Early Induction of Apoptosis in Hematopoietic Cell Lines After Exposure to Flavopiridol

Parker, Bernard W.; Kaur, Gurmeet; Nieves-Neira, Wilberto; Taimi, Mohammed; Kohlhagen, Glenda; Shimizu, Takeshi; Losiewicz, Michael D.; Pommier, ﻿Yves; Sausville, Edward A.; Senderowicz, Adrian M.

doi:10.1182/blood.v91.2.458.458_458_465

Cited by 39 publications

(37 citation statements)

References 27 publications

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“…Flavopiridol (another CDK inhibitor), UCN-01 and roscovitine are currently used in clinical studies on cancer therapy [2,37]. CDK inhibition leads to cell cycle arrest [38][39][40][41], apoptotic cell death [39,41,42], differentiation [43][44][45] and inhibition of angiogenesis [46]. CDK inhibitors also modify the transcript levels of 2-3% of the genes in Saccharomyces cerevisiae, as measured by array methods [47].…”

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confidence: 99%

The expression of retinoblastoma and Sp1 is increased by low concentrations of cyclin‐dependent kinase inhibitors

Peñuelas

Alemany

Noé

et al. 2003

European Journal of Biochemistry

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We examined the effect of suboptimal concentrations of cyclin-dependent kinase inhibitors, which do not interfere with cell proliferation, on retinoblastoma expression in hamster (Chinese hamster ovary K1) and human (K562 and HeLa) cells. To achieve this, we used the chemical inhibitors roscovitine and olomoucine (which inhibit CDK2 preferentially), UCN-01 (which also inhibits CDK4/6) and p21 (as an intrinsic inhibitor). All chemical inhibitors and overexpression of p21 strongly induced retinoblastoma protein expression. UCN-01-mediated retinoblastoma expression was caused by an increase in both the levels of retinoblastoma mRNA and the stability of the protein. The expression of the transcription factor Sp1, a retinoblastomainteracting protein, was also enhanced by all the cyclin-dependent kinase inhibitors tested. However, Sp1 expression was caused by an increase in the levels of Sp1 mRNA without modification in the stability of the protein. By using luciferase experiments, the transcriptional activation of both retinoblastoma and Sp1 promoters by UCN-01 was confirmed. Bisindolylmaleimide I, at concentrations causing a similar or higher inhibition of protein kinase C than UCN-01, provoked a lower activation of retinoblastoma and Sp1 expression. Finally, the effects of cyclin-dependent kinase inhibitors on dihydrofolate reductase gene expression were evaluated. Treatment with UCN-01 increased cellular dihydrofolate reductase mRNA levels, and dihydrofolate reductase enzymatic activity was enhanced by UCN-01, roscovitine, olomoucine and p21, in transient transfection experiments. These results support a mechanism for the self-regulation of retinoblastoma expression, and point to the need to establish the appropriate dose of cyclin-dependent kinase inhibitors as antiproliferative agents in anticancer treatments.Keywords: retinoblastoma gene product; Sp1; UCN-01; roscovitine; dihydrofolate reductase.Cyclin-dependent kinases (CDKs) are key regulators of cell cycle progression. They constitute the catalytic subunits of holoenzymes formed in combination with regulatory subunits named cyclins. Thirteen CDKs [1,2] and at least 25 cyclins [2] have been reported to date. Cyclin expression varies during the cell cycle and the cyclin/CDK holoenzyme is activated by phosphorylation of specific residues in the CDK catalytic subunit by the cdk-activating kinase [3,4]. CDKs are involved in transcriptional control [5], mitotic progression [6], DNA repair (CDK7) [7], differentiation of brain neurons (CDK5) [8] and play a crucial role in the progression of cells from G1 to S phase by regulating the phosphorylation state of the retinoblastoma gene product (Rb). The tumor suppressor Rb is a nuclear protein of 928 amino acids [9] that is present in distinct phosphorylation states depending on the phase of the cell cycle [10,11]: it is nonphosphorylated when newly synthesized; hypophosphorylated in early G1; and hyperphosphorylated in late G1, S, and G2/M phases. In mitosis, a protein phosphatase 1-like protein removes all phosphates f...

