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Synergistic Effect of Endogenous and Exogenous Aldehydes on Doxorubicin Toxicity in Yeast

Anthracyclines are frequently used to treat many cancers including triple negative breast cancer, which is commonly observed in African-American women (AA), and tend to be more aggressive, carry worse prognoses, and are harder to manage because they lack molecular targets. Although effective, anthra...

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Autores principales: Miles, Jana S., Sojourner, Samantha J., Whitmore, Aurellia M., Freeny, Devon, Darling-Reed, Selina, Flores-Rozas, Hernan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998155/
https://www.ncbi.nlm.nih.gov/pubmed/30003101
http://dx.doi.org/10.1155/2018/4938189
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author Miles, Jana S.
Sojourner, Samantha J.
Whitmore, Aurellia M.
Freeny, Devon
Darling-Reed, Selina
Flores-Rozas, Hernan
author_facet Miles, Jana S.
Sojourner, Samantha J.
Whitmore, Aurellia M.
Freeny, Devon
Darling-Reed, Selina
Flores-Rozas, Hernan
author_sort Miles, Jana S.
collection PubMed
description Anthracyclines are frequently used to treat many cancers including triple negative breast cancer, which is commonly observed in African-American women (AA), and tend to be more aggressive, carry worse prognoses, and are harder to manage because they lack molecular targets. Although effective, anthracyclines use can be limited by serious side effects and eventually the development of drug resistance. In S. cerevisiae, mutants of HOM6 display hypersensitivity to doxorubicin. HOM6 is required for synthesis of threonine and interruption of the pathway leads to accumulation of the threonine intermediate L-aspartate-semialdehyde. This intermediate may synergize with doxorubicin to kill the cell. In fact, deleting HOM3 in the first step, preventing the pathway to reach the HOM6 step, rescues the sensitivity of the hom6 strain to doxorubicin. Using several S. cerevisiae strains (wild type, hom6, hom3, hom3hom6, ydj1, siz1, and msh2), we determined their sensitivity to aldehydes and to their combination with doxorubicin, cisplatin, and etoposide. Combination of formaldehyde and doxorubicin was most effective at reducing cell survival by 31-fold–39-fold (in wild type cells) relative to doxorubicin and formaldehyde alone. This effect was dose dependent on doxorubicin. Cotreatment with formaldehyde and doxorubicin also showed increased toxicity in anthracycline-resistant strains siz1 and msh2. The hom6 mutant also showed sensitivity to menadione with a 2.5-fold reduction in cell survival. The potential use of a combination of aldehydes and cytotoxic drugs could potentially lead to applications intended to enhance anthracycline-based therapy.
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spelling pubmed-59981552018-07-12 Synergistic Effect of Endogenous and Exogenous Aldehydes on Doxorubicin Toxicity in Yeast Miles, Jana S. Sojourner, Samantha J. Whitmore, Aurellia M. Freeny, Devon Darling-Reed, Selina Flores-Rozas, Hernan Biomed Res Int Research Article Anthracyclines are frequently used to treat many cancers including triple negative breast cancer, which is commonly observed in African-American women (AA), and tend to be more aggressive, carry worse prognoses, and are harder to manage because they lack molecular targets. Although effective, anthracyclines use can be limited by serious side effects and eventually the development of drug resistance. In S. cerevisiae, mutants of HOM6 display hypersensitivity to doxorubicin. HOM6 is required for synthesis of threonine and interruption of the pathway leads to accumulation of the threonine intermediate L-aspartate-semialdehyde. This intermediate may synergize with doxorubicin to kill the cell. In fact, deleting HOM3 in the first step, preventing the pathway to reach the HOM6 step, rescues the sensitivity of the hom6 strain to doxorubicin. Using several S. cerevisiae strains (wild type, hom6, hom3, hom3hom6, ydj1, siz1, and msh2), we determined their sensitivity to aldehydes and to their combination with doxorubicin, cisplatin, and etoposide. Combination of formaldehyde and doxorubicin was most effective at reducing cell survival by 31-fold–39-fold (in wild type cells) relative to doxorubicin and formaldehyde alone. This effect was dose dependent on doxorubicin. Cotreatment with formaldehyde and doxorubicin also showed increased toxicity in anthracycline-resistant strains siz1 and msh2. The hom6 mutant also showed sensitivity to menadione with a 2.5-fold reduction in cell survival. The potential use of a combination of aldehydes and cytotoxic drugs could potentially lead to applications intended to enhance anthracycline-based therapy. Hindawi 2018-05-30 /pmc/articles/PMC5998155/ /pubmed/30003101 http://dx.doi.org/10.1155/2018/4938189 Text en Copyright © 2018 Jana S. Miles et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Miles, Jana S.
Sojourner, Samantha J.
Whitmore, Aurellia M.
Freeny, Devon
Darling-Reed, Selina
Flores-Rozas, Hernan
Synergistic Effect of Endogenous and Exogenous Aldehydes on Doxorubicin Toxicity in Yeast
title Synergistic Effect of Endogenous and Exogenous Aldehydes on Doxorubicin Toxicity in Yeast
title_full Synergistic Effect of Endogenous and Exogenous Aldehydes on Doxorubicin Toxicity in Yeast
title_fullStr Synergistic Effect of Endogenous and Exogenous Aldehydes on Doxorubicin Toxicity in Yeast
title_full_unstemmed Synergistic Effect of Endogenous and Exogenous Aldehydes on Doxorubicin Toxicity in Yeast
title_short Synergistic Effect of Endogenous and Exogenous Aldehydes on Doxorubicin Toxicity in Yeast
title_sort synergistic effect of endogenous and exogenous aldehydes on doxorubicin toxicity in yeast
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998155/
https://www.ncbi.nlm.nih.gov/pubmed/30003101
http://dx.doi.org/10.1155/2018/4938189
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