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Propranolol Promotes Glucose Dependence and Synergizes with Dichloroacetate for Anti-Cancer Activity in HNSCC

Tumor cell metabolism differs from that of normal cells, conferring tumors with metabolic advantages but affording opportunities for therapeutic intervention. Accordingly, metabolism-targeting therapies have shown promise. However, drugs targeting singular metabolic pathways display limited efficacy...

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Detalles Bibliográficos
Autores principales: Lucido, Christopher T., Miskimins, W. Keith, Vermeer, Paola D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316475/
https://www.ncbi.nlm.nih.gov/pubmed/30513596
http://dx.doi.org/10.3390/cancers10120476
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author Lucido, Christopher T.
Miskimins, W. Keith
Vermeer, Paola D.
author_facet Lucido, Christopher T.
Miskimins, W. Keith
Vermeer, Paola D.
author_sort Lucido, Christopher T.
collection PubMed
description Tumor cell metabolism differs from that of normal cells, conferring tumors with metabolic advantages but affording opportunities for therapeutic intervention. Accordingly, metabolism-targeting therapies have shown promise. However, drugs targeting singular metabolic pathways display limited efficacy, in part due to the tumor’s ability to compensate by using other metabolic pathways to meet energy and growth demands. Thus, it is critical to identify novel combinations of metabolism-targeting drugs to improve therapeutic efficacy in the face of compensatory cellular response mechanisms. Our lab has previously identified that the anti-cancer activity of propranolol, a non-selective beta-blocker, is associated with inhibition of mitochondrial metabolism in head and neck squamous cell carcinoma (HNSCC). In response to propranolol, however, HNSCC exhibits heightened glycolytic activity, which may limit the effectiveness of propranolol as a single agent. Thus, we hypothesized that propranolol’s metabolic effects promote a state of enhanced glucose dependence, and that propranolol together with glycolytic inhibition would provide a highly effective therapeutic combination in HNSCC. Here, we show that glucose deprivation synergizes with propranolol for anti-cancer activity, and that the rational combination of propranolol and dichloroacetate (DCA), a clinically available glycolytic inhibitor, dramatically attenuates tumor cell metabolism and mTOR signaling, inhibits proliferation and colony formation, and induces apoptosis. This therapeutic combination displays efficacy in both human papillomavirus-positive (HPV(+)) and HPV(−) HNSCC cell lines, as well as a recurrent/metastatic model, while leaving normal tonsil epithelial cells relatively unaffected. Importantly, the combination significantly delays tumor growth in vivo with no evidence of toxicity. Additionally, the combination of propranolol and DCA enhances the effects of chemoradiation and sensitizes resistant cells to cisplatin and radiation. This novel therapeutic combination represents a promising treatment strategy which may overcome some of the limitations of targeting individual metabolic pathways in cancer.
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spelling pubmed-63164752019-01-09 Propranolol Promotes Glucose Dependence and Synergizes with Dichloroacetate for Anti-Cancer Activity in HNSCC Lucido, Christopher T. Miskimins, W. Keith Vermeer, Paola D. Cancers (Basel) Article Tumor cell metabolism differs from that of normal cells, conferring tumors with metabolic advantages but affording opportunities for therapeutic intervention. Accordingly, metabolism-targeting therapies have shown promise. However, drugs targeting singular metabolic pathways display limited efficacy, in part due to the tumor’s ability to compensate by using other metabolic pathways to meet energy and growth demands. Thus, it is critical to identify novel combinations of metabolism-targeting drugs to improve therapeutic efficacy in the face of compensatory cellular response mechanisms. Our lab has previously identified that the anti-cancer activity of propranolol, a non-selective beta-blocker, is associated with inhibition of mitochondrial metabolism in head and neck squamous cell carcinoma (HNSCC). In response to propranolol, however, HNSCC exhibits heightened glycolytic activity, which may limit the effectiveness of propranolol as a single agent. Thus, we hypothesized that propranolol’s metabolic effects promote a state of enhanced glucose dependence, and that propranolol together with glycolytic inhibition would provide a highly effective therapeutic combination in HNSCC. Here, we show that glucose deprivation synergizes with propranolol for anti-cancer activity, and that the rational combination of propranolol and dichloroacetate (DCA), a clinically available glycolytic inhibitor, dramatically attenuates tumor cell metabolism and mTOR signaling, inhibits proliferation and colony formation, and induces apoptosis. This therapeutic combination displays efficacy in both human papillomavirus-positive (HPV(+)) and HPV(−) HNSCC cell lines, as well as a recurrent/metastatic model, while leaving normal tonsil epithelial cells relatively unaffected. Importantly, the combination significantly delays tumor growth in vivo with no evidence of toxicity. Additionally, the combination of propranolol and DCA enhances the effects of chemoradiation and sensitizes resistant cells to cisplatin and radiation. This novel therapeutic combination represents a promising treatment strategy which may overcome some of the limitations of targeting individual metabolic pathways in cancer. MDPI 2018-11-30 /pmc/articles/PMC6316475/ /pubmed/30513596 http://dx.doi.org/10.3390/cancers10120476 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lucido, Christopher T.
Miskimins, W. Keith
Vermeer, Paola D.
Propranolol Promotes Glucose Dependence and Synergizes with Dichloroacetate for Anti-Cancer Activity in HNSCC
title Propranolol Promotes Glucose Dependence and Synergizes with Dichloroacetate for Anti-Cancer Activity in HNSCC
title_full Propranolol Promotes Glucose Dependence and Synergizes with Dichloroacetate for Anti-Cancer Activity in HNSCC
title_fullStr Propranolol Promotes Glucose Dependence and Synergizes with Dichloroacetate for Anti-Cancer Activity in HNSCC
title_full_unstemmed Propranolol Promotes Glucose Dependence and Synergizes with Dichloroacetate for Anti-Cancer Activity in HNSCC
title_short Propranolol Promotes Glucose Dependence and Synergizes with Dichloroacetate for Anti-Cancer Activity in HNSCC
title_sort propranolol promotes glucose dependence and synergizes with dichloroacetate for anti-cancer activity in hnscc
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316475/
https://www.ncbi.nlm.nih.gov/pubmed/30513596
http://dx.doi.org/10.3390/cancers10120476
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