Repurposing chlorpromazine in the treatment of glioblastoma multiforme: analysis of literature and forthcoming steps

Abstract

Background: Glioblastoma multiforme is a CNS cancer characterized by diffuse infiltrative growth, aggressive clinical behavior and very poor prognosis. The state-of-art clinical approach to this disease consists of surgical resection followed by radiotherapy plus concurrent and adjuvant chemotherapy with temozolomide. Tumor recurrence occurs in virtually all cases, therefore, despite any treatment, the median survival is very low (14.6 months), which makes the approach to these patients a challenging clinical issue. Main body: The escalating costs and times required for new medications to reach the bedside make repurposing or repositioning of old drugs, when scientific bases allow their use in other pathologies, an appealing strategy.Here, we analyze a number of literature data concerning the antipsychotic chlorpromazine, the founder of the phenothiazines class of drugs, a medication widely used in the clinics for approximately 60 years. The drug exerts its effects on psychiatric patients by interfering with the dopamine receptor D 2 , although more recent pharmacodynamics studies ascribe chlorpromazine a series of biological effects on cancer cells, all converging in hindering also glioblastoma survival capabilities.Short conclusions: On these bases, and assisted by the information on the well-established chlorpromazine toxicity and dosage in humans, we designed a Phase II clinical trial involving the combination of chlorpromazine with the standard treatment, temozolomide, in the adjuvant phase of the therapeutic protocol. Patients displaying hypo-methylation of the MGMT gene, and thus intrinsically resistant to temozolomide, will be enrolled. The endpoints of this study are the analysis of toxicity and clinical activity, as evaluated in terms of Progression-Free Survival, of the association of chlorpromazine with the first-line treatment for this very serious form of cancer.

Head-to-Head Comparison of Sedation and Somnolence Among 37 Antipsychotics in Schizophrenia, Bipolar Disorder, Major Depression, Autism Spectrum Disorders, Delirium, and Repurposed in COVID-19, Infectious Diseases, and Oncology From the FAERS, 2004–2020

“…Researchers in France reported that chlorpromazine, a derivative of methylene blue, inhibits SARS-CoV-2 in vitro and other studies have shown clinical benefit of chlorpromazine in the most invasive glial tumor, the grade IV astrocytoma, glioblastoma multiforme ( Amaral et al, 2004 ; Kamarudin and Parhar, 2019 ; Abbruzzese et al, 2020 ; Plaze et al, 2020 ). Methylene blue, the first synthetic compound in medicine has antimalarial properties, anti-SARS-Cov-2 properties, and a recent study reported the compound to be neuroprotective ( López-Muñoz et al, 2005 ; Poteet et al, 2012 ; Gendrot et al, 2020 ).…”

Chlorpromazine Sensitizes Progestin-Resistant Endometrial Cancer Cells to MPA by Upregulating PRB

“…Repurposing CPZ exhibited much advantage in various cancers including glioblastoma, lung cancer, colon cancer and breast cancer (18)(19)(20). There were no relevant studies of CPZ in endometrial cancer at present.…”

“…CPZ was well-known as an antagonist of dopamine receptor D2(DRD2) (18). It was reported that dopamine acting through DRD2, down regulated insulin-like growth factor-1 (IGF-1) and AKT phosphorylation, thereby inhibited gastric cancer proliferation (33).…”

“…Given that CPZ has come into clinical use since the 1950s, all the data concerning its pharmacology and toxicology as a single drug are well established. Such knowledge enables us to bypass the Phase I clinical investigation and proceed directly to a Phase II clinical investigation (18,36), which could save time and cost to a large extent. In conclusion, CPZ may represent a suitable therapeutic option for patients with EC.…”

“…Given that a lower dosage of CPZ could play an effective anti-EC effect, CPZ was expected to decrease toxic side effects. Furthermore, CPZ could suppressed various cancers including glioblastoma, lung cancer, colon cancer and breast cancer (18)(19)(20). Therefore, we evaluated the possibility of reproposing CPZ in both progestin sensitive and resistant endometrial cancer in the present study.…”