Discovering simple phenylboronic acid and benzoxaborole derivatives for experimental oncology – phase cycle-specific inducers of apoptosis in A2780 ovarian cancer cells

Mateusz Psurski , Agnieszka Łupicka-Słowik , Agnieszka Adamczyk-Woźniak , Joanna Wietrzyk , Andrzej Sporzyński

Abstract

Objective The aim of the study was to evaluate the antiproliferative potential of simple phenylboronic acid and benzoxaborole derivatives as well as to provide preliminary insight into their mode of action in cancer cells in vitro. Methods The antiproliferative activity was assessed in five diverse cancer cell lines via the SRB method (sulforhodamine B) or MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) method after 72 h of treatment. Further studies of the mechanism of action consisted of the influence of the compounds on cell cycle progression and apoptosis induction, which was assessed by flow cytometry, caspase-3 enzymatic activity, fluorescence microscopy and western blot analysis. Results A clear structure-activity relationship was observed for both groups of compounds with several representatives evaluated as highly active antiproliferative agents with low micromolar IC72h50 values. 2-Fluoro-6-formylphenylboronic acid (18) and 3-morpholino-5-fluorobenzoxaborole (27) exhibited strong cell cycle arrest induction in G2/M associated with caspase-3 activation in an A2780 ovarian cancer cell line. These events were accompanied by a mitotic catastrophe cell morphology and an increased percentage of aneuploid and tetraploid cells. Further experiments indicated that the compounds were phase cycle-specific agents since cells co-treated with hydroxyurea were less sensitive. The observed cell cycle arrest resulted from significant p21 accumulation and was associated neither with cyclin B1 nor β-tubulin degradation. Conclusion Phenylboronic acid and benzoxaborole derivatives were found to be highly promising antiproliferative and proapoptotic compounds with a cell cycle-specific mode of action. The presented data support their candidacy for further studies as a novel class of potential anticancer agents.
Author Mateusz Psurski
Mateusz Psurski,,
-
, Agnieszka Łupicka-Słowik
Agnieszka Łupicka-Słowik,,
-
, Agnieszka Adamczyk-Woźniak (FC / DPC)
Agnieszka Adamczyk-Woźniak,,
- Department Of Physical Chemistry
, Joanna Wietrzyk
Joanna Wietrzyk,,
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, Andrzej Sporzyński (FC / DPC)
Andrzej Sporzyński,,
- Department Of Physical Chemistry
Journal seriesInvestigational New Drugs, ISSN 0167-6997, (A 30 pkt)
Issue year2019
Vol37
Pages35-46
Publication size in sheets0.55
Keywords in EnglishPhenylboronic acid Benzoxaborole Anticancer Apoptosis Phase cycle arrest Ovarian cancer
ASJC Classification2736 Pharmacology (medical); 3004 Pharmacology; 2730 Oncology
DOIDOI:10.1007/s10637-018-0611-z
URL https://link.springer.com/article/10.1007%2Fs10637-018-0611-z#citeas
Languageen angielski
File
Investigational New Drugs 37 (2019) 35-46.pdf 2.83 MB
Score (nominal)30
ScoreMinisterial score = 30.0, 11-03-2019, ArticleFromJournal
Ministerial score (2013-2016) = 30.0, 11-03-2019, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2017 = 0.909; WoS Impact Factor: 2017 = 3.502 (2) - 2017=3.118 (5)
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