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Research Article: TRPV1-mediated calcium signaling underlies the synergistic pro-apoptotic effects of lidocaine and melatonin in SH-SY5Y neuroblastoma cells

Date Published: 2026-06-24

Abstract:
Lidocaine, an amide-type local anesthetic, and melatonin, a multifunctional indoleamine with mitochondrial regulatory and anticancer properties, have each been reported to modulate cancer cell survival. However, whether these agents cooperatively promote apoptosis in neuroblastoma cells through transient receptor potential vanilloid 1 (TRPV1)-mediated calcium signaling remains insufficiently defined. This study investigated the individual and combined effects of lidocaine and melatonin on SH-SY5Y human neuroblastoma cells, focusing on TRPV1-dependent intracellular mechanisms. Intracellular Ca² + responses were assessed using Fura-2-AM fluorescence, while apoptosis, reactive oxygen species (ROS) production, mitochondrial membrane potential (??m), and caspase-3/caspase-9 activities were evaluated using spectrofluorometric methods. The lidocaine + melatonin combination significantly increased cytosolic Ca² + levels, ROS production, mitochondrial depolarization, caspase activation, and apoptosis compared with control and single-treatment groups. These responses were attenuated by capsazepine, supporting TRPV1-mediated Ca² + influx as a central mechanism that appears to drive a Ca² + –mitochondria–ROS feed-forward axis leading to mitochondrial dysfunction and caspase-dependent apoptosis. These findings suggest that lidocaine and melatonin synergistically promote apoptosis in SH-SY5Y neuroblastoma cells through TRPV1-linked calcium-dependent pathways and provide a mechanistic basis for further investigation of anesthetic–adjunct interactions in translational oncology research.

Introduction:
Neuroblastoma (NB) represents the most common extracranial solid tumor in childhood, accounting for approximately 15% of all pediatric cancer-related deaths. Arising from neural crest-derived sympathetic nervous system progenitors, neuroblastoma exhibits remarkable clinical heterogeneity, ranging from spontaneous regression to aggressive metastatic disease resistant to conventional therapies ( 1 ). Despite advances in multimodal treatment strategies combining chemotherapy, surgical resection, and autologous…

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