Identification of a Potent Cytotoxic Pyrazole with Anti-Breast Cancer Activity That Alters Multiple Pathways
Denisse A. Gutierrez,
Lisett Contreras,
Paulina J. Villanueva,
Edgar A. Borrego,
Karla Morán-Santibañez,
Jessica D. Hess,
Rebecca DeJesus,
Manuel Larragoity,
Ana P. Betancourt,
Jonathon E. Mohl,
Elisa Robles-Escajeda,
Khodeza Begum,
Sourav Roy,
Robert A. Kirken,
Armando Varela-Ramirez,
Renato J. Aguilera
Affiliations
Denisse A. Gutierrez
Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, Department of Biological Sciences, College of Science, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968-0519, USA
Lisett Contreras
Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, Department of Biological Sciences, College of Science, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968-0519, USA
Paulina J. Villanueva
Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, Department of Biological Sciences, College of Science, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968-0519, USA
Edgar A. Borrego
Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, Department of Biological Sciences, College of Science, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968-0519, USA
Karla Morán-Santibañez
Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, Department of Biological Sciences, College of Science, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968-0519, USA
Jessica D. Hess
Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, Department of Biological Sciences, College of Science, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968-0519, USA
Rebecca DeJesus
Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, Department of Biological Sciences, College of Science, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968-0519, USA
Manuel Larragoity
Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, Department of Biological Sciences, College of Science, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968-0519, USA
Ana P. Betancourt
Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, Department of Biological Sciences, College of Science, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968-0519, USA
Jonathon E. Mohl
Department of Bioinformatics, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968-0519, USA
Elisa Robles-Escajeda
Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, Department of Biological Sciences, College of Science, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968-0519, USA
Khodeza Begum
Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, Department of Biological Sciences, College of Science, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968-0519, USA
Sourav Roy
Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, Department of Biological Sciences, College of Science, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968-0519, USA
Robert A. Kirken
Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, Department of Biological Sciences, College of Science, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968-0519, USA
Armando Varela-Ramirez
Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, Department of Biological Sciences, College of Science, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968-0519, USA
Renato J. Aguilera
Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, Department of Biological Sciences, College of Science, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968-0519, USA
In this study, we identified a novel pyrazole-based derivative (P3C) that displayed potent cytotoxicity against 27 human cancer cell lines derived from different tissue origins with 50% cytotoxic concentrations (CC50) in the low micromolar and nanomolar range, particularly in two triple-negative breast cancer (TNBC) cell lines (from 0.25 to 0.49 µM). In vitro assays revealed that P3C induces reactive oxygen species (ROS) accumulation leading to mitochondrial depolarization and caspase-3/7 and -8 activation, suggesting the participation of both the intrinsic and extrinsic apoptotic pathways. P3C caused microtubule disruption, phosphatidylserine externalization, PARP cleavage, DNA fragmentation, and cell cycle arrest on TNBC cells. In addition, P3C triggered dephosphorylation of CREB, p38, ERK, STAT3, and Fyn, and hyperphosphorylation of JNK and NF-kB in TNBC cells, indicating the inactivation of both p38MAPK/STAT3 and ERK1/2/CREB signaling pathways. In support of our in vitro assays, transcriptome analyses of two distinct TNBC cell lines (MDA-MB-231 and MDA-MB-468 cells) treated with P3C revealed 28 genes similarly affected by the treatment implicated in apoptosis, oxidative stress, protein kinase modulation, and microtubule stability.
