Submit Manuscript  

Article Details


The Antimalarial Drug Pyronaridine Inhibits Topoisomerase II in Breast Cancer Cells and Hinders Tumor Progression In Vivo

[ Vol. 8 , Issue. 1 ]

Author(s):

Paulina J. Villanueva, Denisse A Gutierrez, Lisett Contreras, Karla Parra, Aldo Segura-Cabrera, Armando Varela-Ramirez and Renato J Aguilera*   Pages 50 - 56 ( 7 )

Abstract:


Background: Breast cancer is the most frequently diagnosed cancer in women worldwide. Pyronaridine (PND), an antimalarial drug, was shown to exert anticancer activity on seventeen different human cancer cells, seven from female breast tissue. Additionally, PND induced apoptosis via mitochondrial depolarization, alteration of cell cycle progression, and DNA intercalation. However, the molecular target of PND in cells was not elucidated. <p> Objective: Here, we have further investigated PND&#039;s mode of action by using transcriptome analysis. Preclinical studies were also performed to determine whether PND could affect tumor progression in a human breast cancer xenograft in mice. Moreover, we assessed the combined efficacy of PND with well-known anticancer drugs. <p> Methods: Transcriptome analyses of PND-treated cancer cells were performed. Topoisomerase II activity was evaluated by an in vitro assay. In addition, daily oral administration of PND was given to mice with human breast cancer xenografts. The differential nuclear staining assay measured in- -vitro cell toxicity. <p> Results: The transcriptome signatures suggested that PND might act as a topoisomerase II inhibitor. Thus, topoisomerase inhibition assays were performed, providing evidence that PND is a bona fide topoisomerase II inhibitor. Also, in-vivo studies suggest that PND hinders tumor progression. Besides, combination studies of PND with anticancer drugs cisplatin and gemcitabine revealed higher cytotoxicity against cancer cells than individual drug administration. <p> Conclusion: The findings provide evidence that PND is a topoisomerase II inhibitor and can hinder cancer progression in an animal model, further demonstrating PND&#039;s favorable characteristics as a repurposed anticancer drug.

Keywords:

Anticancer, anticancer drug combination, breast cancer, drug discovery, drug repurposing, in-vivo tumor, multidrugresistance, topoisomerase.

Affiliation:

The Cellular Characterization and Biorepository (CCB) Core Facility, Border Biomedical Research Center, Department of Biological Sciences, the University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968-0519, The Cellular Characterization and Biorepository (CCB) Core Facility, Border Biomedical Research Center, Department of Biological Sciences, the University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968-0519, The Cellular Characterization and Biorepository (CCB) Core Facility, Border Biomedical Research Center, Department of Biological Sciences, the University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968-0519, The Cellular Characterization and Biorepository (CCB) Core Facility, Border Biomedical Research Center, Department of Biological Sciences, the University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968-0519, European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, The Cellular Characterization and Biorepository (CCB) Core Facility, Border Biomedical Research Center, Department of Biological Sciences, the University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968-0519, The Cellular Characterization and Biorepository (CCB) Core Facility, Border Biomedical Research Center, Department of Biological Sciences, the University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968-0519

Graphical Abstract:



Read Full-Text article