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
AbstractRational 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.
|Journal series||Cancers, ISSN 2072-6694, (N/A 140 pkt)|
|Publication size in sheets||1.25|
|Keywords in English||microtubule, RNASeq, tubulin, cell cycle arrest|
|License||Journal (articles only); published final; ; with publication|
|Score||= 140.0, 07-04-2020, ArticleFromJournal|
|Publication indicators||: 2018 = 1.44; : 2018 = 6.162 (2)|
* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.