UCN-01, 7-Hydroxyl-staurosporine, Inhibits Kinase Activity of Cyclin-Dependent Kinases and Reduces the Phosphorylation of the Retinoblastoma Susceptibility Gene Product in A549 Human Lung Cancer Cell Line

Kawakami, Kimihiro; Futami, Hitoyasu; Takahara, Jiro; Yamaguchi, Ken

doi:10.1006/bbrc.1996.0310

Cited by 109 publications

(60 citation statements)

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“…This observation confirms and extends previous reports, indicating the critical role of G1 arrest for sensitivity of carcinoma cell lines to UCN-01 (Seynaeve et al, 1993;Wang et al, 1995;Kawakami et al, 1996;Akiyama et al, 1999a;Akiyama et al, 1999b;Mack et al, 1999;Sugiyama et al, 1999;Usuda et al, 2000).…”

Section: Discussionsupporting

confidence: 92%

“…When administered as a single agent at micromolar concentrations, UCN-01 induces G0/G1 arrest or G2/M arrest, depending on cell type and defects in Rb pathway control (Dai et al, 2001). UCN-01 directly inhibits the activating phosphorylation of CDK2 and CDK4 as well as the expression of both molecules (Kawakami et al, 1996). Furthermore, UCN-01 induces the expression of CDK inhibitors p21 and p27 (Akinaga et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, UCN-01 induces the expression of CDK inhibitors p21 and p27 (Akinaga et al, 2000). Both direct and indirect inhibition of CDKs by UCN-01 is associated with the decrease of phosphorylation of the retinoblastoma protein (pRb) and, eventually, with the accumulation of cells in the G1 phase (Kawakami et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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The broad-range cyclin-dependent kinase inhibitor UCN-01 induces apoptosis in colon carcinoma cells through transcriptional suppression of the Bcl-xL protein

et al. 2004

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The broad-range cyclin-dependent kinase inhibitor 7-hydroxystaurosporine (UCN-01) is known to induce both a G1 cell cycle arrest and apoptosis. The mechanism of UCN-01-induced apoptosis is largely unknown. We analysed the mechanism of cytotoxicity of UCN-01 in four established colon carcinoma cell lines. The cell lines SW48 and LS513 responded to UCN-01 treatment by undergoing apoptosis in a concentration-dependent manner while the cell lines HT-29 and WiDr were completely resistant. Apoptosis in LS513 and SW48 cell lines was concomitant with the suppression of Bcl-x L on mRNA and protein level. In contrast, in the apoptosis-resistant cell lines, Bcl-x L expression was not affected by UCN-01. Stable overexpression of the Bcl-x L protein abrogated UCN-01-triggered apoptosis, but only partially restored growth, indicating that both cell cycle arrest and apoptosis exert the anticancer effect in a coordinated manner. The inhibition of Akt phosphorylation did not correlate with the apoptotic phenotype. UCN-01 inhibited the activating STAT3 phosphorylations on Ser727 and, notably, on Tyr705, but STAT3 did not contribute to Bcl-x L expression in colon carcinoma cells. Moreover, we show for the first time that UCN-01 induces apoptosis by suppression of Bcl-x L expression. The inhibition of this pathway is a new aspect of cytotoxic and modulatory potential of UCN-01.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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The broad-range cyclin-dependent kinase inhibitor UCN-01 induces apoptosis in colon carcinoma cells through transcriptional suppression of the Bcl-xL protein

et al. 2004

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“…Another interesting feature of UCN-01 is in the e ects on G1 cell cycle progression (Akinaga et al, 1994;Akiyama et al, 1997Akiyama et al, , 1999Kawakami et al, 1996;Seynaeve et al, 1993;Shimizu et al, 1996). Human epidermoid carcinoma A431 cells exposed to UCN-01 displayed clear evidence of G1 arrest.…”

Section: Ucn-01mentioning

confidence: 99%

Small molecule modulators of cyclin-dependent kinases for cancer therapy

Senderowicz

2000

Oncogene

111

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“…8,9 Staurosporine has been shown to inhibit cell cycle progression in a variety of cell lines. Staurosporine analogues (UCN-01 [10][11][12][13] and CGP 41251 14 ) with poor activity towards conventional PKC have been shown to interfere directly with the cell cycle machinery and to induce apoptosis. Staurosporine causes biochemical alterations in a variety of cell types irrespective of whether they expressed tumor suppressor genes p53 or Rb and leads to accumulations of CDK inhibitor p 27kip 1 and not of p 21Cip 10 .…”

mentioning

confidence: 99%

Apoptosis is induced in leishmanial cells by a novel protein kinase inhibitor withaferin A and is facilitated by apoptotic topoisomerase I–DNA complex

et al. 2006

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Protein kinase C (PKC) is an important constituent of the signaling pathways involved in apoptosis. We report here that like staurosporine, withaferin A is a potent inhibitor of PKC. In Leishmania donovani, the inhibition of PKC by withaferin A causes depolarization of DW m and generates ROS inside cells. Loss of DW m leads to the release of cytochrome c into the cytosol and subsequently activates caspase-like proteases and oligonucleosomal DNA cleavage. Moreover, in treated cells, oxidative DNA lesions facilitate the stabilization of topoisomerase I-mediated cleavable complexes, which also contribute to DNA fragmentation. However, withaferin A and staurosporine cannot induce cleavable complex formation in vitro with recombinant topoisomerase I nor with nuclear extracts from control cells. Taken together, our results indicate that inhibition of PKC by withaferin A is a central event for the induction of apoptosis and that the stabilization of topoisomerase I-DNA complex is necessary to amplify apoptotic process.

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UCN-01, 7-Hydroxyl-staurosporine, Inhibits Kinase Activity of Cyclin-Dependent Kinases and Reduces the Phosphorylation of the Retinoblastoma Susceptibility Gene Product in A549 Human Lung Cancer Cell Line

Cited by 109 publications

References 0 publications

The broad-range cyclin-dependent kinase inhibitor UCN-01 induces apoptosis in colon carcinoma cells through transcriptional suppression of the Bcl-xL protein

The broad-range cyclin-dependent kinase inhibitor UCN-01 induces apoptosis in colon carcinoma cells through transcriptional suppression of the Bcl-xL protein

Small molecule modulators of cyclin-dependent kinases for cancer therapy

Apoptosis is induced in leishmanial cells by a novel protein kinase inhibitor withaferin A and is facilitated by apoptotic topoisomerase I–DNA complex

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