ATPS-07NEO214, ROLIPRAM CONJUGATED TO PERILLYL ALCOHOL, IS A NOVEL DRUG CYTOTOXIC FOR GLIOMAS BY TARGETING THE DEATH RECEPTOR MEDIATED TRAIL PATHWAY

Abstract

Glioblastoma multiforme (GBM) is a primary brain tumor with a poor prognosis. Treatment with temozolomide (TMZ) usually results in drug resistance and tumor recurrence. This study shows that NEO214, rolipram conjugated to perillyl alcohol, is cytotoxic for a wide range of different TMZ-resistant glioma cells. This conjugate is significantly more effective than either rolipram, perillyl alcohol or the mixture of these agents, demonstrating that NEO214 is a novel entity. NEO214 is effective for drug resistant tumor cells, but not toxic to normal astrocytes or endothelial cells. To identify the mechanism of cell death, effects of NEO214 on death receptor (DR)5 expression were examined. The results show that NEO214 significantly increased the expression of DR5 in both TMZ-sensitive and TMZ-resistant glioma cells. In addition, tumor cells treated with NEO214 and immunostained for DR5 demonstrated over 90% positivity. To show that DR5 receptors were functional, the interaction with the receptor ligand, TRAIL, with NEO214 was tested. The results showed that NEO214 plus TRAIL induced a dramatic increase in cell death. TRAIL alone was not cytotoxic to cells. The combination of NEO214 plus TRAIL resulted in a 60–80% decrease in cell survival. NEO214-treated glioma cells also exhibited an increase in CHOP, marker for ER stress activation. Downregulation of CHOP expression correlated with DR5 expression suggesting that ER stress may be involved in stimulating DR5 expression. To determine effects of NEO214 in vivo, glioma cells were implanted subcutaneously into animals, and treated with NEO214 or vehicle. Results showed that NEO214 caused a significant delay in tumor growth. These results demonstrate that NEO214 is an effective drug against a wide range of different TMZ- resistant gliomas, the combination of NEO214 and TRAIL is very effective in enhancing tumor cytotoxicity, and NEO214 is active in vivo causing significant delays in tumor progression.