Raoud Marayati1, Adele P Williams1, Laura V Bownes1, Colin H Quinn1, Jerry E Stewart1, Elizabeth Mroczek-Musulman2, Venkatram R Atigadda3, Elizabeth A Beierle4. 1. Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA. 2. Department of Pathology, Children's of Alabama, Birmingham, AL, USA. 3. Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA. 4. Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: elizabeth.beierle@childrensal.org.
Abstract
INTRODUCTION: Retinoic acid (RA) is a differentiating agent utilized as maintenance therapy for high-risk neuroblastoma (NB), but associated toxicities limit its use. We have previously shown that a non-toxic, novel rexinoid, 9-cis-UAB30 (UAB30), decreased NB cell proliferation and in vivo tumor growth. A second generation, mono-methylated compound, 6-Methyl-UAB30 (6-Me), has been recently designed having greater potency compared with UAB30. In the current study, we hypothesized that 6-Me would inhibit NB cell proliferation and survival and induce differentiation and cell-cycle arrest. METHODS: Proliferation and viability were measured in four human NB cell lines following treatment with UAB30 or 6-Me. Cell-cycle was analyzed and tumor cell stemness was evaluated with extreme limiting dilution assays and immunoblotting for expression of stem cell markers. A xenograft murine model was utilized to study the effects of 6-Me in vivo. RESULTS: Treatment with 6-Me led to decreased proliferation and viability, induced cell cycle arrest, and increased neurite outgrowth, indicating differentiation of surviving cells. Furthermore, treatment with 6-Me decreased tumorsphere formation and expression of stem cell markers. Finally, inhibition of tumor growth and increased animal survival was observed in vivo following treatment with 6-Me. CONCLUSION: These results indicate a potential therapeutic role for this novel rexinoid in neuroblastoma treatment.
INTRODUCTION:Retinoic acid (RA) is a differentiating agent utilized as maintenance therapy for high-risk neuroblastoma (NB), but associated toxicities limit its use. We have previously shown that a non-toxic, novel rexinoid, 9-cis-UAB30 (UAB30), decreased NB cell proliferation and in vivo tumor growth. A second generation, mono-methylated compound, 6-Methyl-UAB30 (6-Me), has been recently designed having greater potency compared with UAB30. In the current study, we hypothesized that 6-Me would inhibit NB cell proliferation and survival and induce differentiation and cell-cycle arrest. METHODS: Proliferation and viability were measured in four humanNB cell lines following treatment with UAB30 or 6-Me. Cell-cycle was analyzed and tumor cell stemness was evaluated with extreme limiting dilution assays and immunoblotting for expression of stem cell markers. A xenograft murine model was utilized to study the effects of 6-Me in vivo. RESULTS: Treatment with 6-Me led to decreased proliferation and viability, induced cell cycle arrest, and increased neurite outgrowth, indicating differentiation of surviving cells. Furthermore, treatment with 6-Medecreased tumorsphere formation and expression of stem cell markers. Finally, inhibition of tumor growth and increased animal survival was observed in vivo following treatment with 6-Me. CONCLUSION: These results indicate a potential therapeutic role for this novel rexinoid in neuroblastoma treatment.
Authors: Yaël P Mossé; Marci Laudenslager; Luca Longo; Kristina A Cole; Andrew Wood; Edward F Attiyeh; Michael J Laquaglia; Rachel Sennett; Jill E Lynch; Patrizia Perri; Geneviève Laureys; Frank Speleman; Cecilia Kim; Cuiping Hou; Hakon Hakonarson; Ali Torkamani; Nicholas J Schork; Garrett M Brodeur; Gian P Tonini; Eric Rappaport; Marcella Devoto; John M Maris Journal: Nature Date: 2008-08-24 Impact factor: 49.962
Authors: Raoud Marayati; Laura V Bownes; Colin H Quinn; Nikita Wadhwani; Adele P Williams; Hooper R Markert; Venkatram Atigadda; Jamie M Aye; Jerry E Stewart; Karina J Yoon; Elizabeth A Beierle Journal: J Pediatr Surg Date: 2021-02-24 Impact factor: 2.549