N(4)-[B-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan)methyl]-2'-deoxycytidine as a potential boron delivery agent with respect to glioblastoma.

Abstract

Glioblastoma multiforme (GBM) is a central nervous system tumor of grade IV, according to the WHO classification, extremely resistant to all currently used forms of therapy, including resection, radiotherapy, chemotherapy or combined therapy. Therefore, more effective treatment strategies of this tumor are needed, with boron neutron capture therapy (BNCT) being a potential solution, provided a proper cancer cells-targeted 10B delivery agent is found. In search of such an agent, toxicity and capacity to target DNA of a boronated derivative of 2'-deoxycytidine, N(4)-[B-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan)methyl]-2'-deoxycytidine (1), was tested against human tumor vs. normal cells. The present in vitro results revealed 1 to show low toxicity for human U-118 MG glioma cells (in the mM range) and even by 3-4 - fold lower against normal human fibroblasts. In accord, induction of apoptosis dependent on caspase-3 and caspase-7 was detected at high (>20mM) concentration of 1. Although demonstrated to be susceptible to phosphorylation by human deoxycytidine kinase and to undergo incorporation in cellular DNA, the boron analogue did not disturb cell proliferation when applied at non-toxic concentrations and showed low toxicity to a model metazoan organism, Caenorhabditis elegans. Thus, N(4)-[B-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan)methyl]-2'-deoxycytidine appears a promising candidate for a 10B delivery agent to be used in BNCT, with C. elegans indicated as a good model for in vivo studies.

• Authors: Łukasz Uram, Joanna Nizioł, Piotr Maj, Justyna Sobich, Wojciech Rode, Tomasz Ruman
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 95 Pg. 749-755 (Nov 2017) ISSN: 1950-6007 [Electronic] France
• PMID: 28888921 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Chemical References

• 4,4,5,5-tetramethyl(1,3,2)dioxaborolane
• Boron Compounds
• Deoxycytidine
• DNA
• Boron

Topics

• Animals
• Apoptosis (drug effects)
• Boron (pharmacology, therapeutic use)
• Boron Compounds (chemistry, therapeutic use)
• Brain Neoplasms (drug therapy, pathology)
• Caenorhabditis elegans (drug effects)
• Cell Count
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Shape (drug effects)
• DNA (metabolism)
• Deoxycytidine
• Glioblastoma (drug therapy, pathology)
• Mass Spectrometry
• Models, Animal
• Substrate Specificity (drug effects)