2. Adding perphenazine to increase effectiveness of standard glioblastoma chemoirradiation.

Abstract

In the effort to improve treatment effectiveness in glioblastoma, this short note reviewed collected data on the pathophysiology of glioblastoma with particular reference to intersections with the pharmacology of perphenazine. That study identified five areas of potentially beneficial intersection. Data showed seemingly 5 independent perphenazine attributes of benefit to glioblastoma treatment -i) blocking dopamine receptor 2, ii) reducing centrifugal migration of subventricular zone cells by blocking dopamine receptor 3, iii) blocking serotonin receptor 7, iv) activation of protein phosphatase 2, and v) nausea reduction. Perphenazine is fully compatible with current chemoirradiation protocols and with the commonly used ancillary medicines used in clinical practice during the course of glioblastoma. All these attributes argue for a trial of perphenazine's addition to current standard treatment with temozolomide and irradiation. The subventricular zone seeds the brain with mutated cells that become recurrent glioblastoma after centrifugal migration. The current paper shows how perphenazine might reduce that contribution. Perphenazine is an old, generic, cheap, phenothiazine antipsychotic drug that has been in continuous clinical use worldwide since the 1950's. Clinical experience and research data over these decades have shown perphenazine to be well-tolerated in psychiatric populations, in normals, and in non-psychiatric, medically ill populations for whom perphenazine is used to reduce nausea. For now (Summer, 2020) the nature of glioblastoma requires a polypharmacy approach until/unless a core feature and means to address it can be identified in the future. Conclusions: Perphenazine possesses a remarkable constellation of attributes that recommend its use in GB treatment.2. Adding perphenazine to increase effectiveness of standard glioblastoma chemoirradiation.

Neurotransmitters: Potential Targets in Glioblastoma

“…Although the drugs mentioned in our research are mainly applied in vitro, there are several drugs in our studies that have progressed to phase I/II clinical trials, which include memantine [ 159 ], talampanel [ 160 , 161 , 162 ], ONC201 [ 164 , 165 ], chlorpromazine [ 166 ] and escitalopram oxalate [ 167 ]. Furthermore, experiments in mouse models also show good results [ 41 , 127 , 149 , 150 , 157 , 158 ]. Hence, we hold an optimistic perception that, with further research, drugs targeting neurotransmitters may be applied in GBM treatment.…”

Perphenazine and prochlorperazine decrease glioblastoma U‑87 MG cell migration and invasion: Analysis of the ABCB1 and ABCG2 transporters, E‑cadherin, α‑tubulin and integrins (α3, α5, and β1) levels

“…Our findings may be confirmed and explained by the results of other groups. In 2014, Kast et al suggested that the migration of subventricular zone (SVZ) cells to glioblastoma as well as glioblastoma to SVZ was regulated by the D3 dopamine receptor (4), while in 2020 the same authors showed that perphenazine reduced migration of malignant or non-malignant SVZ cells to glioblastoma (44). Thus, the ability of phenothiazines (perphenazine and prochlorperazine) to decrease migration and invasion of U-87 MG cells may be related to dopamine receptors activity, which was confirmed, by Aaberg-Jessen (2013) (45), Bartek factor receptor (EGFR) inhibitors, which impair cellular growth and survival by mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling cascade (12).…”

“…Therefore, it is possible that the first generation of antipsychotics (perphenazine and prochlorperazine), which penetrate the blood-brain-barrier (12), as DRD2 receptors antagonists (44) block the receptor protecting against DRD2 protein expression leading to the increase in glioblastoma invasion. Our findings confirmed that perphenazine and prochlorperazine reduced cellular invasion, and this hypothesis was confirmed by Liu et al (2019), Arrillaga-Romany et al (2020), and He et al (2021) (50)(51)(52).…”

Perphenazine and Prochlorperazine Decrease Glioblastoma U87-MG Cells Migration and Invasion: Analysis of the ABCB1 and ABCG2 Transporters, E-Cadherin, α-Tubulin, and Integrins (α3, α5, and β1) Levels.

“…Our ndings may be con rmed and explained by the results of other groups. In 2014, Kast et al suggested that the migration of subventricular zone (SVZ) cells to glioblastoma as well as glioblastoma to SVZ was regulated by the D3 dopamine receptor (Kast et al 2014), while in 2020 the same authors showed that perphenazine reduced migration of malignant or non-malignant SVZ cells to glioblastoma (Kast et al 2020). Thus, the ability of perphenazine and prochlorperazine to decrease migration and invasion of U87-MG cells may be related to dopamine receptors activity.…”