Chlorpromazine induces cytotoxic autophagy in glioblastoma cells via endoplasmic reticulum stress and unfolded protein response

Abstract Background Glioblastoma (GBM; grade IV glioma) is characterized by a very short overall survival time and extremely low 5-year survival rates. We intend to promote experimental and clinical research on rationale and scientifically driven drug repurposing. This may represent a safe and often...

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Autores principales:	Silvia Matteoni, Paola Matarrese, Barbara Ascione, Lucia Ricci-Vitiani, Roberto Pallini, Veronica Villani, Andrea Pace, Marco G. Paggi, Claudia Abbruzzese
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Glioblastoma Drug repurposing Chlorpromazine Endoplasmic reticulum stress Unfolded protein response Autophagy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/ef489644ed8946898317b0ab7c989266
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spelling	oai:doaj.org-article:ef489644ed8946898317b0ab7c9892662021-11-08T10:44:46ZChlorpromazine induces cytotoxic autophagy in glioblastoma cells via endoplasmic reticulum stress and unfolded protein response10.1186/s13046-021-02144-w1756-9966https://doaj.org/article/ef489644ed8946898317b0ab7c9892662021-11-01T00:00:00Zhttps://doi.org/10.1186/s13046-021-02144-whttps://doaj.org/toc/1756-9966Abstract Background Glioblastoma (GBM; grade IV glioma) is characterized by a very short overall survival time and extremely low 5-year survival rates. We intend to promote experimental and clinical research on rationale and scientifically driven drug repurposing. This may represent a safe and often inexpensive way to propose novel pharmacological approaches to GBM. Our precedent work describes the role of chlorpromazine (CPZ) in hindering malignant features of GBM. Here, we investigate in greater detail the molecular mechanisms at the basis of the effect of CPZ on GBM cells. Methods We employed proteomics platforms, i.e., activity-based protein profiling plus mass spectrometry, to identify potential cellular targets of the drug. Then, by means of established molecular and cellular biology techniques, we assessed the effects of this drug on GBM cell metabolic and survival pathways. Results The experimental output indicated as putative targets of CPZ several of factors implicated in endoplasmic reticulum (ER) stress, with consequent unfolded protein response (UPR). Such a perturbation culminated in a noticeable reactive oxygen species generation and intense autophagic response that resulted in cytotoxic and abortive effects for six GBM cell lines, three of which growing as neurospheres, while it appeared cytoprotective for the RPE-1 human non-cancer neuro-ectodermal cell line. Conclusions This discrepancy could be central in explaining the lethal effects of the drug on GBM cells and the relatively scarce cytotoxicity toward normal tissues attributed to this compound. The data presented here offer support to the multicenter phase II clinical trial we have undertaken, which consists of the addition of CPZ to first-line treatment of GBM patients carrying a hypo- or un-methylated MGMT gene, i.e. those characterized by intrinsic resistance to temozolomide.Silvia MatteoniPaola MatarreseBarbara AscioneLucia Ricci-VitianiRoberto PalliniVeronica VillaniAndrea PaceMarco G. PaggiClaudia AbbruzzeseBMCarticleGlioblastomaDrug repurposingChlorpromazineEndoplasmic reticulum stressUnfolded protein responseAutophagyNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Glioblastoma Drug repurposing Chlorpromazine Endoplasmic reticulum stress Unfolded protein response Autophagy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Glioblastoma Drug repurposing Chlorpromazine Endoplasmic reticulum stress Unfolded protein response Autophagy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Silvia Matteoni Paola Matarrese Barbara Ascione Lucia Ricci-Vitiani Roberto Pallini Veronica Villani Andrea Pace Marco G. Paggi Claudia Abbruzzese Chlorpromazine induces cytotoxic autophagy in glioblastoma cells via endoplasmic reticulum stress and unfolded protein response
description	Abstract Background Glioblastoma (GBM; grade IV glioma) is characterized by a very short overall survival time and extremely low 5-year survival rates. We intend to promote experimental and clinical research on rationale and scientifically driven drug repurposing. This may represent a safe and often inexpensive way to propose novel pharmacological approaches to GBM. Our precedent work describes the role of chlorpromazine (CPZ) in hindering malignant features of GBM. Here, we investigate in greater detail the molecular mechanisms at the basis of the effect of CPZ on GBM cells. Methods We employed proteomics platforms, i.e., activity-based protein profiling plus mass spectrometry, to identify potential cellular targets of the drug. Then, by means of established molecular and cellular biology techniques, we assessed the effects of this drug on GBM cell metabolic and survival pathways. Results The experimental output indicated as putative targets of CPZ several of factors implicated in endoplasmic reticulum (ER) stress, with consequent unfolded protein response (UPR). Such a perturbation culminated in a noticeable reactive oxygen species generation and intense autophagic response that resulted in cytotoxic and abortive effects for six GBM cell lines, three of which growing as neurospheres, while it appeared cytoprotective for the RPE-1 human non-cancer neuro-ectodermal cell line. Conclusions This discrepancy could be central in explaining the lethal effects of the drug on GBM cells and the relatively scarce cytotoxicity toward normal tissues attributed to this compound. The data presented here offer support to the multicenter phase II clinical trial we have undertaken, which consists of the addition of CPZ to first-line treatment of GBM patients carrying a hypo- or un-methylated MGMT gene, i.e. those characterized by intrinsic resistance to temozolomide.
format	article
author	Silvia Matteoni Paola Matarrese Barbara Ascione Lucia Ricci-Vitiani Roberto Pallini Veronica Villani Andrea Pace Marco G. Paggi Claudia Abbruzzese
author_facet	Silvia Matteoni Paola Matarrese Barbara Ascione Lucia Ricci-Vitiani Roberto Pallini Veronica Villani Andrea Pace Marco G. Paggi Claudia Abbruzzese
author_sort	Silvia Matteoni
title	Chlorpromazine induces cytotoxic autophagy in glioblastoma cells via endoplasmic reticulum stress and unfolded protein response
title_short	Chlorpromazine induces cytotoxic autophagy in glioblastoma cells via endoplasmic reticulum stress and unfolded protein response
title_full	Chlorpromazine induces cytotoxic autophagy in glioblastoma cells via endoplasmic reticulum stress and unfolded protein response
title_fullStr	Chlorpromazine induces cytotoxic autophagy in glioblastoma cells via endoplasmic reticulum stress and unfolded protein response
title_full_unstemmed	Chlorpromazine induces cytotoxic autophagy in glioblastoma cells via endoplasmic reticulum stress and unfolded protein response
title_sort	chlorpromazine induces cytotoxic autophagy in glioblastoma cells via endoplasmic reticulum stress and unfolded protein response
publisher	BMC
publishDate	2021
url	https://doaj.org/article/ef489644ed8946898317b0ab7c989266
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Chlorpromazine induces cytotoxic autophagy in glioblastoma cells via endoplasmic reticulum stress and unfolded protein response

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