Outcome of treatment of human HeLa cervical cancer cells with roscovitine strongly depends on the dosage and cell cycle status prior to the treatment

Węsierska‐Gądek, Józefa; Borza, Andreea; Walzi, Eva; Kryštof, Vladimír; Maurer, Margarita; Komina, Oxana; Wandl, Stefanie

doi:10.1002/jcb.22074

Cited by 24 publications

(24 citation statements)

References 56 publications

(75 reference statements)

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“…ROSC, a 2,6,9-trisubstituted purine analogue (also known as Selicliclib TM ; CYC-202; Cyclacel Ltd.) competes for binding to the ATP pocket of the kinase catalytic subunit [De Azevedo et al, 1997;Havlicek et al, 1997;Benson et al, 2007]. Although it affects several kinases, it primarily inhibits CDK2 and CDK7 [McClue et al, 2002;Wesierska-Gadek et al, 2009a]. [Wesierska-Gadek et al, 2009a;Galimberti et al, 2010].…”

Section: Discussionmentioning

confidence: 98%

“…Although it affects several kinases, it primarily inhibits CDK2 and CDK7 [McClue et al, 2002;Wesierska-Gadek et al, 2009a]. [Wesierska-Gadek et al, 2009a;Galimberti et al, 2010]. However, the biological effects of ROSC are strongly dependent on its dose, the duration of treatment, cell type, and cellular context.…”

Section: Discussionmentioning

confidence: 99%

“…In the last 20 years, a number of selective CDK inhibitors have been developed [Lapenna and Giordano, 2009;Węsierska-Gądek et al, 2009b;Galons et al, 2010;Rizzolio et al, 2010] Roscovitine (ROSC), a tri-substituted purine derivative (Selicliclib TM ; CYC-202), inhibits CDK2, 5, 7, and 9 [Vesely et al, 1994;De Azevedo et al, 1997;Havlicek et al, 1997;Meijer et al, 1997]. Its biological effects depend on the cell type, concentration used, and the duration of the treatment [Wesierska-Gadek et al, 2009a]. We and other groups reported several years ago that ROSC efficiently inhibits the proliferation and cell cycle progression of chemoresistant human MCF-7 breast cancer cells [Wojciechowski et al, 2003].…”

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confidence: 99%

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Interference with ER‐α enhances the therapeutic efficacy of the selective CDK inhibitor roscovitine towards ER‐positive breast cancer cells

Węsierska‐Gądek

Gritsch

Zulehner

et al. 2011

J of Cellular Biochemistry

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In recent years many risk factors for the development of breast cancer that are linked to estrogens have been identified, and roscovitine (ROSC), a selective cyclin-dependent kinase (CDK) inhibitor, has been shown to be an efficient inhibitor of the proliferation of human breast cancer cells. Therefore, we have examined the possibility that interference with estrogen signaling pathways, using tamoxifen (TAM), a selective estrogen receptor modulator (SERM), could modulate the efficacy of treatment with ROSC. In conjunction with TAM, ROSC exhibited enhanced anti-proliferative activity and CDK inhibition, particularly in estrogen-dependent MCF-7 cells. The interaction between both drugs was synergistic. However, in ER-α-negative cells the interaction was antagonistic. Exposure of MCF-7 cells to ROSC abolished the activating phosphorylation of CDK2 and CDK7 at Ser(164/170). This in turn prevented the phosphorylation of the carboxyl-terminal repeat domain of RNA Polymerase II and ER-α at Ser(118), resulting in the down-regulation of the latter. Concomitantly, wt p53 was strongly activated by phosphorylation at Ser(46). Our results demonstrate that ROSC negatively affects the functional status of ER-α, making it potentially useful in the treatment of estrogen-dependent breast cancer cells.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Interference with ER‐α enhances the therapeutic efficacy of the selective CDK inhibitor roscovitine towards ER‐positive breast cancer cells

Węsierska‐Gądek

Gritsch

Zulehner

et al. 2011

J of Cellular Biochemistry

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“…Also, it has been shown that Roscovitine can cause cell death (28,29). Therefore, in these experiments we measured whether the reduction in cell number observed when PNUTS siRNA was combined with Roscovitine led to an increase in cell death.…”

Section: Pnuts Knockdown Enhances Cell Death Induced By Roscovitinementioning

confidence: 99%

“…For example, Roscovitine-mediated cdk inhibition prevents phosphorylation of Rb and induces cell cycle arrest in several model systems (25)(26)(27). Depending on dose and cell type, Roscovitine can also induce apoptosis (28,29). In addition, Roscovitine inhibits phosphorylation of the carboxy-terminal domain of the large subunit of RNA polymerase II, which is required for transcriptional activity (28).…”

