Critical Reviews in Oncology / Hematology 128 (2018) 96–109 Contents lists available at ScienceDirect Critical Reviews in Oncology / Hematology journal homepage: www.elsevier.com/locate/critrevonc Targeting the cellular schizophrenia. Likely employment of the T antipsychotic agent pimozide in treatment of refractory cancers and glioblastoma ⁎ Ilhan Elmacia, Meric A. Altinozb,c, a Memorial University, Neuroacademy Group, Istanbul, Turkey b Neurooncology Branch, Neuroacademy Group, Istanbul, Turkey c Department of Psychiatry, Maastricht University, Holland, Turkey ARTICLE INFO ABSTRACT Keywords: Pimozide is currently being used in clinic as a neuroleptic and exerts versatile biological actions. Pimozide is a Pimozide cationic amphiphilic drug (CAD); CADs block the synthesis of neutral lipids, impair cholesterol homeostasis of Refractory cancers cancer cells and increase accumulation of diacylglycerol-3-phosphate. Pimozide exerts tumoricidal activity Glioblastoma 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. 1. Introduction. The cancer problem and targeting cancer with et al., 2017). Hence, there is an urgent need to develop novel innovative Neuroleptic/ antipsychotic drugs strategies to treat metastatic and chemorefractory cancers, cancers with a generally poor prognosis (eg. pancreas and lung cancers) and glio- Despite immense efforts to discover novel anticancer agents; in blastomas. Interestingly, many studies showed decreased risk of cancer 2012, about 14.1 million new cases of cancer occurred globally, causing in schizophrenia patients; and despite most of these patients smoke around 8.2 million deaths (World Cancer heavily, metaanalysis studies also found that the pooled overall cancer Report 2014. World Health Organization (WHO) 2014. pp. Chapter incidence rates for patients with schizophrenia did not parallel their 1.1; The top 10 causes of death Fact sheet No:310. WHO. 2014). The cancer risk factor exposure (Wiklund et al., 2010). Very noteworthy, a financial costs of cancer were estimated at $1.16 trillion US dollars per comprehensive in vivo screen of 297 central nervous system acting year as of 2010 (World Cancer Report 2014. WHO. 2014. pp. Chapter compounds revealed 6.7). Many agents were developed to block the growth of malignancies, that psychoactive agents were 18-fold more likely to exert anti- yet metastatic cancers are systemic diseases which remain manageable proliferative potential when compared with a random population of but incurable. Glioblastomas have the highest incidence among primary molecules (Wiklund et al., 2010). Many subsequent investigations on brain tumors, second only to meningioma with a very poor prognosis (a cancer cell lines confirmed that especially neuroleptic agents as a class 5-year survival rate of about 4% from the time of diagnosis) (Altinoz possesed cytotoxic potential. Tumoricidal actions occurred in a wide ⁎ Corresponding author at: Nurtepe Mh. Guven Sk. No:5, D:6 Kagithane, Istanbul, Turkey. E-mail address: [email protected] (M.A. Altinoz). https://doi.org/10.1016/j.critrevonc.2018.06.004 Received 20 February 2018; Received in revised form 16 May 2018; Accepted 6 June 2018 1040-8428/ © 2018 Elsevier B.V. All rights reserved. I. Elmaci, M.A. Altinoz Critical Reviews in Oncology / Hematology 128 (2018) 96–109 dopamine D2 receptor with a high affinity, which causes both adverse effects (eg. extrapyramidal) and therapeuticity against the positive symptoms of schizophrenia. But as will be suggested, pimozide seems also to act beneficial on negative symptoms of schizophrenia in contrast to other typical neuroleptics. The side effects of pimozide include akathisia, tardive dyskinesia, prolongation of the QT interval, and rarely, neuroleptic malignant syndrome (Zemrak and Kenna, 2008). Diphenylbutylpiperidine class neuroleptics (Fig. 3) including pi- mozide, fluspirilene, penfluridol, and clopimozide, exert structural si- milarity to verapamil-like Ca+2-channel antagonists and inhibit 3H-ni- trendipine binding with IC50 values of 13–30 nM (nitrendipine is a dihydropyridine class