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Therapeutic Potential of the Cyclin-Dependent Kinase Inhibitor Flavopiridol on c-Myc Overexpressing Esophageal Cancer

Tumors with elevated c-Myc expression often exhibit a highly aggressive phenotype, and c-Myc amplification has been shown to be frequent in esophageal cancer. Emerging data suggests that synthetic lethal interactions between c-Myc pathway activation and small molecules inhibition involved in cell cy...

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Autores principales: Hassan, Md Sazzad, Cwidak, Nicholas, Johnson, Chloe, Däster, Silvio, Eppenberger-Castori, Serenella, Awasthi, Niranjan, Li, Jun, Schwarz, Margaret A., von Holzen, Urs
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490822/
https://www.ncbi.nlm.nih.gov/pubmed/34621175
http://dx.doi.org/10.3389/fphar.2021.746385
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author Hassan, Md Sazzad
Cwidak, Nicholas
Johnson, Chloe
Däster, Silvio
Eppenberger-Castori, Serenella
Awasthi, Niranjan
Li, Jun
Schwarz, Margaret A.
von Holzen, Urs
author_facet Hassan, Md Sazzad
Cwidak, Nicholas
Johnson, Chloe
Däster, Silvio
Eppenberger-Castori, Serenella
Awasthi, Niranjan
Li, Jun
Schwarz, Margaret A.
von Holzen, Urs
author_sort Hassan, Md Sazzad
collection PubMed
description Tumors with elevated c-Myc expression often exhibit a highly aggressive phenotype, and c-Myc amplification has been shown to be frequent in esophageal cancer. Emerging data suggests that synthetic lethal interactions between c-Myc pathway activation and small molecules inhibition involved in cell cycle signaling can be therapeutically exploited to preferentially kill tumor cells. We therefore investigated whether exploiting elevated c-Myc expression is effective in treating esophageal cancer with the CDK inhibitor flavopiridol. We found frequent overexpression of c-Myc in human esophageal cancer cell lines and tissues. c-Myc overexpression correlated with accelerated esophageal cancer subcutaneous xenograft tumor growth. Esophageal cancer cells with elevated c-Myc expression were found preferentially more sensitive to induction of apoptosis by the CDK inhibition flavopiridol compared to esophageal cancer cells with lower c-Myc expression. In addition, we observed that flavopiridol alone or in combination with the chemotherapeutic agent nanoparticle albumin-bound paclitaxel (NPT) or in combinations with the targeted agent BMS-754807 significantly inhibited esophageal cancer cell proliferation and subcutaneous xenograft tumor growth while significantly enhancing overall mice survival. These results indicate that aggressive esophageal cancer cells with elevated c-Myc expression are sensitive to the CDK inhibitor flavopiridol, and that flavopiridol alone or in combination can be a potential therapy for c-Myc overexpressing esophageal cancer.
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spelling pubmed-84908222021-10-06 Therapeutic Potential of the Cyclin-Dependent Kinase Inhibitor Flavopiridol on c-Myc Overexpressing Esophageal Cancer Hassan, Md Sazzad Cwidak, Nicholas Johnson, Chloe Däster, Silvio Eppenberger-Castori, Serenella Awasthi, Niranjan Li, Jun Schwarz, Margaret A. von Holzen, Urs Front Pharmacol Pharmacology Tumors with elevated c-Myc expression often exhibit a highly aggressive phenotype, and c-Myc amplification has been shown to be frequent in esophageal cancer. Emerging data suggests that synthetic lethal interactions between c-Myc pathway activation and small molecules inhibition involved in cell cycle signaling can be therapeutically exploited to preferentially kill tumor cells. We therefore investigated whether exploiting elevated c-Myc expression is effective in treating esophageal cancer with the CDK inhibitor flavopiridol. We found frequent overexpression of c-Myc in human esophageal cancer cell lines and tissues. c-Myc overexpression correlated with accelerated esophageal cancer subcutaneous xenograft tumor growth. Esophageal cancer cells with elevated c-Myc expression were found preferentially more sensitive to induction of apoptosis by the CDK inhibition flavopiridol compared to esophageal cancer cells with lower c-Myc expression. In addition, we observed that flavopiridol alone or in combination with the chemotherapeutic agent nanoparticle albumin-bound paclitaxel (NPT) or in combinations with the targeted agent BMS-754807 significantly inhibited esophageal cancer cell proliferation and subcutaneous xenograft tumor growth while significantly enhancing overall mice survival. These results indicate that aggressive esophageal cancer cells with elevated c-Myc expression are sensitive to the CDK inhibitor flavopiridol, and that flavopiridol alone or in combination can be a potential therapy for c-Myc overexpressing esophageal cancer. Frontiers Media S.A. 2021-09-21 /pmc/articles/PMC8490822/ /pubmed/34621175 http://dx.doi.org/10.3389/fphar.2021.746385 Text en Copyright © 2021 Hassan, Cwidak, Johnson, Däster, Eppenberger-Castori, Awasthi, Li, Schwarz and von Holzen. 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
Hassan, Md Sazzad
Cwidak, Nicholas
Johnson, Chloe
Däster, Silvio
Eppenberger-Castori, Serenella
Awasthi, Niranjan
Li, Jun
Schwarz, Margaret A.
von Holzen, Urs
Therapeutic Potential of the Cyclin-Dependent Kinase Inhibitor Flavopiridol on c-Myc Overexpressing Esophageal Cancer
title Therapeutic Potential of the Cyclin-Dependent Kinase Inhibitor Flavopiridol on c-Myc Overexpressing Esophageal Cancer
title_full Therapeutic Potential of the Cyclin-Dependent Kinase Inhibitor Flavopiridol on c-Myc Overexpressing Esophageal Cancer
title_fullStr Therapeutic Potential of the Cyclin-Dependent Kinase Inhibitor Flavopiridol on c-Myc Overexpressing Esophageal Cancer
title_full_unstemmed Therapeutic Potential of the Cyclin-Dependent Kinase Inhibitor Flavopiridol on c-Myc Overexpressing Esophageal Cancer
title_short Therapeutic Potential of the Cyclin-Dependent Kinase Inhibitor Flavopiridol on c-Myc Overexpressing Esophageal Cancer
title_sort therapeutic potential of the cyclin-dependent kinase inhibitor flavopiridol on c-myc overexpressing esophageal cancer
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490822/
https://www.ncbi.nlm.nih.gov/pubmed/34621175
http://dx.doi.org/10.3389/fphar.2021.746385
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