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In Vivo Activity and Pharmacokinetics of Nemorosone on Pancreatic Cancer Xenografts
Pancreatic cancer is one of the leading cancer-related causes of death in the western world with an urgent need for new treatment strategies. Recently, hyperforin and nemorosone have been described as promising anti-cancer lead compounds. While hyperforin has been thoroughly investigated in vitro an...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3764110/ https://www.ncbi.nlm.nih.gov/pubmed/24040280 http://dx.doi.org/10.1371/journal.pone.0074555 |
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author | Wolf, Robert J. Hilger, Ralf A. Hoheisel, Jörg D. Werner, Jens Holtrup, Frank |
author_facet | Wolf, Robert J. Hilger, Ralf A. Hoheisel, Jörg D. Werner, Jens Holtrup, Frank |
author_sort | Wolf, Robert J. |
collection | PubMed |
description | Pancreatic cancer is one of the leading cancer-related causes of death in the western world with an urgent need for new treatment strategies. Recently, hyperforin and nemorosone have been described as promising anti-cancer lead compounds. While hyperforin has been thoroughly investigated in vitro and in vivo, in vivo data for nemorosone are still missing. Thus, we investigated the growth-inhibitory potential of nemorosone on pancreatic cancer xenografts in NMRI nu/nu mice and determined basic pharmacokinetic parameters. Xenograft tumors were treated with nemorosone and gemcitabine, the current standard of care. Tumor sections were subjected to H&E as well as caspase 3 and Ki-67 staining. Nemorosone plasma kinetics were determined by HPLC and mass spectrometry. Induction of CYP3A4 and other metabolizing enzymes by nemorosone and hyperforin was tested on primary hepatocytes using qRT-PCR. At a dose of 50 mg/kg nemorosone per day, a significant growth-inhibitory effect was observed in pancreatic cancer xenografts. The compound was well tolerated and rapidly absorbed into the bloodstream with a half-life of approximately 30 min. Different metabolites were detected, possibly resembling CYP3A4-independent oxidation products. It is concluded that nemorosone is a potential anti-cancer lead compound with good bioavailability, little side-effects and promising growth-inhibitory effects, thus representing a valuable compound for a combination therapy approach. |
format | Online Article Text |
id | pubmed-3764110 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-37641102013-09-13 In Vivo Activity and Pharmacokinetics of Nemorosone on Pancreatic Cancer Xenografts Wolf, Robert J. Hilger, Ralf A. Hoheisel, Jörg D. Werner, Jens Holtrup, Frank PLoS One Research Article Pancreatic cancer is one of the leading cancer-related causes of death in the western world with an urgent need for new treatment strategies. Recently, hyperforin and nemorosone have been described as promising anti-cancer lead compounds. While hyperforin has been thoroughly investigated in vitro and in vivo, in vivo data for nemorosone are still missing. Thus, we investigated the growth-inhibitory potential of nemorosone on pancreatic cancer xenografts in NMRI nu/nu mice and determined basic pharmacokinetic parameters. Xenograft tumors were treated with nemorosone and gemcitabine, the current standard of care. Tumor sections were subjected to H&E as well as caspase 3 and Ki-67 staining. Nemorosone plasma kinetics were determined by HPLC and mass spectrometry. Induction of CYP3A4 and other metabolizing enzymes by nemorosone and hyperforin was tested on primary hepatocytes using qRT-PCR. At a dose of 50 mg/kg nemorosone per day, a significant growth-inhibitory effect was observed in pancreatic cancer xenografts. The compound was well tolerated and rapidly absorbed into the bloodstream with a half-life of approximately 30 min. Different metabolites were detected, possibly resembling CYP3A4-independent oxidation products. It is concluded that nemorosone is a potential anti-cancer lead compound with good bioavailability, little side-effects and promising growth-inhibitory effects, thus representing a valuable compound for a combination therapy approach. Public Library of Science 2013-09-05 /pmc/articles/PMC3764110/ /pubmed/24040280 http://dx.doi.org/10.1371/journal.pone.0074555 Text en © 2013 Wolf et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited. |
spellingShingle | Research Article Wolf, Robert J. Hilger, Ralf A. Hoheisel, Jörg D. Werner, Jens Holtrup, Frank In Vivo Activity and Pharmacokinetics of Nemorosone on Pancreatic Cancer Xenografts |
title |
In Vivo Activity and Pharmacokinetics of Nemorosone on Pancreatic Cancer Xenografts |
title_full |
In Vivo Activity and Pharmacokinetics of Nemorosone on Pancreatic Cancer Xenografts |
title_fullStr |
In Vivo Activity and Pharmacokinetics of Nemorosone on Pancreatic Cancer Xenografts |
title_full_unstemmed |
In Vivo Activity and Pharmacokinetics of Nemorosone on Pancreatic Cancer Xenografts |
title_short |
In Vivo Activity and Pharmacokinetics of Nemorosone on Pancreatic Cancer Xenografts |
title_sort | in vivo activity and pharmacokinetics of nemorosone on pancreatic cancer xenografts |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3764110/ https://www.ncbi.nlm.nih.gov/pubmed/24040280 http://dx.doi.org/10.1371/journal.pone.0074555 |
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