Utilizing Genome-Wide mRNA Profiling to Identify the Cytotoxic Chemotherapeutic Mechanism of Triazoloacridone C-1305 as Direct Microtubule Stabilization

被引：9

作者：

Kroliczewski, Jaroslaw ^{[1
]}

Bartoszewska, Sylwia ^{[2
]}

Dudkowska, Magdalena ^{[3
]}

Janiszewska, Dorota ^{[3
]}

Biernatowska, Agnieszka ^{[4
]}

Crossman, David K. ^{[5
]}

Krzyminski, Karol ^{[6
]}

Wysocka, Malgorzata ^{[6
]}

Romanowska, Anna ^{[6
]}

Baginski, Maciej ^{[7
]}

Markuszewski, Michal ^{[8
]}

Ochocka, Renata J. ^{[1
]}

Collawn, James F. ^{[9
]}

Sikorski, Aleksander F. ^{[10
]}

Sikora, Ewa ^{[3
]}

Bartoszewski, Rafal ^{[1
]}

机构：

[1] Med Univ Gdansk, Dept Biol & Pharmaceut Bot, PL-80416 Gdansk, Poland

[2] Med Univ Gdansk, Dept Inorgan Chem, PL-80416 Gdansk, Poland

[3] Polish Acad Sci, Nencki Inst Expt Biol, Lab Mol Bases Ageing, PL-02093 Warsaw, Poland

[4] Univ Wroclaw, Fac Biotechnol, Dept Cytobiochem, PL-50383 Wroclaw, Poland

[5] Univ Alabama Birmingham, UAB Genom Core Facil, Dept Genet, Birmingham, AL 35233 USA

[6] Univ Gdansk, Fac Chem, PL-80308 Gdansk, Poland

[7] Gdansk Univ Technol, Fac Chem, Dept Pharmaceut Technol & Biochem, PL-80233 Gdansk, Poland

[8] Med Univ Gdansk, Dept Biopharm & Pharmacodynam, PL-80416 Gdansk, Poland

[9] Univ Alabama Birmingham, Dept Cell Dev & Integrat Biol, Birmingham, AL 35294 USA

[10] Reg Specialist Hosp, Res & Dev Ctr, PL-51154 Wroclaw, Poland

来源：

CANCERS | 2020年 / 12卷 / 04期

关键词：

microtubule; RNASeq; tubulin; cell cycle arrest; TOPOISOMERASE-II; IN-VITRO; POLY(ADP-RIBOSE) POLYMERASE-1; CHROMOSOME CONGRESSION; TUMOR-SUPPRESSOR; BETA-TUBULIN; APOPTOSIS; COMPLEX; CELLS; BINDING;

D O I：

10.3390/cancers12040864

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页数：26