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

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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.

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Acknowledgements

This work was supported by a programme grant from the UK Medical Research Council and a “Rapid Access to Preventive Development” (RAPID) grant from the US NCI. We thank Colin Travis and his colleagues in Biomedical Services (Leicester University, UK) for help with the animal husbandry.

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Authors and Affiliations

  1. Department of Cancer Studies, LRI, RKCSB, University of Leicester, Leicester, LE2 7LX, UK

    Richard D. Verschoyle, Hong Cai, William P. Steward & Andreas J. Gescher

  2. MRC Toxicolgy Unit, University of Leicester, Leicester, LE1 9HN, UK

    Peter Greaves

  3. Dr Von Haunersches Kinderspital, LMU Munich, 80337, Munich, Germany

    Arndt Borkhardt

  4. Department of Oncology, Mario Negri Research Institute, 20157, Milan, Italy

    Massimo Broggini & Maurizio D’Incalci

  5. Toxicology and Pharmacology Laboratory, Biosciences Division, SRI International, Menlo Park, CA, 94025-3493, USA

    Ed Riccio & Rupa Doppalapudi

  6. NIH NCI Division of Cancer Prevention, Chemoprevention Agent Development Research Group, Bethesda, MD, 20892-7322, USA

    Izet M. Kapetanovic

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  1. Richard D. Verschoyle
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  2. Peter Greaves
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  3. Hong Cai
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  5. Massimo Broggini
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  6. Maurizio D’Incalci
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  7. Ed Riccio
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  8. Rupa Doppalapudi
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  9. Izet M. Kapetanovic
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  10. William P. Steward
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  11. Andreas J. Gescher
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Correspondence to Andreas J. Gescher.

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Verschoyle, R.D., Greaves, P., Cai, H. et al. Preliminary safety evaluation of the putative cancer chemopreventive agent tricin, a naturally occurring flavone. Cancer Chemother Pharmacol 57, 1–6 (2006). https://doi.org/10.1007/s00280-005-0039-y

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  • DOI: https://doi.org/10.1007/s00280-005-0039-y

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