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

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...

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Published in:	Clinical cancer research 2009-06, Vol.15 (11), p.3716-3724
Main Authors:	HUI, Angela B. Y, SHIJUN YUE, WEI SHI, ALAJEZ, Nehad M, ITO, Emma, GREEN, Simon R, FRAME, Sheelagh, O'SULLIVAN, Brian, LIU, Fei-Fei
Format:	Article
Language:	eng
Subjects:	Animals Antineoplastic agents Antineoplastic Agents - therapeutic use apoptosis Apoptosis - drug effects Apoptosis - radiation effects Biological and medical sciences Blotting, Western Caspase 2 - metabolism Caspase 3 - metabolism Caspase 8 - metabolism Caspase 9 - metabolism Cell Cycle - drug effects Cell Cycle - radiation effects Cell Line, Tumor Cell Survival - drug effects Cell Survival - radiation effects Combined Modality Therapy Cyclin-Dependent Kinases - antagonists & inhibitors DNA Breaks, Double-Stranded - drug effects DNA Breaks, Double-Stranded - radiation effects Dose-Response Relationship, Drug Humans Medical sciences Mice Myeloid Cell Leukemia Sequence 1 Protein nasopharyngeal carcinoma Nasopharyngeal Neoplasms - metabolism Nasopharyngeal Neoplasms - pathology Nasopharyngeal Neoplasms - therapy Otorhinolaryngology. Stomatology Pharmacology. Drug treatments Proto-Oncogene Proteins c-bcl-2 - genetics Proto-Oncogene Proteins c-bcl-2 - metabolism Purines - therapeutic use radiation Radiation, Ionizing Reverse Transcriptase Polymerase Chain Reaction seliciclib Time Factors Treatment Outcome Tumors Upper respiratory tract, upper alimentary tract, paranasal sinuses, salivary glands: diseases, semeiology Xenograft Model Antitumor Assays
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Summary:	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 dose-dependent 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 EBV-positive 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.
ISSN:	1078-0432 1557-3265