The Rolipram–Perillyl Alcohol Conjugate (NEO214) Is A Mediator of Cell Death through the Death Receptor Pathway

Abstract

Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis. Treatment with temozolomide, standard of care for gliomas, usually results in drug resistance and tumor recurrence. Therefore, there is a great need for drugs that target GBM. NEO214 was generated by covalently linking rolipram to perillyl alcohol (POH) via a carbamate bond to form the rolipram-perillyl alcohol conjugate. We show here that NEO214 is effective against both temozolomide-sensitive and temozolomide-resistant glioma cells. Furthermore, NEO214 is effective for different mechanisms of temozolomide resistance: overexpression of MGMT (O 6 -methylguanine methyl-transferase); deficiency in specific mismatch repair proteins; and overexpression of base excision repair (BER) proteins. NEO214-induced cytotoxicity involves apoptosis triggered by endoplasmic retic-ulum (ER) stress, as well as activating the Death Receptor 5 (DR5)/TNF-related apoptosis-inducing ligand (TRAIL/ Apo2L) pathway. In vitro studies show that glioma cells treated with NEO214 express DR5 and exhibit cell death in the presence of recombinant TRAIL, a growth factor constitutively produced by astrocytes. Our in vitro 3D coculture data show that induction of DR5 in glioma cells with NEO214 and TRAIL cause tumor cell death very effectively and specifically for glioma cells. In vivo studies show that NEO214 has antitumor efficacy in orthotropic syngeneic rodent tumor models. Furthermore, NEO214 has therapeutic potential especially for brain tumors because this drug can cross the blood-brain barrier (BBB), and is effective in the TRAIL-rich astrocyte microenvironment. NEO214 is a strong candidate for use in the treatment of GBMs. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

TRAIL mediated signaling in different cancers: cancer in the "Crosshairs"

“…To confirm whether or not NEO214 stimulated CHOP and DR5 in immunocompetent brain tumor models, GL261 mouse glioma cells were implanted into the frontal cortex of syngeneic mice. Results clearly suggested that NEO214 stimulated CHOP and DR5 (34).…”

“…NEO214 was chemically synthesized by covalent linkage of perillyl alcohol with rolipram using a carbamate bond (34). NEO214 was tested for efficacy against intracranial athymic tumor bearing mice and intracranial immunocompetent syngeneic mice.…”

Identification of a Metabolism-Related Risk Signature Associated With Clinical Prognosis in Glioblastoma Using Integrated Bioinformatic Analysis

“…In this study, we used CMap analysis to accurately identify compounds that have been shown to have specific effects on GBM or other tumor types by comparing the different expression genes of GMB samples from 3 clusters. These compounds include the DNA synthesis inhibitor anisomycin ( 73 ), glutamate receptor antagonist amantadine ( 74 ), norepinephrine inhibitor amitriptyline ( 75 , 76 ), solute carrier family member inhibitor bumetanide ( 77 ), PPAR receptor agonist clofibrate ( 78 ), and fenofibrate ( 79 ), selective serotonin reuptake inhibitor (SSRI) fluoxetine ( 75 , 80 ), ATPase inhibitor helveticoside ( 81 , 82 ), norepinephrine reuptake inhibitor imipramine ( 75 , 76 , 83 , 84 ), opioid receptor agonist loperamide ( 85 ), phosphodiesterase inhibitor papaverine ( 86 , 87 ) and rolipram ( 88 – 92 ), polar auxin transport inhibitor quercetin ( 93 , 94 ), cyclooxygenase inhibitor rofecoxib ( 95 , 96 ), calcineurin inhibitor tacrolimus ( 97 ), purinergic receptor antagonist ticlopidine ( 98 , 99 ), HDAC inhibitor vorinostat ( 100 ), Rho associated kinase inhibitor Y-27632 ( 101 – 103 ).…”

The Monoterpenoid Perillyl Alcohol: Anticancer Agent and Medium to Overcome Biological Barriers

“…Although rolipram was never approved for marketing [174], it was considered for repurposing as an anticancer agent based on its recognized beneficial activity in preclinical cancer models [175,176]. In mouse models of intracranial glioblastoma, NEO214 revealed significant therapeutic activity [177], indicating that it was indeed able to effectively cross the BBB, as was predicted from the in silico analysis. Intriguingly, as was observed with NEO212, combination therapy with the individual components, i.e., POH mixed with rolipram, was unable to mimic the much stronger anticancer effects of the conjugated NEO214 molecule [177,178].…”