Advertisement

Investigational New Drugs

, Volume 26, Issue 6, pp 531–540 | Cite as

Aberrant crypt foci and AgNORs as putative biomarkers to evaluate the chemopreventive efficacy of pronyl-lysine in rat colon carcinogenesis

  • Jayabal Panneer Selvam
  • Selvaraj Aranganathan
  • Namasivayam NaliniEmail author
PRECLINICAL STUDIES

Summary

Chemoprevention opens new perspectives in the prevention of cancer and other degenerative diseases. Use of target-organ biological models at the histological and genetic levels can markedly facilitate the identification of potential chemopreventive agents. Our aim was to study the chemopreventive efficacy of pronyl-lysine, a key antioxidant present in bread crust by evaluating, the total number of aberrant crypt foci (ACF), their distributions, dysplastic ACF, colonic tumor incidence and the expression of cell proliferation biomarker such as the argyrophilic nucleolar organizing region-associated proteins (AgNORs) in 1,2-dimethylhydrazine (DMH) induced colon cancer in rats. Male Wistar rats were randomized into seven groups, group 1 were control rats, group 2 received pronyl-lysine (2 mg/kg body weight p.o. everyday), rats in groups 3–7 were administered DMH (20 mg/kg body weight) in the groin for 15 weeks. In addition, group 4 (pre-initiation), 5 (initiation), 6 (post-initiation), and 7 (entire period) received pronyl-lysine (2 mg/kg body weight p.o) everyday. At the end of 34 weeks, pronyl-lysine supplementation showed markedly reduced tumor incidence, ACF development and also lowered number of AgNORs. Overall, these findings confirm that pronyl-lysine has a positive beneficial effect against chemically induced colonic preneoplastic progression in rats.

Keywords

Aberrant crypt foci AgNORs Pronyl-lysine Cell proliferation Chemoprevention 

Notes

Acknowledgement

This work was supported by the Department of Biotechnology (DBT), Ministry of Science & Technology, New Delhi in the form of a Junior Research Fellowship to J. Panneer Selvam and is gratefully acknowledged.

