Molecular Iodine/Cyclophosphamide Synergism on Chemoresistant Neuroblastoma Models.

Winniberg Álvarez-León,Brenda Anguiano,Carmen Aceves,Evangelina Delgado-González,Irasema Mendieta

doi:10.3390/ijms22168936

Winniberg Álvarez-León, Brenda Anguiano + Show 3 more

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https://doi.org/10.3390/ijms22168936

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Abstract

Neuroblastoma (Nb), the most common extracranial tumor in children, exhibited remarkable phenotypic diversity and heterogeneous clinical behavior. Tumors with MYCN overexpression have a worse prognosis. MYCN promotes tumor progression by inducing cell proliferation, de-differentiation, and dysregulated mitochondrial metabolism. Cyclophosphamide (CFF) at minimum effective oral doses (metronomic therapy) exerts beneficial actions on chemoresistant cancers. Molecular iodine (I2) in coadministration with all-trans retinoic acid synergizes apoptosis and cell differentiation in Nb cells. This work analyzes the impact of I2 and CFF on the viability (culture) and tumor progression (xenografts) of Nb chemoresistant SK-N-BE(2) cells. Results showed that both molecules induce dose-response antiproliferative effects, and I2 increases the sensibility of Nb cells to CFF, triggering PPARγ expression and acting as a mitocan in mitochondrial metabolism. In vivo oral I2/metronomic CFF treatments showed significant inhibition in xenograft growth, decreasing proliferation (Survivin) and activating apoptosis signaling (P53, Bax/Bcl-2). In addition, I2 decreased the expression of master markers of malignancy (MYCN, TrkB), vasculature remodeling, and increased differentiation signaling (PPARγ and TrkA). Furthermore, I2 supplementation prevented loss of body weight and hemorrhagic cystitis secondary to CFF in nude mice. These results allow us to propose the I2 supplement in metronomic CFF treatments to increase the effectiveness of chemotherapy and reduce side effects.

Highlights

Neuroblastoma (Nb) is the most common extracranial tumor in children accounting for 15% of pediatric oncology deaths
MYC gene (MYCN) induces cell proliferation, inhibits cell differentiation, and maintains the stem-like phenotype [2]. These levels correlate to metastasis and angiogenesis, and MYCN overexpression affects the mitochondria metabolism to support the higher energy demand of chemoresistant Nb cells [1,2]
We evaluated the impact of oral metronomic CFF doses (20 mg/kg/day; 0.06%) with or without the I2 supplement (8 mg/kg/day; 0.025%) for three weeks

Summary

Introduction

Neuroblastoma (Nb) is the most common extracranial tumor in children accounting for 15% of pediatric oncology deaths. MYCN induces cell proliferation, inhibits cell differentiation, and maintains the stem-like phenotype [2]. These levels correlate to metastasis and angiogenesis, and MYCN overexpression affects the mitochondria metabolism to support the higher energy demand of chemoresistant Nb cells [1,2]. The use of CFF in metronomic therapy has recently been proposed as an effective alternative for chemoresistant cancers [4]. Metronomic therapy uses chronic oral treatments with minimum effective doses that exert their effects by inhibiting angiogenesis, immune modulation of the tumor stroma, and apoptosis of tumor cells. Its long-term and low-dose use reduces side effects and maintains the patient’s quality of life [4]. The use of combined therapies that include cellular re-differentiation or immune reactivation messengers are promising approaches that are currently being tested [5,6]

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