Targeting the cellular schizophrenia. Likely employment of the antipsychotic agent pimozide in treatment of refractory cancers and glioblastoma

Crit Rev Oncol Hematol. 2018 Aug;128:96-109. doi: 10.1016/j.critrevonc.2018.06.004. Epub 2018 Jun 11.

Abstract

Pimozide is currently being used in clinic as a neuroleptic and exerts versatile biological actions. Pimozide is a cationic amphiphilic drug (CAD); CADs block the synthesis of neutral lipids, impair cholesterol homeostasis of cancer cells and increase accumulation of diacylglycerol-3-phosphate. Pimozide exerts tumoricidal activity which was first shown for melanoma and neuroblastoma via proposed anti- dopaminergic effects. Recently, pancreas cancers are shown to elevate dopamine receptor-2 synthesis, which is blocked by pimozide leading growth inhibition. Besides binding to inner mitochondrial membrane and reducing cellular respiration, pimozide also inhibits calmodulin, T-type calcium channels and σ-receptors which all correlate with tumor-inhibitory functions. Pimozide also exerts chemotherapy and radiotherapy-sensitizing effects in cancer cells and acts as an inhibitor of STAT-3 and STAT-5 signaling proteins with potential activity in leukemia, liver and prostate cancer. Pimozide also blocks stem cell features and Wnt-β/catenin signaling in liver cancer. Pimozide interferes with Fatty Acid Protein Binding-4 and activates PPAR-γ and it was proposed to alleviate cancer cachexia. Besides mechanisms of calmodulin and σ-receptor associated pathways, pimozide was proposed to inhibit glioblastoma via serotonin receptor 5-HT7. Pimozide is a selective inducer of autophagy and also inhibits ubiquitine specific protease (USP-1) which may associate with its chemosensizing potential in lung cancer and glioblastoma. Via versatile mechanisms of tumoricidal actions and due to its highly traversing capability through the blood-brain barrier, pimozide highly deserves to be studied in animal models of drug resistant refractory cancers and glioblastoma, which have very poor prognosis.

Keywords: Glioblastoma; Pimozide; Refractory cancers.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Antipsychotic Agents / therapeutic use*
  • Drug Resistance, Neoplasm / drug effects*
  • Glioblastoma / drug therapy*
  • Humans
  • Neoplasms / drug therapy*
  • Pimozide / therapeutic use*
  • Schizophrenia / drug therapy*
  • Signal Transduction / drug effects

Substances

  • Antineoplastic Agents
  • Antipsychotic Agents
  • Pimozide