Ca+2-channel antagonist) (Gould et al., 1983). This inhibition involves receptors for the verapamil/prenylamine class of Ca+2-channel antagonists. These diphenylbutylpiperidines also in- hibit K+-induced Ca+2-dependent contractions of rat vas deferens at concentrations of 40–350 nM. Other phenothiazine and butyrophenone neuroleptics lack such potent Ca+2-antagonist actions (Gould et al., 1983). As suggested, diphenylbutylpiperidines also differ from other typical neuroleptics in their efficacy to relieve negative symptoms of schizophrenia, such as emotional withdrawal, which were proposed to relate to an inhibition of voltage-operated Ca+2 channels (Gould et al., 1983). T-type (“T” for transient) Ca+2 channels are low-voltage activated Ca+2-channels that open during membrane depolarization and are ex- Fig. 1. Molecular Structure of Pimozide. pressed in diverse tissues, including neuronal, cardiovascular, and en- docrine, which regulate the development, maintenance, and repair of range of human cancer cell lines, including those employed in the these tissues (Kopecky et al., 2014). Although low-voltage-activated +2 National Cancer Institute’s screening program, and first generation Ca -channels have limited amino acid homology to the high-voltage- +2 antipsychotics generally appeared to be more cytotoxic than second activated Ca -channel families, which include L-type channels, all +2 generation antipsychotics (Wiklund et al., 2010). The repurposing of voltage-gated Ca -channels are structurally related (Uebele et al., +2 “ ” non-cancer drugs by 2009). The L-type Ca -channel ( L for long-lasting) is part of the +2 screening for novel anti-cancer activity is a plausible and powerful high-voltage activated family of voltage-dependent Ca channels. L- 2+ strategy to fastly determine new cancer therapeutics from the known type Ca channels (Cav1) represent one of the three major classes – +2 pool of small molecules that have already undergone rigorous tests via (Cav1 3) of voltage-gated Ca -channels as the target of clinically used +2 clinical trials for human safety, thus potentially fast-tracking the de- Ca -channel blockers including dihydropyridines (Striessnig et al., velopment and approval process, while reducing life-threatening risks 2014). In almost all electrically excitable cells one or more of these L- 2+ (Fako et al., 2016). In this manuscript, we will discuss the powerful type Ca channels isoforms is expressed. Hence, diverse functions potentials of the neuroleptic pimozide (Fig. 1) as a novel anticancer including muscle, brain, endocrine, and sensory functions depend on 2+ agent against refractory cancers and glioblastoma. proper L-type Ca channels activity and even small changes of their expression or activity may be associated with psychiatric disease or cardiac arrhythmias (Striessnig et al., 2014). Pimozide is a potent in- 2. Pimozide. Chemical structure and interactions with cellular hibitor of T-type Ca2+ channels but with less selectivity than mibe- biology fradil; in pituitary and heart cells, pimozide inhibits L-type Ca2+ channels, whereas in adrenal glomerulosa and spermatogenic cells, it Antipsychotics also known as neuroleptics or major tranquilizers, blocks T channels and Ca2+ influx (Bertolesi et al., 2002). The actions are medicines primarily employed to treat psychosis principally in of pimozide and mibefradil are not restricted to Ca2+ channels but may − schizophrenia (the terms “neuroleptic” and “antipsychotic” are used also affect other ion channels, including K+ and Cl channels (Bertolesi interchangeably in this review). Pimozide (depicted in Fig. 1)isa et al., 2002). neuroleptic of the diphenylbutylpiperidine class which was discovered Pimozide is a strong inhibitor of dopamine as well as the release of in 1963 by the physician Paul Janssen (Awouters and Lewi, 2007; melanocyte stimulating hormone (MSH), corticotropin releasing factor Mothi and Sampson, 2013). Pimozide has neuropsychiatric indications and gonadotropin releasing hormone (GnRH) in rats (Krummel et al., for paranoid personality disorder,