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Notch Signaling–related Therapeutic Strategies With Novel Drugs in Neuroblastoma Spheroids

Ayla, Sule MD; Bilir, Ayhan PhD; Soner, Burak C. MD; Yilmaz-Dilsiz, Ozlem MD; Ergüven, Mine PhD; Oktem, Gulperi MD

Journal of Pediatric Hematology/Oncology: January 2014 - Volume 36 - Issue 1 - p 37–44
doi: 10.1097/MPH.0b013e3182755c73
Original Articles

Neuroblastoma is a severe pediatric tumor characterized by poor prognosis. Identification of novel molecular targets and diversion of investigations on new drug trials is mandatory for cancer therapy. In this study, vinorelbine tartrate, lithium chloride, clomipramine, and medroxyprogesterone acetate are used for the possible new treatment modalities in neuroblastoma cells. Notch and c-kit are novel molecules in cancer research, and Notch pathway is one of the emerging molecules in the neuroblastoma pathogenesis. Cytotoxic effects of these drugs at different time points, with different doses were studied in the SH-SY5Y human neuroblastoma cell line. Analysis of Notch and c-kit signaling with immunohistochemistry were constituted in multicellular tumor spheroids, and morphologic investigation was performed for digital imaging of cancer stem cells (CSCs) with electron microscopy. Size kinetics of spheroids was also determined after drug treatment. Results showed that all drugs were cytotoxic for neuroblastoma cells. Yet, this cytotoxic action did not correlate with the inhibitory effects in cell signaling. Neuroblastoma spheroids showed increased immunoreactivity of Notch signaling and c-kit. Altered ultrastructural CSCs morphology was observed after clomipramine and medroxyprogesterone acetate treatment compared with other drugs. Lithium chloride showed cellular membrane destruction for both CSCs and the remaining population. In this study, independent effects of cytotoxicity in tumor cells with respect to CSCs were determined. Redundant cells, which are the bulk population in tumor a compound, destroyed with therapy, were neither a target for treatment nor a remarkable investigation of cancer.

*Suleymaniye Gynecology and Maternity Training and Research Hospital

Department of Histology and Embryology, Istanbul Medical Faculty, Istanbul University, Capa

Department of Biochemistry, Faculty of Medicine, Yeni Yuzyil University, Istanbul

Department of Pharmacology, Faculty of Medicine, Selcuk University, Konya

§Department of Histology and Embryology, Faculty of Medicine, Ege University, Bornova, Izmir, Turkey

The authors declare no conflict of interest.

Reprints: Gulperi Oktem, MD, Department of Histology and Embryology, Faculty of Medicine, Ege University, Bornova, Izmir, Turkey 35100 (e-mail:

Received May 3, 2012

Accepted September 20, 2012

Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.