Seliciclib (R-roscovitine) induces apoptosis in undifferentiated nasopharyngeal cancer (NPC) in vivo and in vitro

Goh, Boon-Cher; Peh, B.K.; Cui, Changxu; Soo, Ross A.; Loh, Teck Peng; Green, S.; Hsieh, Wen-Chiuan; Lai, Yuen-Liang; Salto–Tellez, Manuel; Mow, Benjamin

doi:10.1200/jco.2005.23.16_suppl.3145

Cited by 6 publications

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“…This agent has now progressed to phase II clinical testing (15). Efficacy of seliciclib has been previously investigated in four human nasopharyngeal carcinoma cell lines (16), wherein apoptosis and cell cycle arrest were both observed. However, these were all EBV-negative models.…”

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confidence: 99%

Therapeutic Efficacy of Seliciclib in Combination with Ionizing Radiation for Human Nasopharyngeal Carcinoma

Hui

Yue

Shi

et al. 2009

Clinical Cancer Research

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Purpose: Seliciclib is a small-molecule cyclin-dependent kinase inhibitor, which has been reported to induce apoptosis and cell cycle arrest in EBV-negative nasopharyngeal carcinoma cell lines. Because most nasopharyngeal carcinoma patients harbor EBV, we proceeded to evaluate the cytotoxic effects of seliciclib in EBV-positive nasopharyngeal carcinoma models. Experimental Design: Cytotoxicity of seliciclib was investigated in the EBV-positive cell line C666-1 and the C666-1 and C15 xenograft models. Caspase activities and cell cycle analyses were measured by flow cytometry. Efficacy of combined treatment of seliciclib with radiation therapy was also evaluated. Results: Seliciclib caused significant cytotoxicity in the C666-1 cells in a time-and dosedependent manner, with accumulation of cells in both sub-G 1 and G 2 -M phases, indicative of apoptosis and cell cycle arrest, respectively. Caspase-2, -3, -8, and -9 activities were all increased, with caspase-3 being the most significantly activated at 48 h after treatment. These cells also showed a reduction of Mcl-1 mRNA and protein levels. Combined treatment of seliciclib with radiation therapy showed a synergistic interaction with enhanced cytotoxicity in C666-1 cells and delayed repair of double-strand DNA breaks. For in vivo models, significant delays in tumor growth were observed for both C666-1 and C15 tumors, which were associated with enhanced apoptosis as determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and immunohistochemistry analyses. Conclusions: Seliciclib enhanced the antitumor efficacy of radiation therapy in EBVpositive nasopharyngeal carcinoma, characterized by G 2 -M arrest, and apoptosis, associated with an induction in caspase activity. This process is mediated by reduction in Mcl-1 expression and by attenuation of double-strand DNA break repair.

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confidence: 99%

Therapeutic Efficacy of Seliciclib in Combination with Ionizing Radiation for Human Nasopharyngeal Carcinoma

Hui

Yue

Shi

et al. 2009

Clinical Cancer Research

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Cellular Protein Kinases as Antiviral Targets

Schang

2011

Protein Kinases as Drug Targets

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The cyclin‐dependent kinase inhibitor roscovitine inhibits kinase activity, cell proliferation, multicellular development, and Cdk5 nuclear translocation in Dictyostelium discoideum

Huber

O’Day

2012

J of Cellular Biochemistry

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Roscovitine, a cyclin-dependent kinase (Cdk) inhibitor, inhibited kinase activity and the axenic growth of Dictyostelium discoideum at micromolar concentrations. Growth was almost fully rescued in 50 µM and ≈ 50% rescued in 100 µM roscovitine-treated cultures by the over-expression of Cdk5-GFP. This supports the importance of Cdk5 function during cell proliferation in Dictyostelium and indicates that Cdk5 is a primary target of the drug. Roscovitine did not affect the expression of Cdk5 protein during axenic growth but did inhibit its nuclear translocation. This novel result suggests that the effects of roscovitine could be due in part to altering Cdk5 translocation in other systems as well. Kinase activity was inhibited by roscovitine in assays using AX3 whole cell lysates, but not in assays using lysates from Cdk5-GFP over-expressing cells. At higher concentrations, roscovitine impaired slug and fruiting body formation. Fruiting bodies that did form were small and produced relatively fewer spores many of which were round. However, roscovitine did not affect stalk cell differentiation. Together with previous findings, these data reveal that roscovitine inhibits Cdk5 during growth and as yet undefined Cdks during mid-late development.

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Seliciclib (R-roscovitine) induces apoptosis in undifferentiated nasopharyngeal cancer (NPC) in vivo and in vitro

Cited by 6 publications

References 0 publications

Therapeutic Efficacy of Seliciclib in Combination with Ionizing Radiation for Human Nasopharyngeal Carcinoma

Therapeutic Efficacy of Seliciclib in Combination with Ionizing Radiation for Human Nasopharyngeal Carcinoma

Cellular Protein Kinases as Antiviral Targets

The cyclin‐dependent kinase inhibitor roscovitine inhibits kinase activity, cell proliferation, multicellular development, and Cdk5 nuclear translocation in Dictyostelium discoideum

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