Acetazolamide potentiates the anti-tumor potential of HDACi, MS-275, in neuroblastoma

Reza Bayat Mokhtari,Narges Baluch,Tina S Homayouni,Karen Aitken,Bikul Das,Sylvain Baruchel,Sushil Kumar,Micky Ka Hon Tsui,Herman Yeger

doi:10.1186/s12885-017-3126-7

Reza Bayat Mokhtari, Narges Baluch + Show 7 more

Open Access

https://doi.org/10.1186/s12885-017-3126-7

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Abstract

BackgroundNeuroblastoma (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.MethodsWe investigated coordinated targeting of essential homeostatic regulatory factors involved in cancer progression, histone deacetylases (HDACs) and carbonic anhydrases (CAs).ResultsWe 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-1α and CAIX. NB xenografts of SH-SY5Y showed a significant increase in apoptosis.ConclusionMS-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.

Highlights

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
It should be noted that AlamarBlue indicates effects on oxidative phosphorylation as it is a substrate for the last step in oxidative phosphorylation
Since the hypoxic niche favors localization of cancer stem cell (CSC) and their growth and survival [21], our results suggest that CSCs are targeted by the AZ + histone deacetylases (HDACs) inhibitor (HDACi) combination

Summary

Introduction

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. Neuroblastoma (NB) is a tumor derived from the primitive neural crest that forms the peripheral sympathetic nervous system. Despite aggressive treatment long-term survival for high-risk NB is less than 40%, due mainly to metastasis and relapse [1]. Intensive multimodal therapy has failed to improve long-term survival significantly [1]. Bayat Mokhtari et al BMC Cancer (2017) 17:156 studies [6]. MS-275 is noted for its potent anti-cancer abilities, long serum half life, and selective HDACi properties [7]. Jaboin et al reported that MS-275 induced apoptosis of NB KNCR in vitro after 48 h, and significantly reduced growth of adrenal orthotopic xenografts [8]. Other studies have shown synergistic effects of HDACi with some of the conventional chemotherapeutic agents [11]

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