Evaluation of the Effect of Mesenchymal Stem Cells on Cisplatin Induced Toxicity in Neuroblastoma Tumor Model

Safiye Aktas,Osman Yılmaz,Hande Evin,Tekincan Çağrı Aktaş,Hatice Nur Olgun,Ayşe Pınar Erçetin,Günay Kırkım,Yüksel Olgun

doi:10.18535/ijmsci/v8i12.02

Abstract

Objective: High-dose cisplatin (CDDP) causes dose-limiting side effects in neuroblastoma (NB) treatment. Mesenchymal stem cells (MSC) are a current research area. The aim of this study is to assess the interaction of MSC with CDDP in nude mouse NB model. Methods: Athymic male nude mice (n=28) thatbhad basal auditory tests, with subcutaneous NB were randomized to control, CDDP, MSC and CDDP+MSC treatment groups. Seven days later, hearing tests were repeatedand the animals were sacrificed. Necrosis, apoptosis and viabilitywere assessed in tumors. MSC rate within the tumor was assessed with flow cytometry for triple CD34+ CD44+ and CD117- expression. Expression of the cochlear cell proteins of calretinin, math-1 and myosin2A were immunohistochemically assessed. Results: Tumor tissues were found to have statistically significantly higher levels of necrosis in CDDP and CDDP+MSC groups. MSC did not change the tumor dimensions in the CDDP group. MSC group had higher triple CD34+ CD44+ and CD117- expression within tumor tissue compared to the control and CDDP groups. In the inner ear, the expression of cochlear cell proteins calretinin, math-1 and myosin2A were identified to be highest in MSC group. 15-decibel loss at 12, 16, 20 and 32 kHz frequencies with CDDP was resolved with MSC administration. Conclusion: MSC prevented hearing loss caused by CDDP without disrupting the antitumor effect of CDDP. Systemic MSC may be assessed for clinical use to reduce the side effects of CDDP.

Highlights

Neuroblastoma (NB) is a noteworthy embryonal tumor with interesting heterogeneous biological behavior rooted in the neural crest of the sympathetic nervous system
While the tumor diameters increased in the control and Mesenchymal stem cells (MSC) groups, the tumor diameters reduced in the CDDP and CDDP+MSC groups
Both CDDP and CDDP+MSC administrations reduced tumor diameter compared to the control group (p=0.01)

Summary

Introduction

Neuroblastoma (NB) is a noteworthy embryonal tumor with interesting heterogeneous biological behavior rooted in the neural crest of the sympathetic nervous system. In spite of intensive protocols and alternative treatment approaches in advanced stage disease, the two-year disease-free survival only reaches 30-40%. Cisplatin (CDDP) is used in the induction therapy cycle for NB in combination with anthracyclines, alkylating agents and topoisomerase II inhibitors [1]. Induction chemotherapy continues with a multimodal approach involving surgical resection, myeloablative treatment and autologous stem cell. Safiye AKTAS, et al / Evaluation of the Effect of Mesenchymal Stem Cells on Cisplatin Induced Toxicity in Neuroblastoma Tumor Model transplant and radiation therapy [2]. Immunotherapy, the ALK inhibitor crizotinib in patients with ALK mutations and targeted treatments based on genomic analysis of tumor samples have been trialed. In NB treatment, side effects of hearing loss (62%), primary hypothyroidism (24%), ovarian failure (41% in women), musculoskeletal system anomalies (19%) and pulmonary anomalies (19%)

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Conclusion