Molecular iodine synergized and sensitized neuroblastoma cells to the antineoplastic effect of ATRA

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Neuroblastoma (NB) is a common pediatric solid tumor.
• All-trans retinoic acid (ATRA) is a standard treatment for reducing residual NB disease.
• Molecular iodine (I2) has shown potential in inducing differentiation and apoptosis in cancer cells via PPARγ activation.

Purpose of the Study:

• To investigate the synergistic effects of coadministered I2 and ATRA on neuroblastoma treatment.
• To analyze the impact of I2 and ATRA on NB cell viability, differentiation, and molecular markers in vitro and in vivo.
• To evaluate the potential of I2 as an adjuvant to ATRA therapy for neuroblastoma.

Main Methods:

• Utilized ATRA-sensitive (SH-SY5Y), partially-sensitive (SK-N-BE(2)), and non-sensitive (SK-N-AS) NB cell lines for in vitro experiments.
• Administered I2 and ATRA to NB cells and xenografts in Foxn1 nu/nu mice.
• Assessed cellular viability, neurite extension, neural marker expression (TH, Trk-A), receptor expression (RARα, PPARγ), Survivin levels, and mitochondrial membrane potential.
• Performed in vivo studies with oral I2 supplementation and ATRA administration, monitoring body weight, side effects, and intratumoral vasculature (CD34) via immunohistochemistry.

Main Results:

• In SH-SY5Y cells, I2 significantly reduced the effective dose of ATRA and promoted neural differentiation markers.
• I2 sensitized non-sensitive SK-N-AS cells to ATRA, upregulating RARα and PPARγ, and downregulating Survivin.
• I2 supplementation enhanced mitochondrial membrane potential in SK-N-AS cells, suggesting mitochondrial involvement in ATRA sensitization.
• In vivo, I2 + ATRA synergistically reduced tumor growth, prevented weight loss and diarrhea, and decreased intratumoral CD34 expression.

Conclusions:

• Coadministration of I2 and ATRA demonstrates synergistic efficacy in treating neuroblastoma.
• I2 enhances ATRA's antiproliferative and differentiation-inducing effects, potentially through mechanisms involving PPARγ and mitochondrial pathways.
• The I2 + ATRA combination shows promise as an adjuvant therapy for neuroblastoma, warranting further preclinical and clinical investigation.