Section: Introductionmentioning

confidence: 99%

PNUTS knockdown potentiates the apoptotic effect of Roscovitine in breast and colon cancer cells

Krucher¹

2010

Int J Oncol

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Abstract. The phosphorylation state of Retinoblastoma protein (Rb) plays a role in cell proliferation and apoptosis. Within cells, cyclin dependent kinases (cdks) phosphorylate Rb in response to growth stimulatory signals, whereas protein phosphatase 1 (PP1) dephosphorylates Rb when cells stop proliferating or undergo apoptosis in response to antiproliferative or stress signals. Stimulation of PP1 activity via siRNA mediated knockdown of its interacting protein PNUTS (Phosphatase Nuclear Targeting Subunit) leads to Rb dephosphorylation and apoptosis in cancer cells. We utilized two separate methods to modulate the phosphorylation state of Rb in cancer cells. Kinase activity toward Rb is inhibited by the clinically relevant cdk inhibitor, Roscovitine. In addition, siRNA mediated PNUTS knockdown stimulates phosphatase activity toward Rb. Either of these treatments in cancer cells causes a 2-fold stimulation of apoptosis. When activation of phosphatase activity is combined with inhibition of cdk activity toward Rb, however, cells exhibit a 4-fold increase in apoptosis. The mechanism by which PNUTS knockdown mediated PP1 activation leads to apoptosis was determined to be dependent on the activity of the transcription factor E2F1. The Rb phosphorylation profiles resulting from each treatment were analyzed and found to be similar but not identical. In addition, the two treatments differentially effect the expression of bcl-2 family proteins. Thus inhibition of cdk activity and activation of PP1 activity toward pRb are functionally distinct processes that together increase the apoptotic effect in cells.

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R‐roscovitine (Seliciclib) affects CLL cells more strongly than combinations of fludarabine or cladribine with cyclophosphamide: Inhibition of CDK7 sensitizes leukemic cells to caspase‐dependent apoptosis

Rogalińska

Błoński

Komina

et al. 2009

J of Cellular Biochemistry

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Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of malignant, apoptosis-resistant B CD19(+)/CD5(+) cells. Populations of CLL cells are heterogeneous and consist primarily of quiescent cells with a minor subset of dividing cells. In this study the efficacy of a first-line in vivo therapy was compared with treatment by R-roscovitine (ROSC) alone or by purine analogues (cladribine and fludarabine) combined with maphosphamide for 14 CLL patients under ex vivo conditions. ROSC induced the highest reduction in numbers of living B-cells, coinciding with an increased rate of apoptosis. After 24 h the percentage of apoptotic cells in ROSC-treated cultures was markedly higher than in untreated controls. ROSC also induced strong activation of the apoptosome and effector caspases in CLL cells. During progression of apoptosis the plasma membrane became permeable, resulting in the release of activated caspases into the culture medium. Leukemic cells were more sensitive to ROSC than normal mononuclear cells. Treatment with ROSC did not affect the activating phosphorylation of CDK2 or CDK1. However, ROSC decreased phosphorylation of survivin, CDK7, and RNA-Pol II, resulting in inhibition of transcription elongation and subsequent down-regulation of levels of anti-apoptotic factors, thereby facilitating apoptosis. Unlike ROSC, two other purine analogues barely affected the cellular levels of anti-apoptotic proteins and more weakly activated effector caspases. In addition, the efficacies of in vivo and ex vivo therapies were found to be correlated. Marked between-patient differences in expression patterns of apoptosis-regulating factors in CLL cells were observed, explaining the variations in patients' sensitivity to therapy.

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Outcome of treatment of human HeLa cervical cancer cells with roscovitine strongly depends on the dosage and cell cycle status prior to the treatment

Cited by 24 publications

References 56 publications

Interference with ER‐α enhances the therapeutic efficacy of the selective CDK inhibitor roscovitine towards ER‐positive breast cancer cells

Interference with ER‐α enhances the therapeutic efficacy of the selective CDK inhibitor roscovitine towards ER‐positive breast cancer cells

PNUTS knockdown potentiates the apoptotic effect of Roscovitine in breast and colon cancer cells

R‐roscovitine (Seliciclib) affects CLL cells more strongly than combinations of fludarabine or cladribine with cyclophosphamide: Inhibition of CDK7 sensitizes leukemic cells to caspase‐dependent apoptosis

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