Screening of GPCR drugs for repurposing in breast cancer.

Autor:	Abdulkareem NM; Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX, United states., Bhat R; Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, United states., Powell RT; Institute of Bioscience and Technology, Texas A&M University, Houston, TX, United states., Chikermane S; Department of Pharmaceutical Health Outcomes and Policy, University of Houston, Houston, TX, United states., Yande S; Department of Pharmaceutical Health Outcomes and Policy, University of Houston, Houston, TX, United states., Trinh L; Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, United states., Abdelnasser HY; Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX, United states., Tabassum M; Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX, United states., Ruiz A; Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, United states., Sobieski M; Institute of Bioscience and Technology, Texas A&M University, Houston, TX, United states., Nguyen ND; Institute of Bioscience and Technology, Texas A&M University, Houston, TX, United states., Park JH; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United states., Johnson CA; Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, United states., Kaipparettu BA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United states., Bond RA; Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX, United states., Johnson M; Department of Pharmaceutical Health Outcomes and Policy, University of Houston, Houston, TX, United states., Stephan C; Institute of Bioscience and Technology, Texas A&M University, Houston, TX, United states., Trivedi MV; Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX, United states.; Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, United states.
Jazyk:	angličtina
Zdroj:	Frontiers in pharmacology [Front Pharmacol] 2022 Dec 06; Vol. 13, pp. 1049640. Date of Electronic Publication: 2022 Dec 06 (Print Publication: 2022).
DOI:	10.3389/fphar.2022.1049640
Abstrakt:	Drug repurposing can overcome both substantial costs and the lengthy process of new drug discovery and development in cancer treatment. Some Food and Drug Administration (FDA)-approved drugs have been found to have the potential to be repurposed as anti-cancer drugs. However, the progress is slow due to only a handful of strategies employed to identify drugs with repurposing potential. In this study, we evaluated GPCR-targeting drugs by high throughput screening (HTS) for their repurposing potential in triple-negative breast cancer (TNBC) and drug-resistant human epidermal growth factor receptor-2-positive (HER2+) breast cancer (BC), due to the dire need to discover novel targets and drugs in these subtypes. We assessed the efficacy and potency of drugs/compounds targeting different GPCRs for the growth rate inhibition in the following models: two TNBC cell lines (MDA-MB-231 and MDA-MB-468) and two HER2+ BC cell lines (BT474 and SKBR3), sensitive or resistant to lapatinib + trastuzumab, an effective combination of HER2-targeting therapies. We identified six drugs/compounds as potential hits, of which 4 were FDA-approved drugs. We focused on β-adrenergic receptor-targeting nebivolol as a candidate, primarily because of the potential role of these receptors in BC and its excellent long-term safety profile. The effects of nebivolol were validated in an independent assay in all the cell line models. The effects of nebivolol were independent of its activation of β3 receptors and nitric oxide production. Nebivolol reduced invasion and migration potentials which also suggests its inhibitory role in metastasis. Analysis of the Surveillance, Epidemiology and End Results (SEER)-Medicare dataset found numerically but not statistically significant reduced risk of all-cause mortality in the nebivolol group. In-depth future analyses, including detailed in vivo studies and real-world data analysis with more patients, are needed to further investigate the potential of nebivolol as a repurposed therapy for BC. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Abdulkareem, Bhat, Powell, Chikermane, Yande, Trinh, Abdelnasser, Tabassum, Ruiz, Sobieski, Nguyen, Park, Johnson, Kaipparettu, Bond, Johnson, Stephan and Trivedi.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu