Utilizing genome-wide mRNA profiling to identify the cytotoxic chemotherapeutic mechanism of triazoloacridone C-1305 as direct microtubule stabilization

Jarosław Króliczewski , Sylwia Bartoszewska , Magdalena Dudkowska , Dorota Janiszewska , Agnieszka Biernatowska , David K. Crossman , Karol Krzymiński , Małgorzata Wysocka , Anna Romanowska , Maciej Baginski , Michał Markuszewski , Renata J. Ochocka , James F. Collawn , Aleksander F. Sikorski , Ewa Sikora , Rafal Bartoszewski

Abstract

Rational drug design and in vitro pharmacology profiling constitute the gold standard in drug development pipelines. Problems arise, however, because this process is often difficult due to limited information regarding the complete identification of a molecule’s biological activities. The increasing affordability of genome-wide next-generation technologies now provides an excellent opportunity to understand a compound’s diverse effects on gene regulation. Here, we used an unbiased approach in lung and colon cancer cell lines to identify the early transcriptomic signatures of C-1305 cytotoxicity that highlight the novel pathways responsible for its biological activity. Our results demonstrate that C-1305 promotes direct microtubule stabilization as a part of its mechanism of action that leads to apoptosis. Furthermore, we show that C-1305 promotes G2 cell cycle arrest by modulating gene expression. The results indicate that C-1305 is the first microtubule stabilizing agent that also is a topoisomerase II inhibitor. This study provides a novel approach and methodology for delineating the antitumor mechanisms of other putative anticancer drug candidates.
Author Jarosław Króliczewski
Jarosław Króliczewski,,
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, Sylwia Bartoszewska
Sylwia Bartoszewska,,
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, Magdalena Dudkowska
Magdalena Dudkowska,,
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, Dorota Janiszewska
Dorota Janiszewska,,
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, Agnieszka Biernatowska
Agnieszka Biernatowska,,
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, David K. Crossman
David K. Crossman,,
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, Karol Krzymiński (FCh / DPCh / LLR)
Karol Krzymiński,,
- Laboratory of Luminescence Research
, Małgorzata Wysocka (FCh / KChBionieorg. / LII)
Małgorzata Wysocka,,
- Laboratory of Intermolecular Interactions
, Anna Romanowska (FCh / DPCh / LLR)
Anna Romanowska,,
- Laboratory of Luminescence Research
, Maciej Baginski
Maciej Baginski,,
-
et al.`
Journal seriesCancers, ISSN 2072-6694, (N/A 140 pkt)
Issue year2020
Vol12
No4
Pages1-26
Publication size in sheets1.25
Article number864
Keywords in Englishmicrotubule, RNASeq, tubulin, cell cycle arrest
ASJC Classification2730 Oncology; 1306 Cancer Research
DOIDOI:10.3390/cancers12040864
URL https://doi.org/10.3390/cancers12040864
Languageen angielski
LicenseJournal (articles only); published final; Uznanie Autorstwa (CC-BY); with publication
Score (nominal)140
Score sourcejournalList
ScoreMinisterial score = 140.0, 07-04-2020, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2018 = 1.44; WoS Impact Factor: 2018 = 6.162 (2)
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