Induced differentiation inhibits sphere formation in neuroblastoma

Craig, Brian T.; Rellinger, Eric J.; Alvarez, Alexandra L.; Dusek, Haley L.; Qiao, Jingbo; Chung, Dai H.

doi:10.1016/j.bbrc.2016.06.053

Cited by 14 publications

(10 citation statements)

References 18 publications

(32 reference statements)

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“…Cells were plated onto an ultra-low attachment 96-well plate at serial dilutions. Each well was scored for presence of sphere formation as previously described [ 31 ].…”

Section: Methodsmentioning

confidence: 99%

Isoxazole compound ML327 blocks MYC expression and tumor formation in neuroblastoma

et al. 2017

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Neuroblastomas are the most common extracranial solid tumors in children and arise from the embryonic neural crest. MYCN-amplification is a feature of ~30% of neuroblastoma tumors and portends a poor prognosis. Neural crest precursors undergo epithelial-to-mesenchymal transition (EMT) to gain migratory potential and populate the sympathoadrenal axis. Neuroblastomas are posited to arise due to a blockade of neural crest differentiation. We have recently reported effects of a novel MET inducing compound ML327 (N-(3-(2-hydroxynicotinamido) propyl)-5-phenylisoxazole-3-carboxamide) in colon cancer cells. Herein, we hypothesized that forced epithelial differentiation using ML327 would promote neuroblastoma differentiation. In this study, we demonstrate that ML327 in neuroblastoma cells induces a gene signature consistent with both epithelial and neuronal differentiation features with adaptation of an elongated phenotype. These features accompany induction of cell death and G1 cell cycle arrest with blockage of anchorage-independent growth and neurosphere formation. Furthermore, pretreatment with ML327 results in persistent defects in proliferative potential and tumor-initiating capacity, validating the pro-differentiating effects of our compound. Intriguingly, we have identified destabilization of MYC signaling as an early and consistent feature of ML327 treatment that is observed in both MYCN-amplified and MYCN-single copy neuroblastoma cell lines. Moreover, ML327 blocked MYCN mRNA levels and tumor progression in established MYCN-amplified xenografts. As such, ML327 may have potential efficacy, alone or in conjunction with existing therapeutic strategies against neuroblastoma. Future identification of the specific intracellular target of ML327 may inform future drug discovery efforts and enhance our understanding of MYC regulation.

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“…Cells were plated onto an ultra-low attachment 96-well plate at serial dilutions. Each well was scored for presence of sphere formation as previously described [ 31 ].…”

Section: Methodsmentioning

confidence: 99%

Isoxazole compound ML327 blocks MYC expression and tumor formation in neuroblastoma

et al. 2017

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“…Investigators have shown that activation of RAR/RXR receptors upregulated transcription of genes involved in differentiation [ 53 ], and downregulated transcription of genes responsible for generation and maintenance of SCLCCs [ 54 ]. In preclinical studies, RA was reported to reduce stemness characteristics in various tumors including neuroblastoma [ 55 ]. Despite the clinical effectiveness of RA therapy for some neuroblastoma patients with minimal residual disease, there are still many high-risk and advanced neuroblastoma patients with tumors that do not respond to RA [ 56 , 57 ].…”

Section: Discussionmentioning

confidence: 99%

9-cis-UAB30, a novel rexinoid agonist, decreases tumorigenicity and cancer cell stemness of human neuroblastoma patient-derived xenografts

