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Screening of GPCR drugs for repurposing in breast cancer

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 du...

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Autores principales: Abdulkareem, Noor Mazin, Bhat, Raksha, Powell, Reid T., Chikermane, Soumya, Yande, Soham, Trinh, Lisa, Abdelnasser, Hala Y., Tabassum, Mantasha, Ruiz, Alexis, Sobieski, Mary, Nguyen, Nghi D., Park, Jun Hyoung, Johnson, Camille A., Kaipparettu, Benny A., Bond, Richard A., Johnson, Michael, Stephan, Clifford, Trivedi, Meghana V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9763283/
https://www.ncbi.nlm.nih.gov/pubmed/36561339
http://dx.doi.org/10.3389/fphar.2022.1049640
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author Abdulkareem, Noor Mazin
Bhat, Raksha
Powell, Reid T.
Chikermane, Soumya
Yande, Soham
Trinh, Lisa
Abdelnasser, Hala Y.
Tabassum, Mantasha
Ruiz, Alexis
Sobieski, Mary
Nguyen, Nghi D.
Park, Jun Hyoung
Johnson, Camille A.
Kaipparettu, Benny A.
Bond, Richard A.
Johnson, Michael
Stephan, Clifford
Trivedi, Meghana V.
author_facet Abdulkareem, Noor Mazin
Bhat, Raksha
Powell, Reid T.
Chikermane, Soumya
Yande, Soham
Trinh, Lisa
Abdelnasser, Hala Y.
Tabassum, Mantasha
Ruiz, Alexis
Sobieski, Mary
Nguyen, Nghi D.
Park, Jun Hyoung
Johnson, Camille A.
Kaipparettu, Benny A.
Bond, Richard A.
Johnson, Michael
Stephan, Clifford
Trivedi, Meghana V.
author_sort Abdulkareem, Noor Mazin
collection PubMed
description 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.
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spelling pubmed-97632832022-12-21 Screening of GPCR drugs for repurposing in breast cancer Abdulkareem, Noor Mazin Bhat, Raksha Powell, Reid T. Chikermane, Soumya Yande, Soham Trinh, Lisa Abdelnasser, Hala Y. Tabassum, Mantasha Ruiz, Alexis Sobieski, Mary Nguyen, Nghi D. Park, Jun Hyoung Johnson, Camille A. Kaipparettu, Benny A. Bond, Richard A. Johnson, Michael Stephan, Clifford Trivedi, Meghana V. Front Pharmacol Pharmacology 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. Frontiers Media S.A. 2022-12-06 /pmc/articles/PMC9763283/ /pubmed/36561339 http://dx.doi.org/10.3389/fphar.2022.1049640 Text en Copyright © 2022 Abdulkareem, Bhat, Powell, Chikermane, Yande, Trinh, Abdelnasser, Tabassum, Ruiz, Sobieski, Nguyen, Park, Johnson, Kaipparettu, Bond, Johnson, Stephan and Trivedi. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Abdulkareem, Noor Mazin
Bhat, Raksha
Powell, Reid T.
Chikermane, Soumya
Yande, Soham
Trinh, Lisa
Abdelnasser, Hala Y.
Tabassum, Mantasha
Ruiz, Alexis
Sobieski, Mary
Nguyen, Nghi D.
Park, Jun Hyoung
Johnson, Camille A.
Kaipparettu, Benny A.
Bond, Richard A.
Johnson, Michael
Stephan, Clifford
Trivedi, Meghana V.
Screening of GPCR drugs for repurposing in breast cancer
title Screening of GPCR drugs for repurposing in breast cancer
title_full Screening of GPCR drugs for repurposing in breast cancer
title_fullStr Screening of GPCR drugs for repurposing in breast cancer
title_full_unstemmed Screening of GPCR drugs for repurposing in breast cancer
title_short Screening of GPCR drugs for repurposing in breast cancer
title_sort screening of gpcr drugs for repurposing in breast cancer
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9763283/
https://www.ncbi.nlm.nih.gov/pubmed/36561339
http://dx.doi.org/10.3389/fphar.2022.1049640
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