Development of an in vitro neuroblastoma 3D model and its application for sterigmatocystin-induced cytotoxicity testing

Zingales, Veronica; Torriero, Noemi; Zanella, Luca; Fernández-Franzón, Mónica; Ruiz, María-José; Esposito, Maria Rosaria; Cimetta, Elisa

doi:10.1016/j.fct.2021.112605

Cited by 15 publications

(19 citation statements)

References 40 publications

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“…Both DIPG cell lines have unamplified MYCN, a gene involved in tumor development and progression. Furthermore, SH-SY5Y is derived from a primary neuroblastoma, while SK-N-AS is from metastases [ 49 , 50 , 51 ].…”

Section: Resultsmentioning

confidence: 99%

Harmaline to Human Mitochondrial Caseinolytic Serine Protease Activation for Pediatric Diffuse Intrinsic Pontine Glioma Treatment

Miciaccia,

Rizzo,

Centonze

et al. 2024

Pharmaceuticals

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Diffuse intrinsic pontine glioma (DIPG), affecting children aged 4–7 years, is a rare, aggressive tumor that originates in the pons and then spreads to nearby tissue. DIPG is the leading cause of death for pediatric brain tumors due to its infiltrative nature and inoperability. Radiotherapy has only a palliative effect on stabilizing symptoms. In silico and preclinical studies identified ONC201 as a cytotoxic agent against some human cancer cell lines, including DIPG ones. A single-crystal X-ray analysis of the complex of the human mitochondrial caseinolytic serine protease type C (hClpP) and ONC201 (PDB ID: 6DL7) allowed hClpP to be identified as its main target. The hyperactivation of hClpP causes damage to mitochondrial oxidative phosphorylation and cell death. In some DIPG patients receiving ONC201, an acquired resistance was observed. In this context, a wide program was initiated to discover original scaffolds for new hClpP activators to treat ONC201-non-responding patients. Harmaline, a small molecule belonging to the chemical class of β-carboline, was identified through Fingerprints for Ligands and Proteins (FLAP), a structure-based virtual screening approach. Molecular dynamics simulations and a deep in vitro investigation showed interesting information on the interaction and activation of hClpP by harmaline.

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Section: Resultsmentioning

confidence: 99%

Harmaline to Human Mitochondrial Caseinolytic Serine Protease Activation for Pediatric Diffuse Intrinsic Pontine Glioma Treatment

Miciaccia,

Rizzo,

Centonze

et al. 2024

Pharmaceuticals

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“…The potential impact of 3D cultures has strongly been emphasised previously, and authors have provided a variety of techniques for introducing 3D culture systems with the aim of attaining more reliable and comprehensive results [108]. Efforts to transfer the experiments to 3D have also been made in NB [109][110][111][112][113]. The hanging drop method has traditionally been used to study spheroid growth.…”

Section: Summary and Discussionmentioning

confidence: 99%

“…Previous studies have reviewed the role of ECM in NB progression, evidencing that alterations of the ECM are tumour progression mediators [79, 115]. Moreover, stiffness regulates the neuroblastoma dynamics and behaviour [77, 116] as well as the chemotherapeutic distribution and efficacy [111]. The combination of long-term 3D culture and microfluidic devices paves the way to a better understanding of tumour spheroid formation, offering a fine methodology with which to feed the computational models.…”

Section: Summary and Discussionmentioning

confidence: 99%

Tumour growth: Bayesian parameter calibration of a multiphase porous media model based on in vitro observations of Neuroblastoma spheroid growth in a hydrogel microenvironment

Hervas-Raluy

Wirthl

Guerrero

et al. 2022

Preprint

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To unravel processes that lead to the growth of solid tumours, it is necessary to link knowledge of cancer biology with the physical properties of the tumour and its interaction with the surrounding microenvironment. Our understanding of the underlying mechanisms is however still imprecise. We therefore developed computational physics-based models, which incorporate the interaction of the tumour with its surroundings based on the theory of porous media. However, the experimental validation of such models represents a challenge to its clinical use as a prognostic tool. This study combines a physics-based model with in vitro experiments based on microfluidic devices used to mimic a 3D tumour microenvironment. By conducting a global sensitivity analysis, we identify the most influential input parameters and infer their posterior distribution based on Bayesian calibration. The resulting probability density is in agreement with the scattering of the experimental data and thus validates the modelling approach. Using the proposed workflow, we demonstrate that we can indirectly characterise the mechanical properties of neuroblastoma spheroids that cannot feasibly be measured experimentally.

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“…FM3A cells treated with equal doses (1 µg/mL) of AFB1 and STC were damaged at different scales with STC treatment, resulting in significantly more chromosomal breaks than AFB1 after 24 h incubation [20]. Alkaline comet assays investigating the DNA-damage effect of STC on human neuroblastoma SH-SY5Y cells detected a significant genotoxic increase in DNA damage [54]. It was also shown, using the same assay, that STC caused DNA double-strand breaks in human BEAS-2B and A549 cell lines [19].…”

Section: Discussionmentioning

confidence: 99%

Comparison Evaluation of the Biological Effects of Sterigmatocystin and Aflatoxin B1 Utilizing SOS-Chromotest and a Novel Zebrafish (Danio rerio) Embryo Microinjection Method

Csenki

Risa

Sárkány

et al. 2022

Toxins

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Aflatoxin B1 (AFB1) is a potent mycotoxin and natural carcinogen. The primary producers of AFB1 are Aspergillus flavus and A. parasiticus. Sterigmatocystin (STC), another mycotoxin, shares its biosynthetic pathway with aflatoxins. While there are abundant data on the biological effects of AFB1, STC is not well characterised. According to published data, AFB1 is more harmful to biological systems than STC. It has been suggested that STC is about one-tenth as potent a mutagen as AFB1 as measured by the Ames test. In this research, the biological effects of S9 rat liver homogenate-activated and non-activated STC and AFB1 were compared using two different biomonitoring systems, SOS-Chromotest and a recently developed microinjection zebrafish embryo method. When comparing the treatments, activated STC caused the highest mortality and number of DNA strand breaks across all injected volumes. Based on the E. coli SOS-Chromotest, the two toxins exerted the same genotoxicities. Moreover, according to the newly developed zebrafish microinjection method, STC appeared more toxic than AFB1. The scarce information correlating AFB1 and STC toxicity suggests that AFB1 is a more potent genotoxin than STC. Our findings contradict this assumption and illustrate the need for more complex biomonitoring systems for mycotoxin risk assessment.

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Development of an in vitro neuroblastoma 3D model and its application for sterigmatocystin-induced cytotoxicity testing

Cited by 15 publications

References 40 publications

Harmaline to Human Mitochondrial Caseinolytic Serine Protease Activation for Pediatric Diffuse Intrinsic Pontine Glioma Treatment

Harmaline to Human Mitochondrial Caseinolytic Serine Protease Activation for Pediatric Diffuse Intrinsic Pontine Glioma Treatment

Tumour growth: Bayesian parameter calibration of a multiphase porous media model based on in vitro observations of Neuroblastoma spheroid growth in a hydrogel microenvironment

Comparison Evaluation of the Biological Effects of Sterigmatocystin and Aflatoxin B1 Utilizing SOS-Chromotest and a Novel Zebrafish (Danio rerio) Embryo Microinjection Method

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