Chromosome condensation induced by fostriecin does not require p34cdc2 kinase activity and histone H1 hyperphosphorylation, but is associated with enhanced histone H2A and H3 phosphorylation.

Guo, Xiaowen; Th'ng, John P.H.; Swank, Richard A.; Anderson, Hilary; Tudan, Christopher; Bradbury, E. Morton; Roberge, Michel

doi:10.1002/j.1460-2075.1995.tb07078.x

Cited by 149 publications

(104 citation statements)

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“…The Ser 10 phosphorylation of histone H3 begins in prophase, peaks during metaphase, and declines during anaphase (38,39). Agents initiating premature chromosome condensation have been shown to increase Ser 10 phosphorylation of histone H3 (40,41). As can be seen in Fig.…”

Section: Sfn Treatment Caused Mitotic Arrest In Lncap Cellsmentioning

confidence: 89%

Induction of p21 protein protects against sulforaphane-induced mitotic arrest in LNCaP human prostate cancer cell line

Herman-Antosiewicz

Xiao

Lew

et al. 2007

Molecular Cancer Therapeutics

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Previous studies have indicated that D,L-sulforaphane (SFN), a synthetic cancer chemopreventive analogue of cruciferous vegetable-derived isomer (À)-1-isothiocyanato-(4R)-(methylsulfinyl)-butane, activates a checkpoint kinase 2 (Chk2) -dependent G 2 -M phase cell cycle arrest in p53-deficient human prostate cancer cells. Because p53 is a downstream target of Chk2 kinase and known to regulate G 2 -M transition by transcriptional regulation of cyclin-dependent kinase (Cdk) inhibitor p21Cip1/Waf1 (p21), the present study was undertaken to determine the role of p21 in SFN-induced cell cycle arrest using wild-type p53 -expressing cell line LNCaP. The SFN treatment caused a modest increase in S phase fraction and a marked increase in G 2 -M fraction in LNCaP cells in a concentration-and time-dependent manner. The SFN-induced S phase arrest correlated with a reduction in protein levels of cyclin D1, cyclin E, Cdk4, and Cdk6, whereas activation of the G 2 -M checkpoint was accompanied by induction of cyclin B1 and down-regulation of Cdk1 and Cdc25C protein levels. The SFN-treated LNCaP cells were also arrested in mitosis as revealed by immunofluorescence microscopy and increased Ser 10 phosphorylation of histone H3, a sensitive marker for mitotic cells. The SFN treatment increased activating phosphorylation of Chk2 (Thr 68 ) that was accompanied by induction of p53 and p21. The SFNinduced mitotic arrest was statistically significantly increased by small interfering RNA -based knockdown of p21. However, p21 protein knockdown did not have any appreciable effect on SFN-induced cytoplasmic histoneassociated DNA fragmentation (apoptosis). In conclusion, the present study indicates that induction of p21 protects against SFN-induced mitotic arrest in LNCaP cells. [Mol Cancer Ther 2007;6(5):1673 -81]

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Section: Sfn Treatment Caused Mitotic Arrest In Lncap Cellsmentioning

confidence: 89%

Induction of p21 protein protects against sulforaphane-induced mitotic arrest in LNCaP human prostate cancer cell line

Herman-Antosiewicz

Xiao

Lew

et al. 2007

Molecular Cancer Therapeutics

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“…Cellular responses to OA include the activation of signaling transduction pathways, nuclear envelope breakdown, premature chromatin condensation, and apoptosis (21)(22)(23)(24)(25)(26)(27)(28). Here, we report that histones H2A, H3, and H4 become phosphorylated after treatment with OA, but with differential kinetics, suggesting distinct regulatory mechanisms for each histone.…”

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confidence: 80%

Global Regulation of Post-translational Modifications on Core Histones

Galasinski

Louie

Gloor

et al. 2002

Journal of Biological Chemistry

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Full-length masses of histones were analyzed by mass spectrometry to characterize post-translational modifications of bulk histones and their changes induced by cell stimulation. By matching masses of unique peptides with full-length masses, H4 and the variants H2A.1, H2B.1, and H3.1 were identified as the main histone forms in K562 cells. Mass changes caused by covalent modifications were measured in a dose-and time-dependent manner following inhibition of phosphatases by okadaic acid. Histones H2A, H3, and H4 underwent changes in mass consistent with altered acetylation and phosphorylation, whereas H2B mass was largely unchanged. Unexpectedly, histone H4 became almost completely deacetylated in a dose-dependent manner that occurred independently of phosphorylation. Okadaic acid also partially blocked H4 hyperacetylation induced by trichostatin-A, suggesting that the mechanism of deacetylation involves inhibition of H4 acetyltransferase activity, following perturbation of cellular phosphatases. In addition, mass changes in H3 in response to okadaic acid were consistent with phosphorylation of methylated, acetylated, and phosphorylated forms. Finally, kinetic differences were observed with respect to the rate of phosphorylation of H2A versus H4, suggesting differential regulation of phosphorylation at sites on these proteins, which are highly related by sequence. These results provide novel evidence that global covalent modifications of chromatin-bound histones are regulated through phosphorylation-dependent mechanisms.

