Pharmacological inhibition of tumor anabolism and host catabolism as a cancer therapy

Abstract The malignant energetic demands are satisfied through glycolysis, glutaminolysis and de novo synthesis of fatty acids, while the host curses with a state of catabolism and systemic inflammation. The concurrent inhibition of both, tumor anabolism and host catabolism, and their effect upon tu...

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Autores principales:	Alejandro Schcolnik-Cabrera, Alma Chavez-Blanco, Guadalupe Dominguez-Gomez, Mandy Juarez, Ariana Vargas-Castillo, Rafael Isaac Ponce-Toledo, Donna Lai, Sheng Hua, Armando R. Tovar, Nimbe Torres, Delia Perez-Montiel, Jose Diaz-Chavez, Alfonso Duenas-Gonzalez
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f99339e0268a4075931c6a4545b04390
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spelling	oai:doaj.org-article:f99339e0268a4075931c6a4545b043902021-12-02T11:35:52ZPharmacological inhibition of tumor anabolism and host catabolism as a cancer therapy10.1038/s41598-021-84538-62045-2322https://doaj.org/article/f99339e0268a4075931c6a4545b043902021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84538-6https://doaj.org/toc/2045-2322Abstract The malignant energetic demands are satisfied through glycolysis, glutaminolysis and de novo synthesis of fatty acids, while the host curses with a state of catabolism and systemic inflammation. The concurrent inhibition of both, tumor anabolism and host catabolism, and their effect upon tumor growth and whole animal metabolism, have not been evaluated. We aimed to evaluate in colon cancer cells a combination of six agents directed to block the tumor anabolism (orlistat + lonidamine + DON) and the host catabolism (growth hormone + insulin + indomethacin). Treatment reduced cellular viability, clonogenic capacity and cell cycle progression. These effects were associated with decreased glycolysis and oxidative phosphorylation, leading to a quiescent energetic phenotype, and with an aberrant transcriptomic landscape showing dysregulation in multiple metabolic pathways. The in vivo evaluation revealed a significant tumor volume inhibition, without damage to normal tissues. The six-drug combination preserved lean tissue and decreased fat loss, while the energy expenditure got decreased. Finally, a reduction in gene expression associated with thermogenesis was observed. Our findings demonstrate that the simultaneous use of this six-drug combination has anticancer effects by inducing a quiescent energetic phenotype of cultured cancer cells. Besides, the treatment is well-tolerated in mice and reduces whole animal energetic expenditure and fat loss.Alejandro Schcolnik-CabreraAlma Chavez-BlancoGuadalupe Dominguez-GomezMandy JuarezAriana Vargas-CastilloRafael Isaac Ponce-ToledoDonna LaiSheng HuaArmando R. TovarNimbe TorresDelia Perez-MontielJose Diaz-ChavezAlfonso Duenas-GonzalezNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Alejandro Schcolnik-Cabrera Alma Chavez-Blanco Guadalupe Dominguez-Gomez Mandy Juarez Ariana Vargas-Castillo Rafael Isaac Ponce-Toledo Donna Lai Sheng Hua Armando R. Tovar Nimbe Torres Delia Perez-Montiel Jose Diaz-Chavez Alfonso Duenas-Gonzalez Pharmacological inhibition of tumor anabolism and host catabolism as a cancer therapy
description	Abstract The malignant energetic demands are satisfied through glycolysis, glutaminolysis and de novo synthesis of fatty acids, while the host curses with a state of catabolism and systemic inflammation. The concurrent inhibition of both, tumor anabolism and host catabolism, and their effect upon tumor growth and whole animal metabolism, have not been evaluated. We aimed to evaluate in colon cancer cells a combination of six agents directed to block the tumor anabolism (orlistat + lonidamine + DON) and the host catabolism (growth hormone + insulin + indomethacin). Treatment reduced cellular viability, clonogenic capacity and cell cycle progression. These effects were associated with decreased glycolysis and oxidative phosphorylation, leading to a quiescent energetic phenotype, and with an aberrant transcriptomic landscape showing dysregulation in multiple metabolic pathways. The in vivo evaluation revealed a significant tumor volume inhibition, without damage to normal tissues. The six-drug combination preserved lean tissue and decreased fat loss, while the energy expenditure got decreased. Finally, a reduction in gene expression associated with thermogenesis was observed. Our findings demonstrate that the simultaneous use of this six-drug combination has anticancer effects by inducing a quiescent energetic phenotype of cultured cancer cells. Besides, the treatment is well-tolerated in mice and reduces whole animal energetic expenditure and fat loss.
format	article
author	Alejandro Schcolnik-Cabrera Alma Chavez-Blanco Guadalupe Dominguez-Gomez Mandy Juarez Ariana Vargas-Castillo Rafael Isaac Ponce-Toledo Donna Lai Sheng Hua Armando R. Tovar Nimbe Torres Delia Perez-Montiel Jose Diaz-Chavez Alfonso Duenas-Gonzalez
author_facet	Alejandro Schcolnik-Cabrera Alma Chavez-Blanco Guadalupe Dominguez-Gomez Mandy Juarez Ariana Vargas-Castillo Rafael Isaac Ponce-Toledo Donna Lai Sheng Hua Armando R. Tovar Nimbe Torres Delia Perez-Montiel Jose Diaz-Chavez Alfonso Duenas-Gonzalez
author_sort	Alejandro Schcolnik-Cabrera
title	Pharmacological inhibition of tumor anabolism and host catabolism as a cancer therapy
title_short	Pharmacological inhibition of tumor anabolism and host catabolism as a cancer therapy
title_full	Pharmacological inhibition of tumor anabolism and host catabolism as a cancer therapy
title_fullStr	Pharmacological inhibition of tumor anabolism and host catabolism as a cancer therapy
title_full_unstemmed	Pharmacological inhibition of tumor anabolism and host catabolism as a cancer therapy
title_sort	pharmacological inhibition of tumor anabolism and host catabolism as a cancer therapy
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f99339e0268a4075931c6a4545b04390
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Pharmacological inhibition of tumor anabolism and host catabolism as a cancer therapy

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