Repurposing neuroleptic drug for brain tumor therapy

Abstract

Brain tumor is considered as one of the most aggressive and incurable form of cancer. Majority of the brain tumors have a median survival rate of only 12%. Even though advanced treatments such as surgical removal, chemotherapy and radiotherapy are available, brain tumor persists to be lethal. Temozolomide (TMZ) is the main therapy for brain tumor but resistance to TMZ is the major cause of treatment failure. This resistance in tumor cells has frequently been linked to the expression of O6‐methylguanine‐DNA methyltransferase (MGMT). Pimozide (PMZ) is a neuroleptic drug used for the treatment of schizophrenia and chronic psychosis. In our study, we observed that pimozide significantly reduced the viability of U87MG, U251MG, DAOY and GBM28 cell lines with an IC50 ranging from 11μM to 20μM after 24 h of treatment. Pimozide induced apoptosis in these cell lines as evaluated by FITC/Annexin assay and further validated by the cleavage of caspase 3 as well as PARP. Western blot analysis resulted in the concentration dependent decrease in the expression of STAT3 signaling mainly targeting the anti‐apoptotic markers BCl‐XL, BCl‐2 and Survivin etc in U87MG, U251MG, DAOY and GBM28 brain cancer cell lines. PMZ alone suppressed the growth of U87MG cells with an IC50 of 10μM, after 96 hours of treatment. On the other hand, treatment of U87MG cells with 750 μM of TMZ in combination with 10μM PMZ for 96 hours increased the killing of U87MG cells by 50% as compared to 10% when treated with TMZ. In addition, PMZ treatment reduced the survival of TMZ resistant U251R cells with an IC50 ranging from 15–20 μM after 24 h of treatment. Our results further demonstrated that oral administration of PMZ (25mg/kg) significantly inhibits the growth of brain tumors in an intracranial tumor model without any apparent signs of toxicity. It is important to note that PMZ is an FDA approved drug with no considerable toxicity. Overall, this study depicts that PMZ is a potential candidate to target brain tumors.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.