Baicalein induces a dual growth arrest by modulating multiple cell cycle regulatory molecules

Hsu, Shih-Lan; Hsieh, Yun-Chih; Hsieh, Wen-Chiuan; Chou, Chen-Jen

doi:10.1016/s0014-2999(01)01144-x

Cited by 34 publications

(29 citation statements)

References 22 publications

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“…Both CDC25 phosphatase and CDC2 kinase inhibitors enhanced the baicalein-induced cancer cell death. Indeed, it has been shown that baicalein can directly inhibit CDC2 kinase activity (44). Therefore, we suggest that the inhibition of CDC2/cyclin B1 by baicalein contributes to the reduction of survivin and the proliferation inhibition in cancer cells.…”

Section: Discussionmentioning

confidence: 66%

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

Liu

2007

Molecular Cancer Therapeutics

128

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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 Mmol/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.

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Section: Discussionmentioning

confidence: 66%

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

Liu

2007

Molecular Cancer Therapeutics

128

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“…To date, studies on the anticancer properties of baicalein have mainly focused on apoptosis, and several mechanisms of action including cdk modulation, cytochrome c release and the activation of caspase 3, caspase 7 and PARP through myeloid leukemia 1 downregulation, have been reported [20][21][22][23]. Here, we report new insights into baicalein anticancer properties, providing strong evidence that autophagy, rather than apoptosis, is the key mechanism through which baicalein induces PC-3 and MDA-MB-231 cell death.…”

Section: Discussionmentioning

confidence: 99%

Baicalein induces autophagic cell death through AMPK/ULK1 activation and downregulation of mTORC1 complex components in human cancer cells

et al. 2014

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Baicalein, a flavonoid and aglycon hydrolyzed from baicalin, has anticancer properties in several human carcinomas, but its molecular mechanisms of action remain unclear. Here, we show that baicalein leads to human cancer cell death by inducing autophagy rather than apoptosis, because cell death induced by baicalein was completely reversed by suppressing the expression levels of key molecules in autophagy such as Beclin 1, vacuolar protein sorting 34 (Vps34), autophagy-related (Atg)5 and Atg7, but not by pan-caspase inhibitor. Our data revealed that baicalein significantly increased the number of green fluorescence protein-cytosol-associated protein light chain 3 (GFP-LC3)-containing puncta and LC3B-II expression levels, which were further enhanced by chloroquine treatment. Furthermore, a luciferase-based reporter assay showed that the ratio of RLuc-LC3wt/RLuc-LC3G120A was greatly reduced. The data suggested that baicalein induced not only autophagosome formation, but also autophagic flux. Experiments using short interfering RNAs and pharmacological inhibitors revealed that Beclin 1, Vps34, Atg5, Atg7 and UNC-51 (Caenorhabditis elegans)-like kinase 1 (ULK1) play pivotal roles in mediating baicalein-induced autophagy. Moreover, baicalein activated AMP-activated protein kinase (AMPK)a, leading to ULK1 activation through phosphorylation at Ser555, whereas both protein and mRNA levels of mammalian target of rapamycin (mTOR) and Raptor, upstream inhibitors of ULK1 and autophagy, were markedly downregulated by baicalein. Our data suggest that the anticancer effects of baicalein are mainly due to autophagic cell death through activation of the AMPK/ULK1 pathway and inhibition of mTOR/Raptor complex 1 expression. These results provide new mechanistic insights into the anticancer functions of autophagy inducers, such as baicalein, which may be used as potential therapeutics for cancer treatment.Abbreviations Δwmt, mitochondrial membrane potential; 3-MA, 3-methyladenine; AMPK, AMP-activated protein kinase; Atg, autophagy-related; cdk, cyclindependent kinase; CQ, chloroquine; DMEM, Dulbecco's modified Eagle's medium; FLICA, fluorescent-labeled inhibitor of caspases; GFP, green fluorescent protein; LC3, microtubule-associated protein light chain 3; mTORC1, mammalian target of kanamycin complex 1; PARP, poly(ADP-ribose) polymerase; PtdIns3K, phosphoinositide 3-kinase; PtIns3P, phosphatidylinositol-3-phosphate; Raptor, regulatory-associated protein of mTOR; siRNA, small interfering RNA; ULK1, UNC-51 (C. elegans)-like kinase 1; Vps34, vacuolar protein sorting 34; wt, wild-type.

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“…baicalensis contains several major flavonoids, including baicalin, baicalein, wogonoside, wogonin, oroxylin A 7-Oglucuronopyranoside (oroxylin A 7-O-glcUA), oroxylin A, and more than 40 other components in trace amounts (10). The molecular mechanism of actions of S baicalensis remains unclear, but some studies have shown that it downregulates cyclin D expression (11), suppresses MAPK activity (12), and inhibits cyclooxygenase-2 (COX-2) (13). Furthermore, it has been shown that different components of S. baicalensis have different biological effects, indicating that each component acts on different molecular pathways in a cell, causing collective inhibition of cell growth (13).…”

Section: Introductionmentioning

confidence: 99%

The Effect ofScutellaria Baicalensison the Signaling Network in Hepatocellular Carcinoma Cells

Che

McMillen

et al. 2009

Nutrition and Cancer

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Scutellaria baicalensis is an anti-inflammatory and antineoplastic Chinese herbal therapy. We have previously shown that S. baicalensis can inhibit hepatocellular carcinoma (HCC) cell growth in vitro. In this study, we sought to determine the effect of S. baicalensis on the cell signaling network using our newly developed Pathway Array technology, which screens cell signaling pathways involved in cell cycle regulation. The HCC cell line (HepG2) was treated with S. baicalensis extract in vitro. The effect on the cell cycle was analyzed by flow cytometry, and the expression of various signaling proteins was assayed with Pathway Array. Our results indicate that S. baicalensis exerts a strong growth inhibition of the HepG2 cells via G(2)/M phase arrest. The Pathway Array analysis of 56 proteins revealed a total of 14 differentially expressed proteins or phosphorylations after treatment. Of these, 9 showed a dose-dependent decrease (p53, ETS1, Cdc25B, p63, EGFR, ERK1/2, XIAP, HIF-2alpha, and Cdc25C) whereas one demonstrated a dose-dependent increase (Cyclin E) after treatment with 200 microg/ml of S. baicalensis. Using computer simulation software, we identified additional hubs in the signaling network activated by S. baicalensis. These results indicate that S. baicalensis exerts a broad effect on cell signaling networks leading to a collective inhibition of cell proliferation.

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Baicalein induces a dual growth arrest by modulating multiple cell cycle regulatory molecules

Cited by 34 publications

References 22 publications

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

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

Baicalein induces autophagic cell death through AMPK/ULK1 activation and downregulation of mTORC1 complex components in human cancer cells

The Effect ofScutellaria Baicalensison the Signaling Network in Hepatocellular Carcinoma Cells

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