Arsenic Trioxide exerts cytotoxic and radiosensitizing effects in pediatric Medulloblastoma cell lines of SHH Subgroup

Author(s):Show less -

dos Santos Klinger, Paulo Henrique ^{[1, 2]} ; Alberici Delsin, Lara Elis ^[3] ; Veiga Cruzeiro, Gustavo Alencastro ^[3] ; Andrade, Augusto Faria ^[3] ; Peixoto Lira, Regia Caroline ^{[4, 1]} ; de Andrade, Pamela Viani ^[3] ; das Chagas, Pablo Ferreira ^[3] ; de Paula Queiroz, Rosane Gomes ^[1] ; Trevisan, Felipe Amstalden ^[5] ; de Oliveira, Ricardo Santos ^{[6, 7]} ; Scrideli, Carlos Alberto ^[1] ; Tone, Luiz Gonzaga ^{[3, 1]} ; Valera, Elvis Terci ^[1]

Affiliation

^[1] Univ Sao Paulo, Dept Pediat, Ribeirao Preto - Brazil

^[2] GRAACC, Inst Oncol Pediat IOP, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Dept Genet, Ribeirao Preto - Brazil

^[4] Ctr Univ Cesmac, Maceio, Alagoas - Brazil

^[5] Univ Sao Paulo, Div Radiotherapy, Ribeirao Preto - Brazil

^[6] Univ Sao Paulo, Fac Med Ribeirao Preto, Ribeirao Preto - Brazil

^[7] Univ Sao Paulo, Div Pediat Neurosurg, Dept Surg & Anat, Ribeirao Preto - Brazil

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 10, n. 1 APR 22 2020.
• Web of Science Citations: 0

Abstract

We evaluated the potential effects of ATO in different pediatric SHH-MB cell lines (ONS-76: TP53-wild type; DAOY and UW402: TP53-mutated). MB cell lines molecular subgroup was confirmed and TP53 mutations were validated. Cell viability, clonogenicity and apoptosis were evaluated after ATO treatment at different concentrations (1-16 mu M) alone or combined with irradiation doses (0.5, 1, 2 and 4Gy). Rad51 and Ku86 proteins were evaluated by WB. ATO treatment reduced cell viability for all SHH-MB cell lines. Significant decrease of clonogenic capacity and higher apoptosis rates were also observed after ATO exposure, being cell death more pronounced (>70%) for the SHH-MB TP53-mutated. Combined treatment of ATO with irradiation also reduced colonies formation in UW402 tumor cells, which was independent of DNA damage repair proteins Rad51 and Ku86. In silico analyses suggested that a set of genes from cell cycle and p53 pathways are differentially expressed in SHH tumor subtypes, suggesting that cell lines may respond to therapies according to the gene expression profiles. Herein, we showed ATO cytotoxicity in pediatric SHH cell lines, with marked radiosensitizing effect for the MB-SHH TP53-mutated cells. These results highlight the potential of ATO, alone or in combination with radiotherapy, supporting further clinical investigations. (AU)

• FAPESP's process: 14/20341-0 - Interactions between emerging therapeutic targets and developmental pathways associated with tumorigenesis: emphasis on pediatric malignancies
• Grantee: Luiz Gonzaga Tone
• Support Opportunities: Research Projects - Thematic Grants