Marayati

Bownes

Stafman

et al. 2021

Translational Oncology

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Retinoic acid (RA) therapy has been utilized as maintenance therapy for high-risk neuroblastoma, but over half of patients treated with RA relapse. Neuroblastoma stem cell-like cancer cells (SCLCCs) are a subpopulation of cells characterized by the expression of the cell surface marker CD133 and are hypothesized to contribute to drug resistance and disease relapse. A novel rexinoid compound, 9- cis -UAB30 (UAB30), was developed having the same anti-tumor effects as RA but a more favorable toxicity profile. In the current study, we investigated the efficacy of UAB30 in neuroblastoma patient-derived xenografts (PDX). Two PDXs, COA3 and COA6, were utilized and alterations in the malignant phenotype were assessed following treatment with RA or UAB30. UAB30 significantly decreased proliferation, viability, and motility of both PDXs. UAB30 induced cell-cycle arrest as demonstrated by the significant increase in percentage of cells in G1 (COA6: 33.7 ± 0.7 vs. 43.3 ± 0.7%, control vs. UAB30) and decrease in percentage of cells in S phase (COA6: 44.7 ± 1.2 vs. 38.6 ± 1%, control vs. UAB30). UAB30 led to differentiation of PDX cells, as evidenced by the increase in neurite outgrowth and mRNA abundance of differentiation markers. CD133 expression was decreased by 40% in COA6 cells after UAB30. The ability to form tumorspheres and mRNA abundance of known stemness markers were also significantly decreased following treatment with UAB30, further indicating decreased cancer cell stemness. These results provide evidence that UAB30 decreased tumorigenicity and cancer cell stemness in neuroblastoma PDXs, warranting further exploration as therapy for high-risk neuroblastoma.

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“…N-MYC promotes a stem-like state by impairing the differentiation pathways and supporting self-renewal and pluripotency. N-MYC-amplified neuroblastoma cell lines, including BE(2)-C cells, form spheres more frequently than non-N-MYC-amplified cell lines and sphere formation is sensitive to cellular differentiation status [ 32 ]. In the present study, BE(2)-C sphere formation was reduced and associated with cell death after EGCG and IIF treatments.…”

Section: Discussionmentioning

confidence: 99%

Epigallocatechin-3-gallate and 6-OH-11-O-Hydroxyphenanthrene Limit BE(2)-C Neuroblastoma Cell Growth and Neurosphere Formation In Vitro

et al. 2018

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We conducted an in vitro study combining a rexinoid, 6-OH-11-O-hydroxyphenanthrene (IIF), and epigallocatechin-3-gallate (EGCG), which is the main catechin of green tea, on BE(2)-C, a neuroblastoma cell line representative of the high-risk group of patients. Neuroblastoma is the most common malignancy of childhood: high-risk patients, having N-MYC over-expression, undergo aggressive therapy and show high mortality or an increased risk of secondary malignancies. Retinoids are used in neuroblastoma therapy with incomplete success: the association of a second molecule might improve the efficacy. BE(2)-C cells were treated by EGCG and IIF, individually or in combination: cell viability, as evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, was reduced, EGCG+IIF being the most effective treatment. Apoptosis occurred and the EGCG+IIF treatment decreased N-MYC protein expression and molecular markers of invasion (MMP-2, MMP-9 and COX-2). Zymography demonstrated nearly 50% inhibition of MMP activity. When BE(2)-C cells were grown in non-adherent conditions to enrich the tumor-initiating cell population, BE(2)-C-spheres were obtained. After 48 h and 72 h treatment, EGCG+IIF limited BE(2)-C-sphere formation and elicited cell death with a reduction of N-MYC expression. We concluded that the association of EGCG to IIF might be applied without toxic effects to overcome the incomplete success of retinoid treatments in neuroblastoma patients.

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Induced differentiation inhibits sphere formation in neuroblastoma

Cited by 14 publications

References 18 publications

Isoxazole compound ML327 blocks MYC expression and tumor formation in neuroblastoma

Isoxazole compound ML327 blocks MYC expression and tumor formation in neuroblastoma

9-cis-UAB30, a novel rexinoid agonist, decreases tumorigenicity and cancer cell stemness of human neuroblastoma patient-derived xenografts

Epigallocatechin-3-gallate and 6-OH-11-O-Hydroxyphenanthrene Limit BE(2)-C Neuroblastoma Cell Growth and Neurosphere Formation In Vitro

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