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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...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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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. |
format | Online Article Text |
id | pubmed-9763283 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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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