1. 9-cis-UAB30, a novel rexinoid agonist, decreases tumorigenicity and cancer cell stemness of human neuroblastoma patient-derived xenografts
- Author
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Jamie M. Aye, Raoud Marayati, Laura L. Stafman, Elizabeth A. Beierle, Adele P. Williams, Laura V. Bownes, Colin H. Quinn, Venkatram R. Atigadda, Karina J. Yoon, and Jerry E. Stewart
- Subjects
0301 basic medicine ,Agonist ,Cancer Research ,Original article ,IRB, Institutional Review Board ,Neurite ,Oct4, Octamer-binding transcription factor 4 ,medicine.drug_class ,GAP43, Growth Associated Protein 43 ,APC, Allophycocyanin ,Cell ,Retinoic acid ,PDX, Patient-derived xenografts ,Motility ,qPCR, Real-time PCR ,CADD, Combined Annotation Dependent Depletion ,IACUC, Institutional Animal Care and Use Committee ,lcsh:RC254-282 ,03 medical and health sciences ,chemistry.chemical_compound ,Sox2, Sex determining region Y-box 2 ,RARE, Retinoic acid response elements ,0302 clinical medicine ,Maintenance therapy ,ELDA, Extreme limiting dilution assay ,Neuroblastoma ,RA, Retinoic acid ,medicine ,RPMI, Roswell Park Memorial Institute ,SCLCCs, Stem cell-like cancer cells ,RAR, Retinoic acid receptor ,HOXC9, Homeobox C9 protein ,DMSO, Dimethyl sulfoxide ,RXR, Retinoid X receptor ,IgG1, Imunoglobulin G1 ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,PBS, Phosphate-buffered saline ,030104 developmental biology ,medicine.anatomical_structure ,SEM, Standard error of the mean ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Cancer cell ,UAB30, 9-cis-UAB30 ,Cancer research ,ANOVA, Analysis of variance ,NSE, Neuron Specific Enolase - Abstract
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.
- Published
- 2021