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Downloaded from the Protein Data Bank (4O2B, PDB)[99], (Figure S6) cancers Article Utilizing Genome-Wide mRNA Profiling to Identify the Cytotoxic Chemotherapeutic Mechanism of Triazoloacridone C-1305 as Direct Microtubule Stabilization 1 2 3, Jarosław Króliczewski , Sylwia Bartoszewska , Magdalena Dudkowska y, 3, 4, 5 6 Dorota Janiszewska y, Agnieszka Biernatowska y, David K. Crossman , Karol Krzymi ´nski , Małgorzata Wysocka 6 , Anna Romanowska 6 , Maciej Baginski 7 , Michal Markuszewski 8 , Renata J. Ochocka 1 , James F. Collawn 9, Aleksander F. Sikorski 10, Ewa Sikora 3 and Rafal Bartoszewski 1,* 1 Department of Biology and Pharmaceutical Botany, Medical University of Gdansk, 80-416 Gdansk, Poland; [email protected] (J.K.); [email protected] (R.J.O.) 2 Department of Inorganic Chemistry, Medical University of Gdansk, 80-416 Gdansk, Poland; [email protected] 3 Laboratory of the Molecular Bases of Ageing, Nencki Institute of Experimental Biology of the Polish Academy of Sciences, 02-093 Warsaw, Poland; [email protected] (M.D.); [email protected] (D.J.); [email protected] (E.S.) 4 Department of Cytobiochemistry, Faculty of Biotechnology, University of Wroclaw, 50-383 Wroclaw Poland; [email protected] 5 Department of Genetics, UAB Genomics Core Facility, University of Alabama at Birmingham, Birmingham, AL 35233, USA; [email protected] 6 Faculty of Chemistry, University of Gdansk, 80-308 Gdansk, Poland; [email protected] (K.K.); [email protected] (M.W.); [email protected] (A.R.) 7 Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, 80-233 Gdansk, Poland; [email protected] 8 Department of Biopharmacy and Pharmacodynamics, Medical University of Gdansk, 80-416 Gdansk, Poland; [email protected] 9 Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; [email protected] 10 Research and Development Centre, Regional Specialist Hospital, 51-154, Wroclaw, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-58-349-32-14; Fax: +48-58-349-32-11 These authors contributed equally to this paper. y Received: 26 February 2020; Accepted: 31 March 2020; Published: 2 April 2020 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. Cancers 2020, 12, 864; doi:10.3390/cancers12040864 www.mdpi.com/journal/cancers Cancers 2020, 12, 864 2 of 26 Cancers 2020, 12 2 of 26 Keywords: microtubule; RNASeq; tubulin; cell cycle arrest Keywords: microtubule; RNASeq; tubulin; cell cycle arrest 1. Introduction 1. Introduction The development of cytotoxic chemotherapy into molecularly targeted cancer drug discovery The development of cytotoxic chemotherapy into molecularly targeted cancer drug discovery provided an opportunity to deliver successful therapies that could change the lives of a large number provided an opportunity to deliver successful therapies that could change the lives of a large number of cancer patients. However, reducing the safety concerns of any drug therapy requires a thorough of cancer patients. However, reducing the safety concerns of any drug therapy requires a thorough evaluation of the molecular mechanisms of the candidate molecules and, importantly, the prediction of evaluation of the molecular mechanisms of the candidate molecules and, importantly, the prediction their off-target effects [1,2]. Nevertheless, despite their obvious benefits, early in-vitro pharmacological of their off-target effects [1,2]. Nevertheless, despite their obvious benefits, early in-vitro profiling approaches that address the molecular mechanisms that define molecular anticancer effects pharmacological profiling approaches that address the molecular mechanisms that define molecular are rarely utilized [1]. anticancer effects are rarely utilized [1]. Studies that focus on presenting the molecular mechanisms governing cytotoxicity, which are Studies that focus on presenting the molecular mechanisms governing cytotoxicity, which are currently fueling the anticancer development pipeline, often focus on single-pathway models that are currently fueling the anticancer development pipeline, often focus on single-pathway models that are difficult to translate into the standard drug development process [1,2]. However, recent