Luz X Vásquez-Bochm1, Mireya Velázquez-Paniagua2, Sandra S Castro-Vázquez3, Sandra L Guerrero-Rodríguez3, Abimael Mondragon-Peralta3, Marisol De La Fuente-Granada4, Sonia M Pérez-Tapia5, Aliesha González-Arenas4, Marco A Velasco-Velázquez6. 1. Department of Pharmacology, School of Medicine, National Autonomous University of Mexico (Universidad Nacional Autónoma de México; UNAM), Mexico City, Mexico; Graduate Program in Chemical Sciences, UNAM, Mexico City, Mexico. 2. Department of Pharmacology, School of Medicine, National Autonomous University of Mexico (Universidad Nacional Autónoma de México; UNAM), Mexico City, Mexico; Department of Physiology, School of Medicine, UNAM, Mexico City, Mexico. 3. Department of Pharmacology, School of Medicine, National Autonomous University of Mexico (Universidad Nacional Autónoma de México; UNAM), Mexico City, Mexico. 4. Department of Genomic Medicine and Environmental Toxicology, Institute of Biomedical Research (IIB), UNAM, Mexico City, Mexico. 5. Unit for Development and Research in Bioprocesses (UDIBI), National School of Biological Sciences, National Polytechnic Institute, Mexico City, Mexico. 6. Department of Pharmacology, School of Medicine, National Autonomous University of Mexico (Universidad Nacional Autónoma de México; UNAM), Mexico City, Mexico; Unit for Research in Translational Biomedicine, Research Division, School of Medicine, UNAM, Mexico City, Mexico. Electronic address: marcovelasco@unam.mx.
Abstract
BACKGROUND: Breast cancer is a neoplastic disease with high morbidity and mortality in women worldwide. Breast cancer stem cells (CSCs) have a significant function in tumor growth, recurrence, and therapeutic resistance. Thus, CSCs have been pointed as targets of new therapies for breast cancer. Herein, we aimed to repurpose certain drugs as breast CSC-targeting agents. METHODS: We compared a consensus breast CSC signature with the transcriptomic changes that were induced by over 1300 bioactive compounds using Connectivity Map. The effects of the selected drugs on SOX2 promoter transactivation, SOX2 expression, viability, clonogenicity, and ALDH activity in breast cancer cells were analyzed by luciferase assay, western blot, MTT assay, mammosphere formation assay, and ALDEFLUOR® test, respectively. Gene Set Enrichment Analysis (GSEA) was performed using the gene expression data from mammary tumors of mice that were treated with lovastatin. RESULTS: Five drugs (fasudil, pivmecillinam, ursolic acid, 16,16-dimethylprostaglandin E2, and lovastatin) induced signatures that correlated negatively with the query CSC signature. In vitro, lovastatin inhibited SOX2 promoter transactivation, and reduced the efficiency of mammosphere formation and the percentage of ALDH+ cells. Mevalonate mitigated the effects of lovastatin, suggesting that the targeting of CSCs by lovastatin was mediated by the inhibition of its reported target, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR). By GSEA, lovastatin downregulated genes that are involved in stemness and invasiveness in mammary tumors, corroborating our in vitro findings. CONCLUSION: Lovastatin is a breast CSC-targeting drug. The inhibition of HMGCR might develop new adjuvant therapeutic strategies for breast tumors.
BACKGROUND:Breast cancer is a neoplastic disease with high morbidity and mortality in women worldwide. Breast cancer stem cells (CSCs) have a significant function in tumor growth, recurrence, and therapeutic resistance. Thus, CSCs have been pointed as targets of new therapies for breast cancer. Herein, we aimed to repurpose certain drugs as breast CSC-targeting agents. METHODS: We compared a consensus breast CSC signature with the transcriptomic changes that were induced by over 1300 bioactive compounds using Connectivity Map. The effects of the selected drugs on SOX2 promoter transactivation, SOX2 expression, viability, clonogenicity, and ALDH activity in breast cancer cells were analyzed by luciferase assay, western blot, MTT assay, mammosphere formation assay, and ALDEFLUOR® test, respectively. Gene Set Enrichment Analysis (GSEA) was performed using the gene expression data from mammary tumors of mice that were treated with lovastatin. RESULTS: Five drugs (fasudil, pivmecillinam, ursolic acid, 16,16-dimethylprostaglandin E2, and lovastatin) induced signatures that correlated negatively with the query CSC signature. In vitro, lovastatin inhibited SOX2 promoter transactivation, and reduced the efficiency of mammosphere formation and the percentage of ALDH+ cells. Mevalonate mitigated the effects of lovastatin, suggesting that the targeting of CSCs by lovastatin was mediated by the inhibition of its reported target, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR). By GSEA, lovastatin downregulated genes that are involved in stemness and invasiveness in mammary tumors, corroborating our in vitro findings. CONCLUSION:Lovastatin is a breast CSC-targeting drug. The inhibition of HMGCR might develop new adjuvant therapeutic strategies for breast tumors.
Authors: Bárbara Lara-Chacón; Sandra L Guerrero-Rodríguez; Karla J Ramírez-Hernández; Angélica Yamilett Robledo-Rivera; Marco Antonio Velasco Velazquez; Roberto Sánchez-Olea; Mónica Raquel Calera Journal: Technol Cancer Res Treat Date: 2019-01-01
Authors: Nabil A Alhakamy; Osama A A Ahmed; Hibah M Aldawsari; Mohammad Y Alfaifi; Basma G Eid; Ashraf B Abdel-Naim; Usama A Fahmy Journal: Int J Mol Sci Date: 2019-11-18 Impact factor: 5.923