Baicalein induces cancer cell death and proliferation retardation by the inhibition of CDC2 kinase and survivin associated with opposite role of p38 mitogen-activated protein kinase and AKT

• Published in: Molecular cancer therapeutics 2007-11, Vol.6 (11), p.3039-3048
• Main Authors: Chao, Jui-I, Su, Wen-Chi, Liu, Huei-Fang
• Format: Article
• Language: English
• Subjects: AKT; apoptosis; baicalein; CDC2 kinase; CDC2 Protein Kinase - antagonists & inhibitors; Cell Death - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cyclin B - metabolism; Cyclin B1; Drug Resistance, Neoplasm - drug effects; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Flavanones - chemistry; Flavanones - pharmacology; Flavonoids - pharmacology; G2 Phase - drug effects; Humans; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins - metabolism; Mitosis - drug effects; Neoplasm Proteins - metabolism; p38 MAPK; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphoproteins - metabolism; Phosphorylation - drug effects; Proto-Oncogene Proteins c-akt - metabolism; survivin; Urinary Bladder Neoplasms - enzymology; Urinary Bladder Neoplasms - pathology
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-07-0281

The bioactive flavonoid baicalein has been shown to have in vitro growth-inhibitory activity in human cancer cells, although the mechanism of action is poorly understood. Baicalein (40–80 μmol/L for 24 h) more effectively induced cytotoxicity compared with other flavonoids (baicalin, catechin, genistein, quercetin, and rutin) in bladder cancer cells. Baicalein induced cell proliferation inhibition and apoptosis. The levels of cyclin B1 and phospho-CDC2 (Thr 161 ) were reduced, whereas the G 2 -M phases were elevated by baicalein. Treatment of CDC2 kinase or CDC25 phosphatase inhibitors augments the baicalein-induced cytotoxicity. A variety of human bladder cancer cell lines expressed survivin proteins, which were located on the mitotic phases and regulated mitotic progression. Baicalein markedly reduced survivin protein expression. Transfection of a survivin small interfering RNA diminished the level of survivin proteins and increased the baicalein-mediated cell death. Overexpression of survivin enhanced cell proliferation and resisted the baicalein-induced cytotoxicity. Interestingly, baicalein induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and AKT. SB203580, a specific p38 MAPK inhibitor, attenuated proliferation inhibition and restored the protein levels of phospho-CDC2 (Thr 161 ) and survivin in the baicalein-exposed cells; conversely, blockade of AKT activation enhanced cytotoxicity and the reduction of phospho-CDC2 (Thr 161 ) and survivin proteins. As a whole, these findings provide that the opposite role of p38 MAPK and AKT regulates CDC2 kinase and survivin and the inhibition of CDC2-survivin pathway by baicalein contributes to apoptosis and proliferation retardation in cancer cells. [Mol Cancer Ther 2007;6(11):3039–48]