Tatiane Roquete Amparo, Kamila de Fátima da Anunciação, Tamires Cunha Almeida, Glenda Nicioli da Silva, Geraldo Célio Brandão
{"title":"Beta-Lapachone: Effects on Proliferation, Survival, Migration, Cell Cycle, and lncRNA Modulation in Bladder Cancer Cells With Distinct TP53 Profiles","authors":"Tatiane Roquete Amparo, Kamila de Fátima da Anunciação, Tamires Cunha Almeida, Glenda Nicioli da Silva, Geraldo Célio Brandão","doi":"10.1002/ddr.70128","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>α-Lapachone (aLAP) and β-lapachone (bLAP) are noteworthy anticancer naphthoquinones. The chemoresistance observed in bladder cancer represents a global health concern, with relation to mutations in the <i>TP53</i> gene and alterations in the expression of long noncoding RNA (lncRNAs). This study evaluated the effects of aLAP and bLAP on bladder tumor cell lines with different <i>TP53</i> statuses: RT4 low-grade tumor with wild-type <i>TP53</i>), T24 and J82 (high-grade tumor with mutation in the <i>TP53</i> gene). Cytotoxicity was assessed using the MTT reduction method and cell migration by scratch assay, while clonogenic survival and cell cycle were evaluated through cell colony counting and flow cytometry, respectively. The expression of lncRNAs linked to bladder cancer and associated with tumor progression and prognosis (<i>JHDM1D-AS1</i>, <i>SBF2-AS1</i>, <i>CDT-2132N18.2</i>, and <i>RP11-363E7.4</i>) and the <i>JHDM1D</i> gene was evaluated through RT-qPCR. bLAP demonstrated greater cytotoxicity than aLAP. Its inhibitory effects on clonogenic survival, migration, and the cell cycle were observed in all cell lines and were related to the modulation of lncRNAs expression. A reduction in lncRNA <i>SBF2-AS1</i> and <i>JHDM1D</i> gene expression was observed in RT4 cells, accompanied by an increase in lncRNA <i>RP11-363E7.4</i>. Conversely, in the cells with mutated <i>TP53</i> (J82), a reduction in <i>JHDM1D-AS1</i> and <i>JHDM1D</i> was observed. The downregulation of <i>JHDM1D-AS1</i> and <i>SBF2-AS1</i>, along with the upregulation of <i>RP11-363E7.4</i>, may be associated with the observed inhibition of proliferation and cell migration following bLAP treatment. The antiproliferative effects of bLAP in bladder cancer cells are independent of <i>TP53</i> statuses, yet occur through a distinct action mechanism, with variations in lncRNAs expression.</p>\n </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 5","pages":""},"PeriodicalIF":3.5000,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Development Research","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ddr.70128","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
α-Lapachone (aLAP) and β-lapachone (bLAP) are noteworthy anticancer naphthoquinones. The chemoresistance observed in bladder cancer represents a global health concern, with relation to mutations in the TP53 gene and alterations in the expression of long noncoding RNA (lncRNAs). This study evaluated the effects of aLAP and bLAP on bladder tumor cell lines with different TP53 statuses: RT4 low-grade tumor with wild-type TP53), T24 and J82 (high-grade tumor with mutation in the TP53 gene). Cytotoxicity was assessed using the MTT reduction method and cell migration by scratch assay, while clonogenic survival and cell cycle were evaluated through cell colony counting and flow cytometry, respectively. The expression of lncRNAs linked to bladder cancer and associated with tumor progression and prognosis (JHDM1D-AS1, SBF2-AS1, CDT-2132N18.2, and RP11-363E7.4) and the JHDM1D gene was evaluated through RT-qPCR. bLAP demonstrated greater cytotoxicity than aLAP. Its inhibitory effects on clonogenic survival, migration, and the cell cycle were observed in all cell lines and were related to the modulation of lncRNAs expression. A reduction in lncRNA SBF2-AS1 and JHDM1D gene expression was observed in RT4 cells, accompanied by an increase in lncRNA RP11-363E7.4. Conversely, in the cells with mutated TP53 (J82), a reduction in JHDM1D-AS1 and JHDM1D was observed. The downregulation of JHDM1D-AS1 and SBF2-AS1, along with the upregulation of RP11-363E7.4, may be associated with the observed inhibition of proliferation and cell migration following bLAP treatment. The antiproliferative effects of bLAP in bladder cancer cells are independent of TP53 statuses, yet occur through a distinct action mechanism, with variations in lncRNAs expression.
期刊介绍：
Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.
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