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Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in Apc(Min/+) mice

Cancer cachexia is a complex wasting condition characterized by chronic inflammation, disrupted energy metabolism, and severe muscle wasting. While evidence in pre-clinical cancer cachexia models have determined that different systemic inflammatory inhibitors can attenuate several characteristics of...

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Autores principales: Narsale, Aditi A., Puppa, Melissa J., Hardee, Justin P., VanderVeen, Brandon N., Enos, Reilly T., Murphy, E. Angela, Carson, James A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312326/
https://www.ncbi.nlm.nih.gov/pubmed/27449092
http://dx.doi.org/10.18632/oncotarget.10699
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author Narsale, Aditi A.
Puppa, Melissa J.
Hardee, Justin P.
VanderVeen, Brandon N.
Enos, Reilly T.
Murphy, E. Angela
Carson, James A.
author_facet Narsale, Aditi A.
Puppa, Melissa J.
Hardee, Justin P.
VanderVeen, Brandon N.
Enos, Reilly T.
Murphy, E. Angela
Carson, James A.
author_sort Narsale, Aditi A.
collection PubMed
description Cancer cachexia is a complex wasting condition characterized by chronic inflammation, disrupted energy metabolism, and severe muscle wasting. While evidence in pre-clinical cancer cachexia models have determined that different systemic inflammatory inhibitors can attenuate several characteristics of cachexia, there is a limited understanding of their effects after cachexia has developed, and whether short-term administration is sufficient to reverse cachexia-induced signaling in distinctive target tissues. Pyrrolidine dithiocarbamate (PDTC) is a thiol compound having anti-inflammatory and antioxidant properties which can inhibit STAT3 and nuclear factor κB (NF-κB) signaling in mice. This study examined the effect of short-term PDTC administration to Apc(Min/+) mice on cachexia-induced disruption of skeletal muscle protein turnover and liver metabolic function. At 16 weeks of age Apc(Min/+) mice initiating cachexia (7% BW loss) were administered PDTC (10mg/kg bw/d) for 2 weeks. Control Apc(Min/+) mice continued to lose body weight during the treatment period, while mice receiving PDTC had no further body weight decrease. PDTC had no effect on either intestinal tumor burden or circulating IL-6. In muscle, PDTC rescued signaling disrupting protein turnover regulation. PDTC suppressed the cachexia induction of STAT3, increased mTORC1 signaling and protein synthesis, and suppressed the induction of Atrogin-1 protein expression. Related to cachectic liver metabolic function, PDTC treatment attenuated glycogen and lipid content depletion independent to the activation of STAT3 and mTORC1 signaling. Overall, these results demonstrate short-term PDTC treatment to cachectic mice attenuated cancer-induced disruptions to muscle and liver signaling, and these changes were independent to altered tumor burden and circulating IL-6.
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spelling pubmed-53123262017-03-06 Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in Apc(Min/+) mice Narsale, Aditi A. Puppa, Melissa J. Hardee, Justin P. VanderVeen, Brandon N. Enos, Reilly T. Murphy, E. Angela Carson, James A. Oncotarget Research Paper Cancer cachexia is a complex wasting condition characterized by chronic inflammation, disrupted energy metabolism, and severe muscle wasting. While evidence in pre-clinical cancer cachexia models have determined that different systemic inflammatory inhibitors can attenuate several characteristics of cachexia, there is a limited understanding of their effects after cachexia has developed, and whether short-term administration is sufficient to reverse cachexia-induced signaling in distinctive target tissues. Pyrrolidine dithiocarbamate (PDTC) is a thiol compound having anti-inflammatory and antioxidant properties which can inhibit STAT3 and nuclear factor κB (NF-κB) signaling in mice. This study examined the effect of short-term PDTC administration to Apc(Min/+) mice on cachexia-induced disruption of skeletal muscle protein turnover and liver metabolic function. At 16 weeks of age Apc(Min/+) mice initiating cachexia (7% BW loss) were administered PDTC (10mg/kg bw/d) for 2 weeks. Control Apc(Min/+) mice continued to lose body weight during the treatment period, while mice receiving PDTC had no further body weight decrease. PDTC had no effect on either intestinal tumor burden or circulating IL-6. In muscle, PDTC rescued signaling disrupting protein turnover regulation. PDTC suppressed the cachexia induction of STAT3, increased mTORC1 signaling and protein synthesis, and suppressed the induction of Atrogin-1 protein expression. Related to cachectic liver metabolic function, PDTC treatment attenuated glycogen and lipid content depletion independent to the activation of STAT3 and mTORC1 signaling. Overall, these results demonstrate short-term PDTC treatment to cachectic mice attenuated cancer-induced disruptions to muscle and liver signaling, and these changes were independent to altered tumor burden and circulating IL-6. Impact Journals LLC 2016-07-19 /pmc/articles/PMC5312326/ /pubmed/27449092 http://dx.doi.org/10.18632/oncotarget.10699 Text en Copyright: © 2016 Narsale et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Narsale, Aditi A.
Puppa, Melissa J.
Hardee, Justin P.
VanderVeen, Brandon N.
Enos, Reilly T.
Murphy, E. Angela
Carson, James A.
Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in Apc(Min/+) mice
title Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in Apc(Min/+) mice
title_full Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in Apc(Min/+) mice
title_fullStr Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in Apc(Min/+) mice
title_full_unstemmed Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in Apc(Min/+) mice
title_short Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in Apc(Min/+) mice
title_sort short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in apc(min/+) mice
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312326/
https://www.ncbi.nlm.nih.gov/pubmed/27449092
http://dx.doi.org/10.18632/oncotarget.10699
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