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

Journal of Experimental & Clinical Cancer Research

Silvia Matteoni¹  Marco G. Paggi¹  Claudia Abbruzzese¹  Lucia Ricci-Vitiani²  Barbara Ascione³  Paola Matarrese³  Roberto Pallini⁴  Andrea Pace⁵  Veronica Villani⁵ 

[1] Cellular Networks and Molecular Therapeutic Targets, Proteomics Unit, IRCCS - Regina Elena National Cancer Institute, 00144, Rome, Italy;Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161, Rome, Italy;Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, 00161, Rome, Italy;Institute of Neurosurgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University School of Medicine, 00168, Rome, Italy;Neuro-Oncology, IRCCS - Regina Elena National Cancer Institute, 00144, Rome, Italy;

关键词: Glioblastoma;    Drug repurposing;    Chlorpromazine;    Endoplasmic reticulum stress;    Unfolded protein response;    Autophagy;    Mitotic catastrophe;    Cell death;   

DOI  :  10.1186/s13046-021-02144-w

来源: Springer

【 摘 要 】

BackgroundGlioblastoma (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.MethodsWe 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.ResultsThe 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.ConclusionsThis 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.

【 授权许可】

CC BY