Induction of cell cycle arrest and apoptosis in human breast cancer cells by quercetin.
Quercetin, a widely distributed bioflavonoid, has been shown to induce growth inhibition in certain cancer cell types. In the present study we have pursued the mechanism of growth inhibition in MCF-7 human breast cancer cells. Quercetin treatment resulted in the accumulation of cells specifically at G2/M phase of the cell cycle. Mitotic index measured by MPM2 staining clearly showed that cells were transiently accumulated in M phase, 24 h after treatment. The transient M phase accumulation was accompanied by a transient increase in the levels of cyclin B1 and Cdc2 kinase activity. However, 24 h or longer treatment caused a marked accumulation of cells in G2 instead of M phase. Levels of cyclin B1 and cyclin B1-associated Cdc2 kinase activity were also decreased. We also found that quercetin markedly increased Cdk-inhibitor p21CIP1/WAF1 protein level after treatment for 48 h or longer, and the induction of p21CIP1/WAF1 increased its association with Cdc2-cyclin B1 complex, however, up-regulation of p53 by quercetin was not observed. Quercetin also induced significant apoptosis in MCF-7 cells in addition to cell cycle arrest, and the induction of apoptosis was markedly blocked by antisense p21CIP1/WAF1 expression. The present data, therefore, demonstrate that a flavonoid quercetin induces growth inhibition in the human breast carcinoma cell line MCF-7 through at least two different mechanisms; by inhibiting cell cycle progression through transient M phase accumulation and subsequent G2 arrest, and by inducing apoptosis.
Choi
J A
JA
Laboratory of Radiation Effect, Korea Cancer Center Hospital, Seoul 139-706, Korea.
Kim
J Y
JY
Lee
J Y
JY
Kang
C M
CM
Kwon
H J
HJ
Yoo
Y D
YD
Kim
T W
TW
Lee
Y S
YS
Lee
S J
SJ
D016375:Antisense Elements (Genetics) / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D006690:Bisbenzimidazole; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D011233:Precipitin Tests; D011794:Quercetin / Q000627:therapeutic use*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016375:Antisense Elements (Genetics); C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53; D011794:Quercetin; D018844:Cyclin-Dependent Kinases; D006690:Bisbenzimidazole