UCN‐01 (7‐Hydroxystaurosporine) Enhances 5‐Fluorouracil Cytotoxicity through Down‐regulation of Thymidylate Synthetase Messenger RNA

Abe, S.; Kubota, Tetsuro; Otani, Yoshihide; Furukawa, Toshiharu; Watanabe, Masahiko; Kumai, Koichiro; Kitajima, Masaki

doi:10.1111/j.1349-7006.2000.tb00904.x

Cited by 13 publications

(8 citation statements)

References 29 publications

(35 reference statements)

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“…However, this study also shows that enzastaurinpemetrexed combination significantly inhibited the activity of TS, potentially leading to synergistic drug interaction. These results are in agreement with previous data demonstrating that UCN-01 was able to enhance the activity of 5-FU through downregulation of TS (Hsueh et al, 1998;Abe et al, 2000).…”

Section: Discussionsupporting

confidence: 83%

Molecular pathways involved in the synergistic interaction of the PKCβ inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells

et al. 2008

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Conventional regimens have limited impact against non-small cell lung cancer (NSCLC). Current research is focusing on multiple pathways as potential targets, and this study investigated molecular mechanisms underlying the combination of the PKCb inhibitor enzastaurin with the multitargeted antifolate pemetrexed in the NSCLC cells SW1573 and A549. Pharmacologic interaction was studied using the combination-index method, while cell cycle, apoptosis induction, VEGF secretion and ERK1/2 and Akt phosphorylation were studied by flow cytometry and ELISAs. Reverse transcription -PCR, western blot and activity assays were performed to assess whether enzastaurin influenced thymidylate synthase (TS) and the expression of multiple targets involved in cancer signaling and cell cycle distribution. Enzastaurin-pemetrexed combination was highly synergistic and significantly increased apoptosis. Enzastaurin reduced both phosphoCdc25C, resulting in G2/M checkpoint abrogation and apoptosis induction in pemetrexed-damaged cells, and GSK3b and Akt phosphorylation, which was additionally reduced by drug combination (À58% in A549). Enzastaurin also significantly reduced pemetrexed-induced upregulation of TS expression, possibly through E2F-1 reduction, whereas the combination decreased TS in situ activity (450% in both cell lines) and VEGF secretion. The effects of enzastaurin on signaling pathways involved in cell cycle control, apoptosis and angiogenesis, as well as on the expression of genes involved in pemetrexed activity provide a strong experimental basis to their evaluation as pharmacodynamic markers in clinical trials of enzastaurin-pemetrexed combination in NSCLC patients.

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Section: Discussionsupporting

confidence: 83%

Molecular pathways involved in the synergistic interaction of the PKCβ inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells

et al. 2008

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“…As a modulator, UCN-01 enhances the antitumour activity of several antitumour agents, including mitomycin C (Akinaga et al, 1993), cisplatin (Bunch and Eastman, 1996;Husain et al, 1997) and 5-FU both in vitro (Abe et al, 2000) and in vivo (Koh et al, 2002). The potentiation of cytotoxicity by UCN-01 is ascribed to its ability to abrogate the G2/M checkpoint Wang et al, 1996), as previously reported for caffeine (Powell et al, 1995;Fan et al, 1997).…”

Section: Introductionmentioning

confidence: 52%

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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“…Over-expression of TS is one mechanism by which tumours may develop resistance to such drugs . Previous studies have shown that treatment of cancer cells with the CDK inhibitors UCN-01 and flavopiridol led to a downregulation of TS levels and sensitised cells to 5-fluorouracil (Hsueh et al, 1998;Abe et al, 2000). UCN-01 is a broad-specificity kinase inhibitor, known to inhibit not only CDKs but also PKC and Chk1 (Akinaga et al, 1991;Busby et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Expression of thymidylate synthase in human cells is an early G1 event regulated by CDK4 and p16INK4A but not E2F

2007

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Thymidylate synthase (TS) is the enzyme that catalyses the last step in de novo thymidylate synthesis. It is of interest clinically because it is an effective target for drugs such as 5-fluorouracil, often used in combination therapy. Despite a number of earlier reports indicating that TS is a cell cycle-dependent enzyme, this remains equivocal. Here, we show that in HCT116 cells synchronised by serum starvation, there is a clear dissociation between the expression of cyclin E (a well-characterised cell-cycle protein) and TS. Although both cyclin E and TS mRNA and protein increased during G 1 , TS upregulation was delayed. Moreover, TS levels did not decrease following S-phase completion while cyclin E decreased sharply. Similarly, clear differences were seen between cyclin E and TS as asynchronously growing HCT116 cells were growth-inhibited by low-serum treatment. In contrast to previous reports using rodent cells, adenovirus-mediated over-expression of E2F1 and cyclin E in three human cell lines had no effect on TS. Cell-cycle progression was blocked by treatment of cells with pharmacological inhibitors of CDK2 and CDK4 and by ectopic expression of p16INK4A. Whereas CDK2 inhibition had no effect on TS levels, inhibition of CDK4 was associated with decreased TS protein levels. These results provide the first evidence that drugs targeting CDK4 may be useful with anti-TS drugs as combination therapy for cancer.

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UCN‐01 (7‐Hydroxystaurosporine) Enhances 5‐Fluorouracil Cytotoxicity through Down‐regulation of Thymidylate Synthetase Messenger RNA

Cited by 13 publications

References 29 publications

Molecular pathways involved in the synergistic interaction of the PKCβ inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells

Molecular pathways involved in the synergistic interaction of the PKCβ inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells

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

Expression of thymidylate synthase in human cells is an early G1 event regulated by CDK4 and p16INK4A but not E2F

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