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

Abstract

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.

The cyclin-dependent kinase inhibitor SNS-032 has single agent activity in AML cells and is highly synergistic with cytarabine

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Dual blockade of lipid and cyclin-dependent kinases induces synthetic lethality in malignant glioma

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An Orthotopic Model of Metastatic Nasopharyngeal Carcinoma and Its Application in Elucidating a Therapeutic Target That Inhibits Metastasis

“…[8][9][10][11][12] To date, most NPC xenograft studies have involved the growth of a mass of tumor cells, often subcutaneously, that do not recapitulate human disease because they remain discrete and encapsulated. [8][9][10] In comparison, clinically advanced NPC is characterized by aggressive invasion with erosion and remodeling of facial and skull base cranial bones 13 as well as distant metastasis to solid organs, most commonly bone, lung, and liver. 14,15 To more accurately replicate advanced human disease, we have developed an orthotopic mouse xenograft model of NPC by inserting luciferasetagged tumor cells into the nasopharyngeal region and then following patterns of growth and metastasis over time.…”