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Complex molecular mechanisms cooperate to mediate histone deacetylase inhibitors anti-tumour activity in neuroblastoma cells

Journal Article · · Molecular Cancer
 [1];  [2];  [3];  [3];  [3];  [4];  [3]
  1. Univ. Hospital, Lausanne (Switzerland). Paediatric Dept. Paediatric Oncology; DOE/OSTI
  2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division
  3. Univ. Hospital, Lausanne (Switzerland). Paediatric Dept. Paediatric Oncology
  4. Univ. Hospital, Lausanne (Switzerland). Padeiatric Dept. Paediatric Surgery
+ Show Author Affiliations
Background: Histone deacetylase inhibitors (HDACi) are a new class of promising anti-tumour agent inhibiting cell proliferation and survival in tumour cells with very low toxicity toward normal cells. Neuroblastoma (NB) is the second most common solid tumour in children still associated with poor outcome in higher stages and, thus NB strongly requires novel treatment modalities. Results: We show here that the HDACi Sodium Butyrate (NaB), suberoylanilide hydroxamic acid (SAHA) and Trichostatin A (TSA) strongly reduce NB cells viability. The anti-tumour activity of these HDACi involved the induction of cell cycle arrest in the G2/M phase, followed by the activation of the intrinsic apoptotic pathway, via the activation of the caspases cascade. Moreover, HDACi mediated the activation of the pro-apoptotic proteins Bid and BimEL and the inactivation of the anti-apoptotic proteins XIAP, Bcl-xL, RIP and survivin, that further enhanced the apoptotic signal. Interestingly, the activity of these apoptosis regulators was modulated by several different mechanisms, either by caspases dependent proteolytic cleavage or by degradation via the proteasome pathway. In addition, HDACi strongly impaired the hypoxia-induced secretion of VEGF by NB cells. Conclusion: HDACi are therefore interesting new anti-tumour agents for targeting highly malignant tumours such as NB, as these agents display a strong toxicity toward aggressive NB cells and they may possibly reduce angiogenesis by decreasing VEGF production by NB cells.
Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
OSTI ID:
1626575
Journal Information:
Molecular Cancer, Journal Name: Molecular Cancer Journal Issue: 1 Vol. 7; ISSN 1476-4598
Publisher:
BioMed CentralCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (12)

Targeting of epigenetic regulators in neuroblastoma journal April 2018
Low Concentration of Sodium Butyrate from Ultrabraid+NaBu suture, Promotes Angiogenesis and Tissue Remodelling in Tendon-bones Injury journal October 2016
Anti-GD2 mAb and Vorinostat synergize in the treatment of neuroblastoma journal March 2016
Sodium butyrate enhances the cytotoxic effect of cisplatin by abrogating the cisplatin imposed cell cycle arrest journal January 2010
Cell Proliferation in Neuroblastoma journal January 2016
Multiple Mechanisms Mediate Resistance to Sorafenib in Urothelial Cancer journal November 2014
Circulating Metabolites Originating from Gut Microbiota Control Endothelial Cell Function journal November 2019
Valproic acid inhibits tumor angiogenesis in mice transplanted with Kasumi-1 leukemia cells journal November 2013
Valproic acid overcomes hypoxia-induced resistance to apoptosis journal December 2011
Short‐chain fatty acids inhibit bovine rumen epithelial cells proliferation via upregulation of cyclin‐dependent kinase inhibitors 1A, but not mediated by G protein‐coupled receptor 41 journal December 2019
Small-molecule inhibitors of the HIF pathway and synthetic lethal interactions journal April 2012
Knockdown of survivin (BIRC5) causes apoptosis in neuroblastoma via mitotic catastrophe journal August 2011

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Biochemistry & molecular biology
SAHA
cell cycle arrest
lactacystin
oncology
sodium butyrate
survivin expression