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confidence: 99%

The expression of retinoblastoma and Sp1 is increased by low concentrations of cyclin‐dependent kinase inhibitors

Peñuelas

Alemany

Noé

et al. 2003

European Journal of Biochemistry

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“…Total number of SUDHL‐4 and Jurkat cells after incubation for 72 h increased by 10 and 15 times of the number of the initial cells, respectively (Figure 6c). The cell doubling time of SUDHL‐4 and Jurkat was 21 and 18 h, respectively 9. The same test was conducted with PPE2 and no death cell was observed in the presence of PPE2 (Figure S6 in supporting information).…”

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confidence: 89%

Conjugated Polyelectrolyte‐Antibody Hybrid Materials for Highly Fluorescent Live Cell‐Imaging

Lee

Jeong

et al. 2012

Advanced Materials

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Conjugated polyelectrolyte‐antibody hybrid materials promise to enhance the utility of conjugated polymers in bioimaging field. Polymer‐antibody conjugates that are biologically safe and highly sensitive and selective to cells are designed to image human T or B lymphocytes. In the clear state, the observed efficiency of luminescence is superior to that of commercially available FITC‐antibody probe.

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“…threefold higher than administered to solid tumor patients; drugrelated toxicities, including grade 1 hypokalemia and grade 2 nausea, only 24-h drug exposure, with no additional benefit from more prolonged exposure. Flavopiridol induces the apoptosis of CLL and lymphoma cells (71)(72)(73). Apoptosis occurs without a change in expression of Bcl-2 or Bax, even in the setting of decreased p53 expression, and may relate to the cleavage of caspase 3 (72,74).…”

Section: Flavopiridolmentioning

confidence: 99%

New Drugs for the Treament of Chronic Lymphocytic Leukemia

Cheson¹,

Dancey²,

Murgo³

2000

Rev Clin Exp Hematol

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Novel strategies are needed to improve the prognosis of patients with chronic lymphocytic leukemia CLL). One approach is to identify new drugs with unique mechanisms of action. Compound GW506U78, the prodrug for arabinosylguanine, is an interesting new purine analog, which induces responses in about one‐third of patients with relapsed or refractory CLL. A multicenter study is currently evaluating patients with CLL who have failed treatment with both fludarabine and an alkylating agent. Other agents in clinical development include retinoids and arsenicals which induce apoptosis, farnesyl transferase inhibitors, proteasome inhibitors and the signal transduction modulators, bryostatin and UCN‐01. UCN‐01 not only inhibits protein kinase C, but also modulates the G2 checkpoint. In vitro synergy has been demonstrated with fludarabine and a phase I trial of this combination is ongoing at the National Cancer Institute, USA. Flavopiridol is a semisynthetic flavone derivative which is active against cycling as well as noncycling cells. It inhibits a variety of cyclins and induces apoptosis. The histone deacetylase inhibitor depsipeptide has selective activity against CLL cells in vitro. An increasing body of evidence has implicated angiogenesis in hematologic malignancies, such as multiple myeloma, lymphoma and CLL. Several angiogenesis inhibitors are currently in clinical trials, including thalidomide, SU5416 and SU6668. Future strategies must be directed at appropriate therapeutic targets using rational combinations of these drugs and other new compounds with the goal of curing patients with CLL.

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Early Induction of Apoptosis in Hematopoietic Cell Lines After Exposure to Flavopiridol

Cited by 39 publications

References 27 publications

The expression of retinoblastoma and Sp1 is increased by low concentrations of cyclin‐dependent kinase inhibitors

The expression of retinoblastoma and Sp1 is increased by low concentrations of cyclin‐dependent kinase inhibitors

Conjugated Polyelectrolyte‐Antibody Hybrid Materials for Highly Fluorescent Live Cell‐Imaging

New Drugs for the Treament of Chronic Lymphocytic Leukemia

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