Comparison of ability of protein kinase C inhibitors to arrest cell growth and to alter cellular protein kinase C localisation

Courage, C; Budworth, Joanna; Gescher, Andreas J.

doi:10.1038/bjc.1995.137

Cited by 72 publications

(63 citation statements)

References 28 publications

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“…Staurosporine at 10 -9 M and its analogues UCN-01, RO 31 8220 and GF 109203X in the 10 -7 to 10 .6 M range cause the translocation of PKC-e from the cytosol to the membrane and nucleus of A549 cells [12]. In contrast, CGP 41251 does not possess this property.…”

Section: Discussionmentioning

confidence: 84%

“…To that end nine well-characterised PKC inhibitors, including staurosporine and four analogues, were investigated with respect to their ability to inhibit PKC prepared from the cytosol or membrane of human-derived MCF-7 breast cancer cells. The susceptibility of these cells towards the growth-arresting ability of PKC inhibitors has recently been described [12]. …”

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confidence: 99%

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Differential inhibition of cytosolic and membrane‐derived protein kinase C activity by staurosporine and other kinase inhibitors

Budworth

Gescher

1995

FEBS Letters

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The hypothesis was tested that 9 kinase inhibitors with diverse specificities for protein kinase C (PKC), including staurosporine and four of its analogues, interfere differently with PKC derived from either the cytosolic or particulate fractions of MCF-7 breast carcinoma cells. GF 109203X inhibited the enzyme identically in either preparation. CGP 41251 and calphostin C inhibited cytosolic PKC more effectively than membrane-derived PKC with ratios of ICso (cytosolic PKC) over IC50 (membrane-derived PKC) of 0.07 and 0.04, respectively. The other six agents inhibited membrane-derived PKC more potently than cytosolic enzyme. Staurosporine and RO 31 8220 exhibited IC50 ratios of 12.3 and 21.6, respectively. The results suggest that there are dramatic differences between kinase inhibitors in their divergent effects on cytosolic and membrane-derived PKC which should be borne in mind in the interpretation of their pharmacological properties.but possess much better selectivity for PKC [7][8][9][10]. Two such PKC-specific analogues, UCN-01 and CGP 41251, have been shown to possess antineoplastic activity in human tumour models grown in rodents [9,11]. In most investigations of the ability of compounds to inhibit PKC, cytosolic enzyme preparations have been used. In the light of the fact that it is predominantly PKC in the membrane which is of functional importance, we tested the hypothesis that kinase inhibitors display different potencies against membrane-derived as compared to cytosolic enzyme. To that end nine well-characterised PKC inhibitors, including staurosporine and four analogues, were investigated with respect to their ability to inhibit PKC prepared from the cytosol or membrane of human-derived MCF-7 breast cancer cells. The susceptibility of these cells towards the growth-arresting ability of PKC inhibitors has recently been described [12].

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Section: Discussionmentioning

confidence: 84%

mentioning

confidence: 99%

Differential inhibition of cytosolic and membrane‐derived protein kinase C activity by staurosporine and other kinase inhibitors

Budworth

Gescher

1995

FEBS Letters

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“…per well for the 2 and 4 day experiments, respectively, to ensure that similar cell numbers were found in control cultures at both time points. Drug concentrations were between 2 and 5 times the concentration which caused 50% growth inhibition (IC50) after 4 days (Courage et al, 1995).…”

Section: Methodsmentioning

confidence: 99%

“…The following properties were compared: (1) their effects on the cell cycle at equicytostatic concentrations; (2) the time dependency and reversibility associated with their cytostatic properties; and (3) their acute cytotoxic potential. The investigations were performed using human-derived A549 lung carcinoma cells, the growth of which has been shown to be sensitive towards PKC inhibitors (Courage et al, 1995).…”

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confidence: 99%

Differential effects of staurosporine analogues on cell cycle, growth and viability in A549 cells

