Titre du document / Document title

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

Auteur(s) / Author(s)

BROWN Judith ⁽¹⁾ ; O'PREY Jim ⁽¹⁾ ; HARRISON P. R. ⁽¹⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ The Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, ROYAUME-UNI

Résumé / Abstract

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.

Revue / Journal Title

Carcinogenesis   ISSN 0143-3334   CODEN CRNGDP 

Source / Source

2003, vol. 24, n^o2, pp. 171-177 [7 page(s) (article)] (61 ref.)

Langue / Language

Anglais

Editeur / Publisher

Oxford University Press, Oxford, ROYAUME-UNI  (1980) (Revue)

Mots-clés anglais / English Keywords

Oral cavity disease ; ENT disease ; Enzyme ; Transferases ; Tumor progression ; Flavonoid ; Signal transduction ; Mechanism of action ; Carcinogenesis ; Flavone derivatives ; Anticarcinogen ; Antineoplastic agent ; Sensitivity resistance ; Comparative study ; Tumor cell ; Squamous cell carcinoma ; Premalignant lesion ; Dysplasia ; Normal ; Mucosa ; Oral cavity ; Malignant tumor ; Established cell line ; In vitro ; Protein kinase ; Human ;

Mots-clés français / French Keywords

Cavité buccale pathologie ; ORL pathologie ; Enzyme ; Transferases ; Protein kinase AKT ; Morine ; Flavonol dérivé ; Progression carcinogenèse ; Flavonoïde ; Transduction signal ; Mécanisme action ; Carcinogenèse ; Flavone dérivé ; Anticarcinogène ; Anticancéreux ; Sensibilité résistance ; Etude comparative ; Cellule tumorale ; Carcinome épidermoïde ; Lésion précancéreuse ; Dysplasie ; Normal ; Muqueuse ; Cavité buccale ; Tumeur maligne ; Lignée cellulaire établie ; In vitro ; Protein kinase ; Homme ;

Mots-clés espagnols / Spanish Keywords

Cavidad bucal patología ; ORL patología ; Enzima ; Transferases ; Progresión carcinogénesis ; Flavonoide ; Transducción señal ; Mecanismo acción ; Carcinogénesis ; Flavona derivado ; Anticarcinógeno ; Anticanceroso ; Sensibilidad resistencia ; Estudio comparativo ; Célula tumoral ; Carcinoma epidermoide ; Lesión precancerosa ; Displasia ; Normal ; Mucosa ; Cavidad bucal ; Tumor maligno ; Línea celular establecida ; In vitro ; Protein kinase ; Hombre ;

Localisation / Location

INIST-CNRS, Cote INIST : 18776, 35400010773514.0030