Cancer Chemotherapy and Pharmacology

, Volume 57, Issue 1, pp 1–6 | Cite as

Preliminary safety evaluation of the putative cancer chemopreventive agent tricin, a naturally occurring flavone

  • Richard D. Verschoyle
  • Peter Greaves
  • Hong Cai
  • Arndt Borkhardt
  • Massimo Broggini
  • Maurizio D’Incalci
  • Ed Riccio
  • Rupa Doppalapudi
  • Izet M. Kapetanovic
  • William P. Steward
  • Andreas J. Gescher
Original Article

Abstract

Purpose: Naturally occurring flavonoids such as quercetin and genistein possess cancer chemopreventive properties in experimental models. However, adverse effects such as their mutagenicity confound their potential clinical usefulness. Furthermore in leukaemia cells some flavonoids cleave the breakpoint cluster region of the mixed lineage leukaemia (MLL) gene as a consequence of inhibition of topoisomerase II. The choice of flavonoids to be developed as cancer chemopreventive agents depends crucially on their safety. Here, we explored safety aspects of the novel flavone tricin, a constituent of rice bran and other grass species, which has recently been found to interfere with murine gastrointestinal carcinogenesis. Methods: Evidence of pathological or morphological changes in liver, lung, heart, spleen, kidney, adrenal gland, pancreas or thymus tissues was studied in mice which received tricin, genistein or quercetin 1,000 mg/kg daily by the oral route on five consecutive days. The ability of tricin (50 μM) to cleave the MLL gene was studied in human leukaemia cells by Southern blotting, and its effect on human topoisomerase II activity was investigated in incubations with supercoiled DNA. The mutagenicity of tricin was assessed in the Salmonella/Escherichia coli assay, and its clastogenicity was adjudged by chromosomal aberrations in Chinese hamster ovary cells and occurrence of micronuclei in bone marrow erythrocytes in Swiss-Webster mice. Results: Neither tricin, quercetin, or genistein caused pathological or morphological changes in any of the murine tissues studied. Tricin (50 μM) failed to cause MLL gene breakage, and it inhibited topoisomerase II only at 500 μM, but not at 10, 50 or 100 μM. Tricin lacked genotoxic properties in the systems studied here. Conclusion: The results tentatively suggest that tricin may be considered safe enough for clinical development as a cancer chemopreventive agent.