developments difficult to translate into the standard drug development process [1,2]. However, recent and the decreasing costs of high-throughput genotyping technologies like deep sequencing [3,4] now developments and the decreasing costs of high-throughput genotyping technologies like deep allow investigators to address these research limitations. sequencing [3,4] now allow investigators to address these research limitations. Several lines of evidence have indicated that the triazoloacridinone derivative, C-1305 (Figure1) Several lines of evidence have indicated that the triazoloacridinone derivative, C-1305 (Figure 1) altered gene and protein expression and promoted apoptosis [5]. Furthermore, the antitumor activity altered gene and protein expression and promoted apoptosis [5]. Furthermore, the antitumor activity of C-1305 [6,7] was connected with its ability to intercalate to DNA and/or inhibit topoisomerase II of C-1305 [6,7] was connected with its ability to intercalate to DNA and/or inhibit topoisomerase II activity in in-vitro assays [8]. The genome-wide impact of C-1305, however, and its exact mechanism activity in in-vitro assays [8]. The genome-wide impact of C-1305, however, and its exact mechanism of action, remain unknown. of action, remain unknown. Figure 1. Triazoloacridinone1. Triazoloacridinone derivative, derivative, C-1305. (A)C-1305. Chemical ( formulaA) Chemical of 5-((3-(dimethylamino)propyl) formula of 5-((3- amino)-8-hydroxy-6H-[1,2,3]triazolo[4,5,1-de]acridin-6-one(dimethylamino)propyl)amino)-8-hydroxy-6H-[1,2,3]triazolo[4,5,1-de]acridin-6-one (C18H19N5O2)—C-1305; (C (B18)H Predicted19N5O2)— 3-dimensionalC-1305; (B) Predicted (3D) structure 3-dimensional of C-1305. (3D) The structure 3D structure of C-1305. was generated The 3Das structure described was under generated materials as anddescribed methods under section materials (red-oxygen, and methods blue-nitrogen, section black-carbon, (red-oxygen, grey-hydrogen). blue-nitrogen, black-carbon, grey- hydrogen). In this study, we used an unbiased approach in lung cancer and colon cell lines (A549 and HTC 116, respectively)In this study,to we identify used an universal unbiased early approach transcriptomic in lung cancer signatures and colon of C-1305 cell lines cytotoxicity (A549 and and HTC to highlight116, respectively) the novel to pathways identify responsibleuniversal early for itstranscriptomic biological activity. signatures The cancer of C-1305 cell linescytotoxicity chosen forand our to studieshighlight were the previouslynovel pathways reported responsible as very for sensitive its biolog to theical potentactivity. anticancer The cancer activity cell lines of C-1305, chosen [for7–9 our]. studiesOur were results previously identified reported C-1305-mediated as very sensitive direct to the microtubule potent anticancer stabilization activity as of the C-1305, central [7–9]. mediator that leadsOur results to apoptosis. identified Furthermore, C-1305-mediated we demonstrated direct microtubule that C-1305 stabilization promotes as the G2 central cell cycle mediator arrest bythat modulating leads to apoptosis. gene expression. Furthermore, The we results demonstrated indicate that that C-1305 C-1305 is promotes the first identified G2 cell cycle microtubule arrest by stabilizingmodulating agent gene coupled expression. with topoisomeraseThe results indicate II inhibitory that activity.C-1305 is Our the work first provides identified a framework microtubule to understandstabilizing agent the eff coupledects of C-1305 with topoisomerase on cancer cells II and inhibitory serves asactivity. a resource Our forwork delineating provides the a framework antitumor mechanismsto understand of otherthe effects putative of C-1305 anticancer on drugcancer candidates. cells and serves as a resource for delineating the antitumor mechanisms of other putative anticancer drug candidates. Cancers 2020, 12, 864 3 of 26 Cancers 2020, 12 3 of 26 2.2. Results 2.1. Evaluation of C-1305 Cytotoxicity Profile 2.1. Evaluation of C-1305 Cytotoxicity Profile TheThe synthesissynthesis ofof compoundcompound C-1305C-1305 waswas
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