Anticancer Properties of the Antipsychotic Drug Chlorpromazine and Its Synergism With Temozolomide in Restraining Human Glioblastoma Proliferation In Vitro.

Silvia Matteoni,Lucia Ricci-Vitiani,Barbara Ascione,Mariachiara Buccarelli,Andrea Pace,Roberto Pallini,Veronica Villani,Marco G Paggi,Paola Matarrese,Claudia Abbruzzese

doi:10.3389/fonc.2021.635472

Abstract

The extremely poor prognosis of patients affected by glioblastoma (GBM, grade IV glioma) prompts the search for new and more effective therapies. In this regard, drug repurposing or repositioning can represent a safe, swift, and inexpensive way to bring novel pharmacological approaches from bench to bedside. Chlorpromazine, a medication used since six decades for the therapy of psychiatric disorders, shows in vitro several features that make it eligible for repositioning in cancer therapy. Using six GBM cell lines, three of which growing as patient-derived neurospheres and displaying stem-like properties, we found that chlorpromazine was able to inhibit viability in an apoptosis-independent way, induce hyperdiploidy, reduce cloning efficiency as well as neurosphere formation and downregulate the expression of stemness genes in all these cell lines. Notably, chlorpromazine synergized with temozolomide, the first-line therapeutic in GBM patients, in hindering GBM cell viability, and both drugs strongly cooperated in reducing cloning efficiency and inducing cell death in vitro for all the GBM cell lines assayed. These results prompted us to start a Phase II clinical trial on GBM patients (EudraCT # 2019-001988-75; ClinicalTrials.gov Identifier: NCT04224441) by adding chlorpromazine to temozolomide in the adjuvant phase of the standard first-line therapeutic protocol.

Highlights

Glioblastoma (GBM, glioblastoma multiforme) is the most frequent and severe adult malignant brain tumor
The current therapeutic protocol for newly diagnosed GBM results in suboptimal clinical outcomes. In this urgent need for novel therapeutic strategies, scientifically supported drug repurposing represents an appealing alternative, since it involves the use of compounds with shorter development timelines and lower risks for the patients, allowing faster and less expensive delivery from bench to bedside of potentially effective drugs
We confirm the ability of CPZ in restraining key cancer cell features, adding further information concerning the effect of the drug on six human GBM cell lines, either anchorage-dependent or patient-derived neurospheres

Summary

Introduction

Glioblastoma (GBM, glioblastoma multiforme) is the most frequent and severe adult malignant brain tumor. GBM’s highly aggressive, chemo-resistant and relapse-prone behavior is mainly attributed to its intra-tumor molecular heterogeneity associated with unpredictable genetic drift under therapeutic pressure [2]. Such an adverse scenario prompts for the identification of novel therapeutic approaches even by using repurposed/repositioned drugs that, when supported by robust evidence, represent an attracting alternative to novel drugs, being safer, less expensive, and characterized by a shorter timeframe from laboratory to the clinics. We focused our attention on chlorpromazine (CPZ, Largactil, Thorazine), the first member of the tricyclic drugs phenothiazines, a medication used since six decades in the treatment of psychiatric disorders This molecule acts as an antagonist of the brain dopamine receptor D2 (DRD2), decreasing post-synaptic dopamine stimulating activity [3, 4]. Epidemiological data suggest a reduction of cancer risk in psychiatric patients treated with CPZ or related antipsychotic compounds [16, 17], and anecdotal reports of favorable GBM evolution in psychiatric patients treated with neuroleptic medications have been published [16, 18]

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