Dose-Dependent Cellular Phenotypic Change Induced by 177Lu-Oxodotreotide Treatment in IMR-32 Cells

TL;DR

This study shows that 177Lu-Oxodotreotide causes increasing cell damage in neuroblastoma cells as the dose increases, through DNA damage and mitochondrial issues.

Contribution

The study reveals the dose-dependent molecular mechanisms of 177Lu-Oxodotreotide-induced cellular damage in neuroblastoma cells.

Findings

Cell viability decreased linearly with increasing Lutathera dose, showing strong dose correlation.

Apoptosis and DNA damage (γ-H2AX) increased significantly with higher doses of Lutathera.

Mitochondrial membrane potential and cell proliferation were dose-dependently suppressed.

Abstract

Objectives: Beta-emitting radionuclide therapy, exemplified by 177Lu-Oxodotreotide (Lutathera®), enables targeted treatment of neuroendocrine tumors by delivering β-radiation to tumor cells. However, the dose-dependent molecular mechanisms underlying cellular damage remain insufficiently characterized. This study aimed to investigate the phenotypic changes in IMR-32 human neuroblastoma cells following Lutathera exposure, with a focus on the dose-dependent relationship between radiation and cellular damage. Methods: IMR-32 cells were allocated to control, low- (0.05 MBq/mL), medium- (0.5 MBq/mL), and high-dose (5 MBq/mL) groups and treated with 177Lu-Oxodotreotide for 24 h. Flow cytometry was employed to assess cell viability, apoptosis, mitochondrial membrane potential, γ-H2AX expression (a marker of DNA damage), and proliferation. Results: Lutathera induced dose-dependent cytotoxic effects. Cell viability declined linearly with increasing dose (control: 100% vs. high-dose: 13.48%; r = −0.955, p < 0.001). Apoptosis was significantly elevated (control: 35.34% vs. high-dose: 88.12%; r = 0.999), accompanied by increased γ-H2AX levels (control: 5.26 × 104 vs. high-dose: 13.13 × 104; r = 0.930), indicating DNA double-strand breaks. Mitochondrial membrane potential decreased (control: 6.06 × 104 vs. high-dose: 46.27 × 104; r = 0.999), and proliferation was suppressed (control: 91.10 × 104 vs. high-dose: 103.84 × 104; r = 0.954), both showing strong dose correlations (p < 0.001). Conclusions: 177Lu-Oxodotreotide exerts dose-dependent cytotoxicity in IMR-32 cells via DNA damage, mitochondrial dysfunction, and apoptosis induction. These findings underscore the necessity of optimizing dosing regimens to balance therapeutic efficacy and safety in clinical settings, providing a foundation for personalized β-emitter therapies.

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