Cargando…
Chemically Modified Variants of Fenofibrate with Antiglioblastoma Potential()()
Anticancer effects of a common lipid-lowering drug, fenofibrate, have been described in the literature for a quite some time; however, fenofibrate has not been used as a direct anticancer therapy. We have previously reported that fenofibrate in its unprocessed form (ester) accumulates in the mitocho...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Neoplasia Press
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514324/ https://www.ncbi.nlm.nih.gov/pubmed/31078963 http://dx.doi.org/10.1016/j.tranon.2019.04.006 |
_version_ | 1783417868415664128 |
---|---|
author | Stalinska, J. Zimolag, E. Pianovich, NA. Zapata, A. Lassak, A. Rak, M. Dean, M. Ucar-Bilyeu, D. Wyczechowska, D. Culicchia, F. Marrero, L. Del Valle, L. Sarkaria, J. Peruzzi, F. Jursic, BS Reiss, K. |
author_facet | Stalinska, J. Zimolag, E. Pianovich, NA. Zapata, A. Lassak, A. Rak, M. Dean, M. Ucar-Bilyeu, D. Wyczechowska, D. Culicchia, F. Marrero, L. Del Valle, L. Sarkaria, J. Peruzzi, F. Jursic, BS Reiss, K. |
author_sort | Stalinska, J. |
collection | PubMed |
description | Anticancer effects of a common lipid-lowering drug, fenofibrate, have been described in the literature for a quite some time; however, fenofibrate has not been used as a direct anticancer therapy. We have previously reported that fenofibrate in its unprocessed form (ester) accumulates in the mitochondria, inhibits mitochondrial respiration, and triggers a severe energy deficit and extensive glioblastoma cell death. However, fenofibrate does not cross the blood brain barrier and is quickly processed by blood and tissue esterases to form the PPARα agonist fenofibric acid, which is practically ineffective effective in triggering cancer cell death. To address these issues, we have made several chemical modifications in fenofibrate structure to increase its stability, water solubility, tissue penetration, and ultimately anticancer potential. Our data show that, in comparison to fenofibrate, four new compounds designated here as PP1, PP2, PP3, and PP4 have improved anticancer activity in vitro. Like fenofibrate, the compounds block mitochondrial respiration and trigger massive glioblastoma cell death in vitro. In addition, one of the lead compounds, PP1, has improved water solubility and is significantly more stable when exposed to human blood in comparison to fenofibrate. Importantly, mice bearing large intracranial glioblastoma tumors demonstrated extensive areas of tumor cell death within the tumor mass following oral administration of PP1, and the treated mice did not show any major signs of distress, and accumulated PP1 at therapeutically relevant concentrations in several tissues, including brain and intracranial tumors. |
format | Online Article Text |
id | pubmed-6514324 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Neoplasia Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-65143242019-05-21 Chemically Modified Variants of Fenofibrate with Antiglioblastoma Potential()() Stalinska, J. Zimolag, E. Pianovich, NA. Zapata, A. Lassak, A. Rak, M. Dean, M. Ucar-Bilyeu, D. Wyczechowska, D. Culicchia, F. Marrero, L. Del Valle, L. Sarkaria, J. Peruzzi, F. Jursic, BS Reiss, K. Transl Oncol Original article Anticancer effects of a common lipid-lowering drug, fenofibrate, have been described in the literature for a quite some time; however, fenofibrate has not been used as a direct anticancer therapy. We have previously reported that fenofibrate in its unprocessed form (ester) accumulates in the mitochondria, inhibits mitochondrial respiration, and triggers a severe energy deficit and extensive glioblastoma cell death. However, fenofibrate does not cross the blood brain barrier and is quickly processed by blood and tissue esterases to form the PPARα agonist fenofibric acid, which is practically ineffective effective in triggering cancer cell death. To address these issues, we have made several chemical modifications in fenofibrate structure to increase its stability, water solubility, tissue penetration, and ultimately anticancer potential. Our data show that, in comparison to fenofibrate, four new compounds designated here as PP1, PP2, PP3, and PP4 have improved anticancer activity in vitro. Like fenofibrate, the compounds block mitochondrial respiration and trigger massive glioblastoma cell death in vitro. In addition, one of the lead compounds, PP1, has improved water solubility and is significantly more stable when exposed to human blood in comparison to fenofibrate. Importantly, mice bearing large intracranial glioblastoma tumors demonstrated extensive areas of tumor cell death within the tumor mass following oral administration of PP1, and the treated mice did not show any major signs of distress, and accumulated PP1 at therapeutically relevant concentrations in several tissues, including brain and intracranial tumors. Neoplasia Press 2019-05-09 /pmc/articles/PMC6514324/ /pubmed/31078963 http://dx.doi.org/10.1016/j.tranon.2019.04.006 Text en © 2019 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original article Stalinska, J. Zimolag, E. Pianovich, NA. Zapata, A. Lassak, A. Rak, M. Dean, M. Ucar-Bilyeu, D. Wyczechowska, D. Culicchia, F. Marrero, L. Del Valle, L. Sarkaria, J. Peruzzi, F. Jursic, BS Reiss, K. Chemically Modified Variants of Fenofibrate with Antiglioblastoma Potential()() |
title | Chemically Modified Variants of Fenofibrate with Antiglioblastoma Potential()() |
title_full | Chemically Modified Variants of Fenofibrate with Antiglioblastoma Potential()() |
title_fullStr | Chemically Modified Variants of Fenofibrate with Antiglioblastoma Potential()() |
title_full_unstemmed | Chemically Modified Variants of Fenofibrate with Antiglioblastoma Potential()() |
title_short | Chemically Modified Variants of Fenofibrate with Antiglioblastoma Potential()() |
title_sort | chemically modified variants of fenofibrate with antiglioblastoma potential()() |
topic | Original article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514324/ https://www.ncbi.nlm.nih.gov/pubmed/31078963 http://dx.doi.org/10.1016/j.tranon.2019.04.006 |
work_keys_str_mv | AT stalinskaj chemicallymodifiedvariantsoffenofibratewithantiglioblastomapotential AT zimolage chemicallymodifiedvariantsoffenofibratewithantiglioblastomapotential AT pianovichna chemicallymodifiedvariantsoffenofibratewithantiglioblastomapotential AT zapataa chemicallymodifiedvariantsoffenofibratewithantiglioblastomapotential AT lassaka chemicallymodifiedvariantsoffenofibratewithantiglioblastomapotential AT rakm chemicallymodifiedvariantsoffenofibratewithantiglioblastomapotential AT deanm chemicallymodifiedvariantsoffenofibratewithantiglioblastomapotential AT ucarbilyeud chemicallymodifiedvariantsoffenofibratewithantiglioblastomapotential AT wyczechowskad chemicallymodifiedvariantsoffenofibratewithantiglioblastomapotential AT culicchiaf chemicallymodifiedvariantsoffenofibratewithantiglioblastomapotential AT marrerol chemicallymodifiedvariantsoffenofibratewithantiglioblastomapotential AT delvallel chemicallymodifiedvariantsoffenofibratewithantiglioblastomapotential AT sarkariaj chemicallymodifiedvariantsoffenofibratewithantiglioblastomapotential AT peruzzif chemicallymodifiedvariantsoffenofibratewithantiglioblastomapotential AT jursicbs chemicallymodifiedvariantsoffenofibratewithantiglioblastomapotential AT reissk chemicallymodifiedvariantsoffenofibratewithantiglioblastomapotential |