Effect of low doses of actinomycin D on neuroblastoma cell lines
Cortes Crignola, Constanza (Institut d'Investigació Biomèdica de Bellvitge)
Veiga, Sonia R. (Institut Català d'Oncologia)
Almacellas, Eugènia (Institut d'Investigació Biomèdica de Bellvitge)
Hernandez-Losa, Javier (Hospital Universitari Vall d'Hebron)
Ferreres Piñas, Joan Carles (Hospital Universitari Vall d'Hebron)
Kozma, Sara C. (Division of Hematology and Oncology, Department of Internal Medicine, College of Medicine, University of Cincinnati)
Ambrosio, Santiago (Institut d'Investigació Biomèdica de Bellvitge)
Thomas, George (Institut d'Investigació Biomèdica de Bellvitge)
Tauler, Albert (Institut d'Investigació Biomèdica de Bellvitge)
Universitat Autònoma de Barcelona

Date:	2016
Abstract:	Neuroblastoma is a malignant embryonal tumor occurring in young children, consisting of undifferentiated neuroectodermal cells derived from the neural crest. Current therapies for high-risk neuroblastoma are insufficient, resulting in high mortality rates and high incidence of relapse. With the intent to find new therapies for neuroblastomas, we investigated the efficacy of low-doses of actinomycin D, which at low concentrations preferentially inhibit RNA polymerase I-dependent rRNA trasncription and therefore, ribosome biogenesis. Neuroblastoma cell lines with different p53 genetic background were employed to determine the response on cell viability and apoptosis of low-dose of actinomycin D. Subcutaneously-implanted SK-N-JD derived neuroblastoma tumors were used to assess the effect of low-doses of actinomycin D on tumor formation. Low-dose actinomycin D treatment causes a reduction of cell viability in neuroblastoma cell lines and that this effect is stronger in cells that are wild-type for p53. MYCN overexpression contributes to enhance this effect, confirming the importance of this oncogene in ribosome biogenesis. In the wild-type SK-N-JD cell line, apoptosis was the major mechanism responsible for the reduction in viability and we demonstrate that treatment with the MDM2 inhibitor Nutlin-3, had a similar effect to that of actinomycin D. Apoptosis was also detected in p53 −/− deficient LA1-55n cells treated with actinomycin D, however, only a small recovery of cell viability was found when apoptosis was inhibited by a pan-caspase inhibitor, suggesting that the treatment could activate an apoptosis-independent cell death pathway in these cells. We also determined whether actinomycin D could increase the efficacy of the histone deacetylase inhibitor, SAHA, which is in being used in neuroblastoma clinical trials. We show that actinomycin D synergizes with SAHA in neuroblastoma cell lines. Moreover, on subcutaneously-implanted neuroblastoma tumors derived from SK-N-JD cells, actinomycin D led to tumor regression, an effect enhanced in combination with SAHA. The results presented in this work demonstrate that actinomycin D, at low concentrations, inhibits proliferation and induces cell death in vitro, as well as tumor regression in vivo. From this study, we propose that use of ribosome biogenesis inhibitors should be clinically considered as a potential therapy to treat neuroblastomas. The online version of this article (doi:10. 1186/s12943-015-0489-8) contains supplementary material, which is available to authorized users.
Grants:	Instituto de Salud Carlos III IIS12-00002
Note:	Altres ajuts: BFU/BFU2009-09933
Note:	Altres ajuts: BFU/BFU2012-38867
Note:	Altres ajuts: SAF/SAF2011-2496
Note:	Altres ajuts: RD/RD12-0036-0049
Note:	Altres ajuts: RD/RD12-0036/0029
Note:	Altres ajuts: RD/RD12-0036-0057
Note:	Altres ajuts: GCB/GCB14-2035-AECC
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Actinomycin D ; Neuroblastoma ; Apoptosis ; Therapy ; SAHA
Published in:	Molecular cancer, Vol. 15 (january 2016) , ISSN 1476-4598

DOI: 10.1186/s12943-015-0489-8
PMID: 26728659

13 p, 3.4 MB

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