title: Improved therapy for neuroblastoma using a combination approach: superior efficacy with vismodegib and topotecan.
abstract: Aberrant activation/expression of pathways/molecules including NF-kB, mTOR, hedgehog and polo-like-kinase-1 (PLK1) are correlated with poor-prognosis neuroblastoma. Therefore, to identify a most efficacious treatment for neuroblastoma, we investigated the efficacy of NF-kB/mTOR dual-inhibitor 13-197, hedgehog inhibitor vismodegib and PLK1 inhibitor BI2536 alone or combined with topotecan against high-risk neuroblastoma. The in vitro efficacy of the inhibitors alone or combined with topotecan on cell growth/apoptosis and molecular mechanism(s) were investigated. Results showed that as single agents 13-197, BI2536 and vismodegib significantly decreased neuroblastoma cell growth and induced apoptosis by targeting associated pathways/molecules. In combination with topotecan, 13-197 did not show significant additive/synergistic effects against neuroblastoma. However, BI2536 or vismodegib further significantly decreased neuroblastoma cell growth/survival. These results clearly showed that vismodegib combination with topotecan was synergistic and more efficacious compared with BI2536 in combination. Together, in vitro data demonstrated that vismodegib was most efficacious in potentiating topotecan-induced antineuroblastoma effects. Therefore, we tested the combined efficacy of vismodegib and topotecan against neuroblastoma in vivo using NSG mice. This resulted in significantly (p<0.001) reduced tumor growth and increased survival of mice. Together, the combination of vismodegib and topotecan showed a significant enhanced antineuroblastoma efficacy by targeting associated pathways/molecules which warrants further preclinical evaluation for translation to the clinic.
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Nagendra K
authors.initials: NK
authors.lastname: Chaturvedi
authors.affiliation: Department of Pharmacy Practice, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: McGuire
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology and Oncology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Don W
authors.initials: DW
authors.lastname: Coulter
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Ashima
authors.initials: A
authors.lastname: Shukla
authors.affiliation: Department of Pharmacy Practice, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Erin M
authors.initials: EM
authors.lastname: McIntyre
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: John Graham
authors.initials: JG
authors.lastname: Sharp
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Shantaram S
authors.initials: SS
authors.lastname: Joshi
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D004359:Drug Therapy, Combination; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology; D019772:Topotecan / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; C538724:HhAntag691; D011725:Pyridines; D059004:Topoisomerase I Inhibitors; D019772:Topotecan
keywords: MYCN; chemotherapy; hedgehog inhibitor; neuroblastoma; small molecule inhibitors