Keywords

Flavonoids Chemoprevention Genotoxicity Toxicity 

References

  1. 1.
    Miller AB (1990) Diet and cancer: a review. Acta Oncol 29:87–95PubMedCrossRefGoogle Scholar
  2. 2.
    Verma AK, Johnson JA, Gould MN, Tanner MA (1988) Inhibition of 7,12-dimethylbenz[a]anthracene- and N-nitrosomethylurea-induced rat mammary cancer by dietary flavonol quercetin. Cancer Res 48:5754–5758PubMedGoogle Scholar
  3. 3.
    Lamartiniere CA, Moore JB, Brown NM, Thompson R, Hardin MJ, Barnes S (1995) Genistein suppresses mammary cancer in rats. Carcinogenesis 16:2833–2840PubMedCrossRefGoogle Scholar
  4. 4.
    Murrill WB, Brown NM, Zhang J-X, Manzolillo PA, Barnes S, Lamartiniere CA (1996) Prepubertal genistein exposure suppresses mammary cancer and enhances gland differentiation in rats. Carcinogenesis 17:1451–1457PubMedCrossRefGoogle Scholar
  5. 5.
    Iwashina T (2000) The structure and distribution of the flavonoids in plants. J Plant Res 113:287–299CrossRefGoogle Scholar
  6. 6.
    Seino Y, Nagao M, Yahagi T, Sugimura T, Yasuda T, Nishimura S (1978) Identification of a mutagenic substance in a spice, sumac, as quercetin. Mutat Res 58:225–229CrossRefPubMedGoogle Scholar
  7. 7.
    Nakayasu M, Sakamoto H, Terada M, Nagao M, Sugimura T (1986) Mutagenicity of quercetin in Chinese hamster lung cells in culture. Mutat Res 174:79–83CrossRefPubMedGoogle Scholar
  8. 8.
    Rao CV, Wang CX, Simi B, Lubet R, Kelloff G, Steele V, Reddy BS (1997) Enhancement of experimental colon cancer by genistein. Cancer Res 57:3717–3722PubMedGoogle Scholar
  9. 9.
    Strick R, Strissel PL, Borgers S, Smith SL, Rowley JD (2000) Dietary bioflavonoids induce cleavage in the MLL gene and may contribute to infant leukemia. Proc Natl Acad Sci USA 97:4790–4795CrossRefPubMedGoogle Scholar
  10. 10.
    Hudson EA, Dinh PA, Kokubun T, Simmonds MSJ, Gescher A (2000) Characterization of potentially chemopreventive phenols in extracts of brown rice that inhibit the growth of human breast and colon cancer cells. Cancer Epidemiol Biomarkers Prev 9:1163–1170PubMedGoogle Scholar
  11. 11.
    Cai H, Verschoyle RD, Tunstall RG, Al-Fayez M, Platton S, Steward WP, Gescher AJ (2005) Inhibition of intestinal carcinogenesis in mice by rice bran or its constituent flavone tricin, a potent cyclooxygenase inhibitor. (Submitted)Google Scholar
  12. 12.
    Workman P, Twentyman P, Balkwill F, Balmain A, Chaplin D, Double J, Embleton J, Newell DR, Raymond R, Stables R, Stephens T, Wallace J, Navaratnam V (1998) United Kingdom Co-ordinating Committee on Cancer Research (UKCCCR) guidelines for the welfare of animals in experimental neoplasia (second edition). Br J Cancer 77:1–10Google Scholar
  13. 13.
    Cai H, Steward WP, Gescher AJ (2005) Determination of the putative cancer chemopreventive flavone tricin in plasma and tissues of mice by HPLC with UV-visible detection. Biomed Chromatogr (in press)Google Scholar
  14. 14.
    Codegoni AM, Castagna S, Mangioni C, Scovassi AI, Broggini M, D’Incalci M (1998) DNA-topoisomerase I activity and content in epithelial ovarian cancer. Ann Oncol 9:313–319CrossRefPubMedGoogle Scholar
  15. 15.
    Sorensen IK, Kristiansen E, Mortensen A, Nicolaisen GM, Wijnandes JAH, van Kranen HJ, van Kreijl CF (1998) The effect of soy isoflavones on the development of intestinal neoplasia in the Apc(Min) mouse. Cancer Lett 130:217–225CrossRefPubMedGoogle Scholar
  16. 16.
    Mahmoud NN, Carothers AM, Grunberger D, Bilinski RT, Churchill MR, Martucci C, Newmark HL, Bertagnolli MM (2000) Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis. Carcinogenesis 21:921–927CrossRefPubMedGoogle Scholar
  17. 17.
    Ferry DR, Smith A, Malkhandi J, Fyfe DW, DeTakats GG, Anderson D, Baker J, Kerr DJ (1996) Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res 2:659–668PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Richard D. Verschoyle
    • 1
  • Peter Greaves
    • 2
  • Hong Cai
    • 1
  • Arndt Borkhardt
    • 3
  • Massimo Broggini
    • 4
  • Maurizio D’Incalci
    • 4
  • Ed Riccio
    • 5
  • Rupa Doppalapudi
    • 5
  • Izet M. Kapetanovic
    • 6
  • William P. Steward
    • 1
  • Andreas J. Gescher
    • 1
  1. 1.Department of Cancer Studies, LRI, RKCSBUniversity of LeicesterLeicesterUK
  2. 2.MRC Toxicolgy UnitUniversity of LeicesterLeicesterUK
  3. 3.Dr Von Haunersches KinderspitalLMU MunichMunichGermany
  4. 4.Department of OncologyMario Negri Research InstituteMilanItaly
  5. 5.Toxicology and Pharmacology Laboratory, Biosciences DivisionSRI InternationalMenlo ParkUSA
  6. 6.NIH NCI Division of Cancer PreventionChemoprevention Agent Development Research GroupBethesdaUSA

Personalised recommendations