The broad-range cyclin-dependent kinase inhibitor UCN-01 induces apoptosis in colon carcinoma cells through transcriptional suppression of the Bcl-x L protein
M. Bhonde,M.L. Hanski,Roberta Magrini,Dhatchana Moorthy,Antje Müller,Edward A. Sausville,Kimitoshi Kohno,Peter Wiegand,Peter T. Daniel,Martin Zeitz,C. Hanski +10 more
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TL;DR: It is shown for the first time that UCN-01 induces apoptosis by suppression of Bcl-xL expression, indicating that both cell cycle arrest and apoptosis exert the anticancer effect in a coordinated manner.
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Abstract: 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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Signal Transducer and Activator of Transcription‐3, Inflammation, and Cancer
Bharat B. Aggarwal,Ajaikumar B. Kunnumakkara,Kuzhuvelil B. Harikumar,Shan R. Gupta,Sheeja T. Tharakan,Cemile Koca,Sanjit Dey,Bokyung Sung +7 more
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Classical PKC isoforms in cancer
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DNA Damage-induced Expression of p53 Suppresses Mitotic Checkpoint Kinase hMps1 THE LACK OF THIS SUPPRESSION IN p53MUT CELLS CONTRIBUTES TO APOPTOSIS
M. Bhonde,M.L. Hanski,Jan Budczies,Minh Cao,Bernd Gillissen,Dhatchana Moorthy,Federico Simonetta,Hans Scherübl,Matthias Truss,Christian Hagemeier,Hans-Werner Mewes,Peter T. Daniel,Martin Zeitz,C. Hanski +13 more
TL;DR: It is indicated that the high expression of mitotic genes in p53MUT cells after SN-38 treatment contributes to DNA damage-induced apoptosis, whereas their suppression in p 53WT cells acts as a safeguard mechanism preventing mitosis initiation and the subsequent apoptosis.
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ATP-noncompetitive CDK inhibitors for cancer therapy: An overview
TL;DR: Recent approaches aimed at developing more specific CDK inhibitors mostly through the aid of computational drug design studies are reviewed and various small molecules and peptides, which resulted in promising CDK ATP-noncompetitive inhibitors are reported.
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UCN-01 induces S and G2/M cell cycle arrest through the p53/p21(waf1) or CHK2/CDC25C pathways and can suppress invasion in human hepatoma cell lines.
TL;DR: Findings suggest that UCN-01 induces hepatoma cell growth inhibition by regulating the p53/p21waf1 and CHK2/CDC25 pathways.
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