Quercetin induces necrosis and apoptosis in SCC-9 oral cancer cells.
Evidence has accumulated that dietary polyphenols, in particular, flavonoids, have protective effects against oral cancer. In this study, we have examined the effects of quercetin, a major dietary flavonoid, on cell growth and necrosis/apoptosis and cell cycle regulation in human oral squamous carcinoma SCC-9 cells. Quercetin induced dose- and time-dependent, irreversible inhibition of cell growth and cellular DNA synthesis. Light microscopy and lactate dehydrogenase measurements showed modifications in the morphology and membrane integrity of these cells after quercetin treatment. Propidium iodide/annexin V staining showed that quercetin induced necrosis at 24 h and 48 h, whereas at 72 h cells underwent apoptosis, correlating with caspase-3 activation. Flow cytometry studies of the cell cycle distribution showed that quercetin induced mainly S-phase arrest. Thymidylate synthase (TS), a key S-phase enzyme, was inhibited in a time- and dose-dependent fashion by quercetin at the protein level. A lack of effect on TS mRNA suggested that TS down-regulation occurred at the translational level. In conclusion, our data support a view that quercetin initially induces a stress response, resulting in necrosis of these oral epithelial cells. Prolonged exposure of the surviving cells to quercetin causes apoptosis, presumably mediated by inhibition of TS protein.
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, USA.
Maricela
M
Haghiac
Thomas
T
Walle
D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005434:Flow Cytometry; D006801:Humans; D009062:Mouth Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D011794:Quercetin / Q000494:pharmacology*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000187:drug effects; D013997:Time Factors; D048069:Tumor Necrosis Factors / Q000378:metabolism
D048069:Tumor Necrosis Factors; D004247:DNA; D011794:Quercetin; D013940:Thymidylate Synthase; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases