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p38MAPK inhibition: a new combined approach to reduce neuroblastoma resistance under etoposide treatment
Author(s) -
Marengo Barbara,
Ricciarelli Roberta,
De Ciucis Chiara,
Furfaro AnnaLisa,
Colla Renata,
Canepa Elisa,
Traverso Nicola,
Marinari Umberto Maria,
Pronzato Maria Adelaide,
Domenicotti Cinzia
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1088.14
Subject(s) - etoposide , cancer research , context (archaeology) , protein kinase b , neuroblastoma , viability assay , p38 mitogen activated protein kinases , mapk/erk pathway , kinase , pi3k/akt/mtor pathway , chemotherapy , apoptosis , cell culture , biology , pharmacology , medicine , chemistry , signal transduction , microbiology and biotechnology , biochemistry , genetics , paleontology
Neuroblastoma (NB), the second most common pediatric tumor, is characterized by biological and clinical heterogeneity. Considering the limited success of chemotherapy, the aim of our study is to identify and target key molecular pathways associated with NB chemoresistance. In this context, we analyzed the main survival and death pathways triggered by etoposide, a commonly used chemotherapeutic agent, in HTLA‐230, a MYCN‐amplified NB cell line isolated from a high‐risk patient. Etoposide induced a concentration‐dependent reduction of cell viability and, at very high doses, totally counteracted cell tumorigenicity and neurosphere formation. In addition, etoposide activated p38 Mitogen‐activated protein Kinase (MAPK), AKT and c‐Jun N‐terminal kinase. Therefore, the treatment with etoposide combined with SB203580, an inhibitor of p38MAPK activity, decreased cell viability and tumorigenicity, counteracted neurosphere generation and slowed down the cell migration and invasion. In this context, the expression of COX‐2, ICAM‐1 and CXCR4 was down regulated, the formation of capillary‐like structures was prevented, by generating a phenotype inadequate for tumor development.. Collectively, our results suggest that p38MAPK inhibitors, in combination with standard chemotherapy, could be a novel strategy to counteract NB resistance and relapse. Grants: PRIN 2009M8FKBB_002; Genoa University.