2. Academic Validation
  3. Acetazolamide potentiates the anti-tumor potential of HDACi, MS-275, in neuroblastoma

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

  • BMC Cancer. 2017 Feb 24;17(1):156. doi: 10.1186/s12885-017-3126-7.
Reza Bayat Mokhtari 1 2 3 4,  Narges Baluch 5,  Micky Ka Hon Tsui 6,  Sushil Kumar 6,  Tina S Homayouni 6,  Karen Aitken 6,  Bikul Das 7,  Sylvain Baruchel 8,  Herman Yeger 9 10 11
Affiliations

Affiliations

  • 1 Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada. [email protected].
  • 2 Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada. [email protected].
  • 3 Institute of Medical Science, University of Toronto, Toronto, ON, Canada. [email protected].
  • 4 Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA. [email protected].
  • 5 Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.
  • 6 Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada.
  • 7 Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.
  • 8 Department of Paediatrics, Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.
  • 9 Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada. [email protected].
  • 10 Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada. [email protected].
  • 11 Institute of Medical Science, University of Toronto, Toronto, ON, Canada. [email protected].
PMID: 28235409 DOI: 10.1186/s12885-017-3126-7
Abstract

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-1α 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.

Keywords

Acetazolamide; Carbonic anhydrases; HDAC inhibitor; Histone deacetylases; MS-275; Neuroblastoma.

Figures
Products