References

  1. 1.
    Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ (2006) Cancer statistics, 2006. CA Cancer J Clin 56:106–130PubMedGoogle Scholar
  2. 2.
    Sinha R, Anderson DE, McDonald SS, Greenwald P (2003) Cancer risk and diet in India. J Postgrad Med 49:222–228PubMedGoogle Scholar
  3. 3.
    Sengottuvelan M, Viswanathan P, Nalini N (2006) Chemopreventive effect of trans-resveratrol-a phytoalexin against colonic aberrant crypt foci and cell proliferation in 1,2-dimethylhydrazine induced colon carcinogenesis. Carcinogenesis 27:1038–1046PubMedCrossRefGoogle Scholar
  4. 4.
    Deeptha K, Kamaleeswari M, Sengottuvelan M, Nalini N (2006) Dose dependent inhibitory effect of dietary caraway on 1,2-dimethylhydrazine induced colonic aberrant crypt foci and bacterial enzyme activity in rats. Invest New Drugs 24:479–488PubMedCrossRefGoogle Scholar
  5. 5.
    Lindenmeier M, Faist V, Hofmann T (2002) Structural and functional characterization of pronyl-lysine, a novel protein modification in bread crust melanoidins showing in vitro antioxidative and phase I/II enzyme modulating activity. J Agric Food Chem 50:6997–7006PubMedCrossRefGoogle Scholar
  6. 6.
    Marko D, Kemeny M, Bernady E, Habermeyer M, Weyand U, Meiers S, Frank O, Hofmann T (2002) Studies on the inhibition of tumor cell growth and microtubule assembly by 3-hydroxy-4-[(E)-(2-furyl) methylidene]methyl-3-cyclopentene-1,2-dione, an intensively coloured Maillard reaction product. Food Chem Toxicol 40:9–18PubMedCrossRefGoogle Scholar
  7. 7.
    Somoza V, Wenzel E, Lindenmeier M, Grothe D, Erbersdobler HF, Hofmann T (2005) Influence of feeding malt, bread crust, and a pronylated protein on the activity of chemopreventive enzymes and antioxidative defense parameters in vivo. J Agric Food Chem 53:8176–8182PubMedCrossRefGoogle Scholar
  8. 8.
    Schmiedlin-Ren P, Thummel KE, Fisher JM, Paine MF, Lown KS, Watkins PB (1997) Expression of enzymatically active CYP3A4 by Caco-2 cells grown on extracellular matrixcoated permeable supports in the presence of 1-alpha, 25-dihydroxyvitamin D3. Mol Pharmacol 51:741–754PubMedGoogle Scholar
  9. 9.
    Wilkinson J, Clapper ML (1997) Detoxication enzymes and chemoprevention. Proc Soc Exp Biol Med 216:192–200PubMedGoogle Scholar
  10. 10.
    Somoza V, Lindenmeier M, Hofmann T, Frank O, Erbersdobler Hf, Baynes Jw, Thorpe Sr, Heidland A, Zill H, Bek S, Huber J, Weigle T, Scheidler S, Busch Ae, Sebekova K (2005) Dietary bread crust advanced glycation end products bind to the receptor for AGEs in HEK-293 kidney cells but are rapidly excreted after oral administration to healthy and subtotally nephrectomized rats. Ann NY Acad Sci 1043:492–500PubMedCrossRefGoogle Scholar
  11. 11.
    McLellan EA, Medline A, Bird RP (1991) Sequential analyses of the growth and morphological characteristics of aberrant crypt foci: putative preneoplastic lesions. Cancer Res 51:5270–5274PubMedGoogle Scholar
  12. 12.
    Yamada Y, Mori H (2003) Pre-cancerous lesions for colorectal cancers in rodents: a new concept. Carcinogenesis 24:1015–1019PubMedCrossRefGoogle Scholar
  13. 13.
    Bird RP (1995) Role of aberrant crypt foci in understanding the pathogenesis of colon cancer. Cancer Lett 93:55–71PubMedCrossRefGoogle Scholar
  14. 14.
    Hirose Y, Kuno T, Yamada Y, Sakata K, Katayama M, Yoshida K, Qiao Z, Hata K, Yoshimi N, Mori H (2003) Azoxymethane-induced beta-catenin-accumulated crypts in colonic mucosa of rodents as an intermediate biomarker for colon carcinogenesis. Carcinogenesis 24:107–111PubMedCrossRefGoogle Scholar
  15. 15.
    Wargovich MJ, Chen CD, Jimenez A, Steele VE, Velasco M, Stephens LC, Price R, Gray K, Kelloff GJ (1996) Aberrant crypts as a biomarker for colon cancer: evaluation of potential chemopreventive agents in the rat. Cancer Epidemiol Biomarkers Prev 5:355–360PubMedGoogle Scholar
  16. 16.
    Thorup I (1997) Histomorphological and immunochemical characterization of colonic aberrant crypt foci in rats: relation to growth factor expression. Carcinogenesis 18:465–472PubMedCrossRefGoogle Scholar
  17. 17.
    Yamada Y, Mori H (2003) Pre-cancerous lesions for colorectal cancers in rodents: a new concept. Carcinogenesis 24:1015–1019PubMedCrossRefGoogle Scholar
  18. 18.