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“…The topo II catalytic inhibitor fostriecin is expected to have increased activity against tumour cells with low topo II levels and this was confirmed in in vitro studies (De Jong et al, 1991). In vitro, fostriecin also inhibited nuclear protein phosphatases involved with cell cycle regulation and histone phosphatases involved with chromosome condensation during mitosis (Roberge et al, 1994;Guo et al, 1995).…”

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confidence: 92%

Phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin

Jong

Mulder

Uges³

et al. 1999

Br J Cancer

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SummaryWe conducted a phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin. Fostriecin was administered intravenously over 60 min on days 1-5 at 4-week intervals. Dose was escalated from 2 mg m -2 day -1 to 20 mg m -2 day -1 in 20 patients. Drug pharmacokinetics was analysed with high performance liquid chromatography with UV-detection. Plasma collected during drug administration was tested in vitro for growth inhibition of a teniposide-resistant small-cell lung cancer (SCLC) cell line. The predominant toxicities were elevated liver transaminases (maximum common toxicity criteria (CTC) grade 4) and serum creatinine (maximum CTC grade 2). These showed only a limited increase with increasing doses, often recovered during drug administration and were fully reversible. Duration of elevated alanine-amino transferase (ALT) was dose-limiting in one patient at 20 mg m -2 . Other frequent toxicities were grade 1-2 nausea/vomiting, fever and mild fatigue. Mean fostriecin plasma half-life was 0.36 h (initial; 95% CI, 0-0.76 h) and 1.51 h (terminal; 95% CI, 0.41-2.61 h). A metabolite, most probably dephosphorylated fostriecin, was detected in plasma and urine. No tumour responses were observed, but the plasma concentrations reached in the patients were insufficient to induce significant growth inhibition in vitro. The maximum tolerated dose (MTD) has not been reached, because drug supply was stopped at the 20 mg m -2 dose level. However, further escalation seems possible and is warranted to achieve potentially effective drug levels. Fostriecin has a short plasma half-life and longer duration of infusion should be considered.Keywords: fostriecin; topoisomerase II; phase I; pharmacokinetics 882British Journal of Cancer (1999) 79(5/6), 882-887 © 1999 Cancer Research Campaign Article no. bjoc.1998 Received prior chemo-, immuno-or radiotherapy for at least 4 weeks before study entry; white blood cell (WBC) count ≥ 4000 µl -1 and platelet count ≥ 100 000 µl -1 ; bilirubin ≤ 25 µmol l -1 and aspartate-amino transferase (AST) and alanine-amino transferase (ALT) within 2.5 times the normal upper limit; normal prothrombin time (PT); creatinine clearance ≥ 60 ml min -1 . Written informed consent was obtained from all patients. The protocol was approved by the Medical Ethical Committee of the University Hospital Groningen.Fostriecin was supplied by NCI (Bethesda, MD, USA) as a lyophilized powder and was diluted with 0.9% NaCl to 50 or 100 ml. It was administered as a 60-min intravenous (IV) infusion through an UV-light protected system on days 1-5 at 4-week intervals. The dose was initially escalated according to the Fibonacci scheme, with subsequent dose steps of 2, 4, 6.6, 10 and 12.2 mg m -2 day -1 and thereafter increased to 20 mg m -2 (the protocol was amended during the study to allow more rapid dose escalation). Three patients were entered at each dose level, with a maximum of three additional patients when one out of three experienced dose-limiting toxicity (DLT). When no DLT was observed, ...

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Chromosome condensation induced by fostriecin does not require p34cdc2 kinase activity and histone H1 hyperphosphorylation, but is associated with enhanced histone H2A and H3 phosphorylation.

Cited by 149 publications

References 56 publications

Induction of p21 protein protects against sulforaphane-induced mitotic arrest in LNCaP human prostate cancer cell line

Induction of p21 protein protects against sulforaphane-induced mitotic arrest in LNCaP human prostate cancer cell line

Global Regulation of Post-translational Modifications on Core Histones

Phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin

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