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

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.

Induction of <i>MYCN</i>-amplified neuro­blastoma differentiation through NMYC suppression using PPAR-γ antagonist

“…Increased ratio of G1 phases could be associated with the differentiation of CHP212 cells in part, because it is well-known that the determination of differentiation is made in G1 phase, and induction of differentiation requires cell-cycle arrest. (23)(24)(25) That treatment with a PPAR-γ antagonist suppresses NMYC expression and induces differentiation and apoptosis in MYCN-amplified neuroblastoma has not been reported until date. Moreover, the treatment with a PPAR-γ antagonist effectively induced differentiation of CHP212 cells, that is one of the 1p36 − neuroblastoma cells and resistant to RA treatment.…”

Differentiating Neuroblastoma: A Systematic Review of the Retinoic Acid, Its Derivatives, and Synergistic Interactions

“…However, the subsequent in vivo studies established their unfavourable pharmacokinetic and toxic profiles, limiting their use as NB treatments. Despite the positive effects of differentiation therapy giving better survival scores than checkpoint inhibition, there are some side effects and tumour relapses which warrant the need for more physiological safe and persistent RA derivatives [ 98 , 99 ].…”