    Ruschoff J, Plate K, Bittinger A, Thomas C (1989) Nucleolar organizer regions (NORs). Basic concepts and practical application in tumor pathology. Pathol Res Pract 185:878–885PubMedGoogle Scholar
  19. 19.
    Contractor H, Ruschoff J, Hanisch T, Ulshofer B, Neumann K, Schultze-Seemann W, Thomas C (1991) Silver-stained structures in prostatic carcinoma: evaluation of diagnostic and prognostic relevance by automated image analysis. Urol Int 46:9–14PubMedCrossRefGoogle Scholar
  20. 20.
    Risio M, Rossini FP (1993) Cell proliferation in colorectal adenomas containing invasive carcinoma. Anticancer Res 13:43–47PubMedGoogle Scholar
  21. 21.
    Ruschoff J, Zimmermann R, Ulshofer B, Thomas C (1992) Silver-stained nucleolar organizer proteins in urothelial bladder lesions. A morphometric study. Pathol Res Pract 188:593–598PubMedGoogle Scholar
  22. 22.
    Lindenmeier M, Hofmann T (2004) Influence of baking conditions and precursor supplementation on the amounts of the antioxidant pronyl-L-lysine in bakery products. J Agric Food Chem 52:350–354PubMedCrossRefGoogle Scholar
  23. 23.
    Ochiai M, Watanabe M, Nakanishi M, Taguchi A, Sugimura T, Nakagama H (2005) Differential staining of dysplastic aberrant crypt foci in the colon facilitates prediction of carcinogenic potentials of chemicals in rats. Cancer Lett 220:67–74PubMedCrossRefGoogle Scholar
  24. 24.
    Nyska A, Zusman I, Klein T, Sheila N, Weis O, Madar Z, Klein B (1995) Assessment of the nucleolar organizer regions by automated image analysis in benign and malignant colonic tumours and adjacent tissues in rats. J Comp Pathol 113:45–50PubMedCrossRefGoogle Scholar
  25. 25.
    Tanaka T, Makita H, Kawamori T, Kawabata K, Mori H, Murakami A, Satoh K, Hara A, Ohigashi H, Koshimizu K (1997) A xanthine oxidase inhibitor 1′-acetoxychavicol acetate inhibits azoxymethane-induced colonic aberrant crypt foci in rats. Carcinogenesis 18:1113–1118PubMedCrossRefGoogle Scholar
  26. 26.
    Kanna PS, Mahendrakumar CB, Chakraborty T, Hemalatha P, Banerjee P, Chatterjee M (2003) Effect of vanadium on colonic aberrant crypt foci induced in rats by 1,2 dimethyl hydrazine. World J Gastroenterol 9:1020–1027PubMedGoogle Scholar
  27. 27.
    Agner AR, Bazo AP, Ribeiro LR, Salvadori DM (2005) DNA damage and aberrant crypt foci as putative biomarkers to evaluate the chemopreventive effect of annatto (Bixa orellana L.) in rat colon carcinogenesis. Mutat Res 582:146–154PubMedGoogle Scholar
  28. 28.
    Lipkin M (1988) Biomarkers of increased susceptibility to gastrointestinal cancer: new application to studies of cancer prevention in human subjects. Cancer Res 48:235–245PubMedGoogle Scholar
  29. 29.
    Bird RP, Good CK (2000) The significance of aberrant crypt foci in understanding the pathogenesis of colon cancer. Toxicol Lett 112–113:395–402PubMedCrossRefGoogle Scholar
  30. 30.
    Kawamori T, Tanaka T, Hara A, Yamahara J, Mori H (1995) Modifying effects of naturally occurring products on the development of colonic aberrant crypt foci induced by azoxymethane in F344 rats. Cancer Res 55:1277–1282PubMedGoogle Scholar
  31. 31.
    Waitzberg DL, Goncalves EL, Faintuch J, Bevilacqua LR, Rocha CL, Cologni AM (1989) Effect of diets with different protein levels on the growth of Walker 256 carcinosarcoma in rats. Braz J Med Biol Res 22:447–455PubMedGoogle Scholar
  32. 32.
    Poulsen M, Molck AM, Thorup I, Breinholt V, Meyer O (2001) The influence of simple sugars and starch given during pre- or post-initiation on aberrant crypt foci in rat colon. Cancer Lett 167:135–143PubMedCrossRefGoogle Scholar
  33. 33.
    Yamaguchi A, Tsukioka Y, Kurosaka Y, Nishimura G, Kanno M, Yonemura Y, Mivazaki I (1993) Prognostic value of nucleolar organizer regions in endoscopically biopsied tissues of colorectal cancers. Oncology 50:121–126PubMedCrossRefGoogle Scholar
  34. 34.
    Wong WM, Wright NA (1999) Cell proliferation in gastrointestinal mucosa. J Clin Pathol 52:321–333PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Jayabal Panneer Selvam
    • 1
  • Selvaraj Aranganathan
    • 1
  • Namasivayam Nalini
    • 1
    Email author
  1. 1.Department of Biochemistry and BiotechnologyAnnamalai UniversityAnnamalainagarIndia

Personalised recommendations