Journal Article

Enhanced sensitivity of human oral tumours to the flavonol, morin, during cancer progression: involvement of the Akt and stress kinase pathways

Judith Brown, Jim O’Prey and P.R. Harrison

in Carcinogenesis

Volume 24, issue 2, pages 171-177
Published in print February 2003 | ISSN: 0143-3334
Published online February 2003 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/24.2.171
Enhanced sensitivity of human oral tumours to the flavonol, morin, during cancer progression: involvement of the Akt and stress kinase pathways

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Various naturally occurring flavonoids have been found to be cancer-protective in chemically induced animal cancer models and synthetic flavonoid derivatives are being tested for potential chemotherapeutic usefulness in clinical trials. This report demonstrates that human oral squamous carcinoma cells (SCC) are significantly more sensitive to growth inhibition by the naturally occurring flavonoid, morin (3,5,7,2′,4′-pentahydroxyflavone) than normal oral mucosa (NOMC) (SCC IC50 = 115 μM; NOMC IC50 = 173 μM; P for difference = 0.009). Structure/function comparisons indicate that both the 2′ and 4′ hydroxyl groups in morin are required for its tumour selectivity. Morin causes growth arrest in G2/M, without inducing apoptosis, and this is associated with induction of GADD45 and phosphorylation and inactivation of the cell cycle kinase, cdc2. Morin also has pleiotropic effects on kinase signalling pathways, including inhibition of activation of protein kinase B by mitogens (but not extracellular-regulated kinases 1/2) and activation of the stress pathway kinases, Jun N-terminal kinase and p38 kinase. p38 kinase activation is functionally important since inhibition of its activation by the specific inhibitor SB202190 partially prevented cell cycle arrest by morin. However, analysis of dose–response relationships reveals that the enhanced tumour sensitivity to morin may be explained by the fact that activation of AKT is inhibited at lower concentrations of morin in carcinomas than normal oral mucosa, whereas Jun N-terminal kinase, p38 kinase and GADD45 are all induced in parallel with the same dose–response curves in carcinomas and normal oral mucosa.

Keywords: DMBA, 7,12-dimethylbenz[a]antracene; MAPK, mitogen activated protein kinase; NOMC, normal human oral mucosa cells; SSC, squamous cell carcinomas.

Journal Article.  5846 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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