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Temozolomide, sirolimus and chloroquine is a new therapeutic combination that synergizes to disrupt lysosomal function and cholesterol homeostasis in GBM cells

Glioblastoma (GBM) cells are characterized by high phagocytosis, lipogenesis, exocytosis activities, low autophagy capacity and high lysosomal demand are necessary for survival and invasion. The lysosome stands at the cross roads of lipid biosynthesis, transporting, sorting between exogenous and end...

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Autores principales: Hsu, Sanford P.C., Kuo, John S., Chiang, Hsin-Chien, Wang, Hsin-Ell, Wang, Yu-Shan, Huang, Cheng-Chung, Huang, Yi-Chun, Chi, Mau-Shin, Mehta, Minesh P., Chi, Kwan-Hwa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805523/
https://www.ncbi.nlm.nih.gov/pubmed/29467937
http://dx.doi.org/10.18632/oncotarget.23855
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author Hsu, Sanford P.C.
Kuo, John S.
Chiang, Hsin-Chien
Wang, Hsin-Ell
Wang, Yu-Shan
Huang, Cheng-Chung
Huang, Yi-Chun
Chi, Mau-Shin
Mehta, Minesh P.
Chi, Kwan-Hwa
author_facet Hsu, Sanford P.C.
Kuo, John S.
Chiang, Hsin-Chien
Wang, Hsin-Ell
Wang, Yu-Shan
Huang, Cheng-Chung
Huang, Yi-Chun
Chi, Mau-Shin
Mehta, Minesh P.
Chi, Kwan-Hwa
author_sort Hsu, Sanford P.C.
collection PubMed
description Glioblastoma (GBM) cells are characterized by high phagocytosis, lipogenesis, exocytosis activities, low autophagy capacity and high lysosomal demand are necessary for survival and invasion. The lysosome stands at the cross roads of lipid biosynthesis, transporting, sorting between exogenous and endogenous cholesterol. We hypothesized that three already approved drugs, the autophagy inducer, sirolimus (rapamycin, Rapa), the autophagy inhibitor, chloroquine (CQ), and DNA alkylating chemotherapy, temozolomide (TMZ) could synergize against GBM. This repurposed triple therapy combination induced GBM apoptosis in vitro and inhibited GBM xenograft growth in vivo. Cytotoxicity is caused by induction of lysosomal membrane permeabilization and release of hydrolases, and may be rescued by cholesterol supplementation. Triple treatment inhibits lysosomal function, prevents cholesterol extraction from low density lipoprotein (LDL), and causes clumping of lysosome associated membrane protein-1 (LAMP-1) and lipid droplets (LD) accumulation. Co-treatment of the cell lines with inhibitor of caspases and cathepsin B only partially reverse of cytotoxicities, while N-acetyl cysteine (NAC) can be more effective. A combination of reactive oxygen species (ROS) generation from cholesterol depletion are the early event of underling mechanism. Cholesterol repletion abolished the ROS production and reversed the cytotoxicity from QRT treatment. The shortage of free cholesterol destabilizes lysosomal membranes converting aborted autophagy to apoptosis through either direct mitochondria damage or cathepsin B release. This promising anti-GBM triple therapy combination severely decreases mitochondrial function, induces lysosome-dependent apoptotic cell death, and is now poised for further clinical testing and validation.
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spelling pubmed-58055232018-02-21 Temozolomide, sirolimus and chloroquine is a new therapeutic combination that synergizes to disrupt lysosomal function and cholesterol homeostasis in GBM cells Hsu, Sanford P.C. Kuo, John S. Chiang, Hsin-Chien Wang, Hsin-Ell Wang, Yu-Shan Huang, Cheng-Chung Huang, Yi-Chun Chi, Mau-Shin Mehta, Minesh P. Chi, Kwan-Hwa Oncotarget Research Paper Glioblastoma (GBM) cells are characterized by high phagocytosis, lipogenesis, exocytosis activities, low autophagy capacity and high lysosomal demand are necessary for survival and invasion. The lysosome stands at the cross roads of lipid biosynthesis, transporting, sorting between exogenous and endogenous cholesterol. We hypothesized that three already approved drugs, the autophagy inducer, sirolimus (rapamycin, Rapa), the autophagy inhibitor, chloroquine (CQ), and DNA alkylating chemotherapy, temozolomide (TMZ) could synergize against GBM. This repurposed triple therapy combination induced GBM apoptosis in vitro and inhibited GBM xenograft growth in vivo. Cytotoxicity is caused by induction of lysosomal membrane permeabilization and release of hydrolases, and may be rescued by cholesterol supplementation. Triple treatment inhibits lysosomal function, prevents cholesterol extraction from low density lipoprotein (LDL), and causes clumping of lysosome associated membrane protein-1 (LAMP-1) and lipid droplets (LD) accumulation. Co-treatment of the cell lines with inhibitor of caspases and cathepsin B only partially reverse of cytotoxicities, while N-acetyl cysteine (NAC) can be more effective. A combination of reactive oxygen species (ROS) generation from cholesterol depletion are the early event of underling mechanism. Cholesterol repletion abolished the ROS production and reversed the cytotoxicity from QRT treatment. The shortage of free cholesterol destabilizes lysosomal membranes converting aborted autophagy to apoptosis through either direct mitochondria damage or cathepsin B release. This promising anti-GBM triple therapy combination severely decreases mitochondrial function, induces lysosome-dependent apoptotic cell death, and is now poised for further clinical testing and validation. Impact Journals LLC 2018-01-03 /pmc/articles/PMC5805523/ /pubmed/29467937 http://dx.doi.org/10.18632/oncotarget.23855 Text en Copyright: © 2018 Hsu et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Hsu, Sanford P.C.
Kuo, John S.
Chiang, Hsin-Chien
Wang, Hsin-Ell
Wang, Yu-Shan
Huang, Cheng-Chung
Huang, Yi-Chun
Chi, Mau-Shin
Mehta, Minesh P.
Chi, Kwan-Hwa
Temozolomide, sirolimus and chloroquine is a new therapeutic combination that synergizes to disrupt lysosomal function and cholesterol homeostasis in GBM cells
title Temozolomide, sirolimus and chloroquine is a new therapeutic combination that synergizes to disrupt lysosomal function and cholesterol homeostasis in GBM cells
title_full Temozolomide, sirolimus and chloroquine is a new therapeutic combination that synergizes to disrupt lysosomal function and cholesterol homeostasis in GBM cells
title_fullStr Temozolomide, sirolimus and chloroquine is a new therapeutic combination that synergizes to disrupt lysosomal function and cholesterol homeostasis in GBM cells
title_full_unstemmed Temozolomide, sirolimus and chloroquine is a new therapeutic combination that synergizes to disrupt lysosomal function and cholesterol homeostasis in GBM cells
title_short Temozolomide, sirolimus and chloroquine is a new therapeutic combination that synergizes to disrupt lysosomal function and cholesterol homeostasis in GBM cells
title_sort temozolomide, sirolimus and chloroquine is a new therapeutic combination that synergizes to disrupt lysosomal function and cholesterol homeostasis in gbm cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805523/
https://www.ncbi.nlm.nih.gov/pubmed/29467937
http://dx.doi.org/10.18632/oncotarget.23855
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