Courage

Snowden²,

Gescher³

1996

Br J Cancer

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Summary Staurosporine is a potent but non-specific kinase inhibitor. It has served as synthetic template for a variety of analogues with high specificity for protein kinase C (PKC). Here staurosporine and four PKCselective analogues, the indolocarbazoles, UCN-01 and CGP 41251, and the bisindolylmaleimides, Ro 31-8220 and GF 109203X, were investigated as growth inhibitors of human-derived A549 human lung adenocarcinoma cells. They were compared with respect to (1) effect on the cell cycle, (2) time dependency of growth arrest and (3) cytotoxic potency. Cells were exposed for 1, 2 and 4 days, or for 6, 12 and 24 h in the case of cyclesynchronised cells, to staurosporine analogues at concentrations at which they inhibited growth by 80% after 4 day exposure. Staurosporine and UCN-01 retarded cells in Go/, and CGP 41251 appeared to inhibit cell growth without cell cycle specificity. Ro 31-8220 slowed progression of synchronised cells through the cycle; over a longer time period it induced a weak block in G2/M. GF 109203X induced potent G2/M arrest in synchronised cells. This was not so apparent in asynchronous cells, which by day 4 were slowed in Go/, instead.Growth arrest induced by these inhibitors was more potent after incubation for 4 rather than 2 days. Incubation for 1 day followed by maintenance in drug-free medium for 3 days was sufficient to exert some cytostasis. The differences between cytotoxic and cytostatic concentrations, the former measured by release from cells of lactate dehydrogenase, were 15 000-fold for staurosporine, 300-fold for UCN-01, -400-fold for CGP 41251, 25-fold for Ro 31-8220 and -4-fold for GF 109203X. The results show that PKC-selective staurosporine analogues differ with respect to the mechanisms by which they interfere with the cell cycle. The necessity of long-term exposure for effective growth inhibition and the considerable margin between cytostatic and acute cytotoxic indolocarbazole concentrations are findings which might influence the planning and interpretation of clinical trials of these kinase inhibitors.

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“…Studies identifying the cellular pathways affected by UCN-01 resulting in Gl arrest suggest that although UCN-01 possesses potent PKC-inhibitory activity, inhibition of PKC activity is not essential for its growth inhibitory activity (Courage et al, 1995). Recent studies on the role of cell cycle regulators in UCN-01-mediated Gl arrest indicate that in human epidermoid carcinoma A431 cells, UCN-01-induced Gl arrest was accompanied by decreased cyclin-dependent kinase 2 (CDK2) activity and induction of CDK inhibitors p21 and p27 (Akiyama et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Cyclin E, A Potential Prognostic Marker in Breast Cancer

Keyomarsi¹

1998

105

143

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PuMic reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining fS^adta heeded, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for Teducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and to the Office of Management and Budget,, Washington, DC 20503 AGENCY USE ONLY (Leave blank) REPORT DATE April 2000 REPORT TYPE AND DATES COVEREDFinal (1 Oct 94 -30 Mar 00) TITLE AND SUBTITLE Cyclin E, a Potential Prognostic Marker in Breast Cancer AUTHOR(S)Khandan Keyomarsi, Ph.D. Cyclin E, a G1 cyclin essential for S phase entry with a profound role in oncogenesis, is overexpressed and present in lower molecular weight (LMW) isoforms in breast cancer cells and tumor tissues. Alteration and overexpression of cyclin E are linked to poor patient outcome. We have established the use of cyclin E as a prognostic marker for breast cancer. Tumor specimens from 400 breast cancer patients were examined; changes of cyclin E expression were compared with seven other established tumor markers to patient outcome. Altered expression of cyclin E was observed in 91% of all breast cancers with poor prognosis where patients either died of breast cancer or were still with cancer at the last contact date. Similarly in 93% of all breast cancer patients where cyclin E was either not altered, or its alteration was minimal, patients had a favorable prognosis. We have also deciphered the mechanism of deregulation of cyclin E in breast cancer cells giving rise to the LMW forms of cyclin E. Our studies show that the LMW forms of cyclin E detected at a much higher level in tumor cells, arise from post-translational action of a protease. We have been able to generate and knockout the tumor specific LMW pattern of cyclin E by transient transfection of FLAG-tagged cyclin E constructs harboring these mutations in a breast cancer cell line. We have identified a novel elastase-type consensus sequence in the amino-terminus of cyclin E responsible for generating these tumor specific LMW isoforms. Lastly, studies using the drug Lovastatin demonstrated that this highly prescribed drug used to lower cholesterol levels is also capable of inducing all four cyclin dependent kinase inhibitors (CKIs) in a cell specific manner via cell cycle independent mechanism, through the inhibition of the proteasome. We have also devised a novel treatment strategy that protects normal cells against the toxic effects of chemotherapeutic agents, by reversibly arresting the normal cells in the G1 phase of the cell cycle. Where copyrighted material is quoted, permission has been obtained to use such material. FUNDING NUMBERS DAMD17-94-J-4081 PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)H...

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Comparison of ability of protein kinase C inhibitors to arrest cell growth and to alter cellular protein kinase C localisation

Cited by 72 publications

References 28 publications

Differential inhibition of cytosolic and membrane‐derived protein kinase C activity by staurosporine and other kinase inhibitors

Differential inhibition of cytosolic and membrane‐derived protein kinase C activity by staurosporine and other kinase inhibitors

Differential effects of staurosporine analogues on cell cycle, growth and viability in A549 cells

Cyclin E, A Potential Prognostic Marker in Breast Cancer

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