenocarcinoma of glandular stomach in Wistar rats induced by N-methyl-N'-nitro-N-nitrosoguanidine. An electron microscopic and histochemical study. Virchows Arch A Pathol Anat Histol 1977; 373:37-54.

54. Zhang ZX, Li YQ, Li GR, Sun ZX. Induction of gastric adenocarcinoma in rats by N-methyl-N-nitro-N-nitroso-guanidine and ultrastructural changes of epithelial cells of the pyloric gland region. Sci Sin  1981; 24:416-422.

55. Zaidi NH, O'Connor PJ, Butler WH. N-methyl-N'-nitro-N-nitrosoguanidine-induced carcinogenesis: differential pattern of upper gastrointestinal tract tumours in Wistar rats after single or chronic oral doses. Carcinogenesis 1993 ; 14:1561-1567.

56.Palmer HJ, Paulson KE. Reactive oxygen species and antioxidants in signal transduction and gene expression. . Nutr Rev 1997; 55:353-361.

57. Suzuki YS, Forman JJ, Sevanian A. Oxidants as stimulators of signal transduction. Free Radic Biol Med 1997; 22:269-285.

58. Przybyszewski J, Box HC, . MK-M. Induction of reactiveoxygen species without 8-hydroxydeoxyguanosine formation in DNA of initiated mouse keratinocytes treated with 12-O-tetradecanoylphorbol- 13-acetate. Carcinogenesis 1998; 19:1467-1474.

59. Abdullaev FI, Frenkel GD. The effect of saffron on intracellular DNA, RNA and protein synthesis in malignant and non-malignant human cells. Biofactors 1992; 4:43-45.

60. Wanebo H, Kennedy B, Chemiel J, Steele JG, Winchester D, Osteen R. Cancer of stomach: a patient care study by the american college of surgeons. Ann Surg 1993; 218:583-592.

61. Bast C Robert KWD, Pollock l E Raphae, Weichselbaum  R Ralph , Holland  F James, Frei Emil, editor. Holland-Frei Cancer Medicine. 5th ed. BC Decker; 2000.

62. Wu C-W, Li AF-Y, Chi C-W, Huang CL, Shen


K-H, Liu W-Y, et al. Human Gastric Cancer Kinase Profile and Prognostic Significance of MKK4 Kinase. Am J Pathol 2000; 156:2007-2015.

63. Wahby M, Shelef LA, Luk GD, Majumdar APN. Induction of gastric mucosal cell proliferation by the fungicide captan: role of tyrosine kinase. Toxicol Lett  1990; 54:189-198.

64. Adamson E. Oncogenes in development. Development 1987; 49:449-471.

65. Land H, Parada LF, Weinberg RA. Cellular oncogenes and multistep carcinogenesis. Science 1983; 222:771-777.

66. Majumdar APN, Edgerton EA, Arlow FL. Gastric mucosal tyrosine kinase activity during aging and its relationship to cell proliferation in rats. Biochem Biophys Acta  1988; 965:97-105.