Preliminary safety evaluation of the putative cancer chemopreventive agent tricin, a naturally occurring flavone.
OBJECTIVE
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 microM) 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 microM) failed to cause MLL gene breakage, and it inhibited topoisomerase II only at 500 microM, but not at 10, 50 or 100 microM. Tricin lacked genotoxic properties in the systems studied here.


CONCLUSIONS
The results tentatively suggest that tricin may be considered safe enough for clinical development as a cancer chemopreventive agent.
Verschoyle
Richard D
RD
Department of Cancer Studies, LRI, RKCSB, University of Leicester, Leicester, LE2 7LX, UK.
Greaves
Peter
P
Cai
Hong
H
Borkhardt
Arndt
A
Broggini
Massimo
M
D'Incalci
Maurizio
M
Riccio
Ed
E
Doppalapudi
Rupa
R
Kapetanovic
Izet M
IM
Steward
William P
WP
Gescher
Andreas J
AJ
D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D001835:Body Weight / Q000187:drug effects*; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations / Q000139:chemically induced*; D006224:Cricetinae; D003412:Cricetulus; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D015321:Gene Rearrangement / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced*; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D009928:Organ Specificity; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D014018:Tissue Distribution
D016588:Anticarcinogenic Agents; D005419:Flavonoids; C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; C017769:tricin; D011495:Histone-Lysine N-Methyltransferase; D004250:DNA Topoisomerases, Type II