科研之友
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摘要
Background: Neuroblastoma (NB), a tumor of the primitive neural crest, despite aggressive treatment portends a poor long-term survival for patients with advanced high stage NB. New treatment strategies are required. Methods: We investigated coordinated targeting of essential homeostatic regulatory factors involved in cancer progression, histone deacetylases (HDACs) and carbonic anhydrases (CAs). Results: We evaluated the antitumor potential of the HDAC inhibitor (HDACi), pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl] benzyl} carbamate (MS 275) in combination with a pan CA inhibitor, acetazolamide (AZ) on NB SH SY5Y, SK-N-SH and SK-N-BE(2) cells. The key observation was that the combination AZ + MS-275 significantly inhibited growth, induced cell cycle arrest and apoptosis, and reduced migration capacity of NB cell line SH-SY5Y. In addition, this combination significantly inhibited tumor growth in vivo, in a pre-clinical xenograft model. Evidence was obtained for a marked reduction in tumorigenicity and in the expression of mitotic, proliferative, HIF-1 alpha and CAIX. NB xenografts of SH-SY5Y showed a significant increase in apoptosis. Conclusion: MS-275 alone at nanomolar concentrations significantly reduced the putative cancer stem cell (CSC) fraction of NB cell lines, SH-SY5Y and SK-N-BE(2), in reference to NT2/D1, a teratocarcinoma cell line, exhibiting a strong stem cell like phenotype in vitro. Whereas stemness genes (OCT4, SOX2 and Nanog) were found to be significantly downregulated after MS-275 treatment, this was further enhanced by AZ co-treatment. The significant reduction in initial tumorigenicity and subsequent abrogation upon serial xenografting suggests potential elimination of the NB CSC fraction. The significant potentiation of MS-275 by AZ is a promising therapeutic approach and one amenable for administration to patients given their current clinical utility.
- 出版日期2017-2-24
- 单位河北医科大学
