Abstract 2915: Penfluridol suppresses glioblastoma tumor growth by inhibiting sonic hedgehog signaling

Abstract

Abstract Glioblastoma (GBM) is the most common brain tumor with poor survival rate. The main obstacle in the treatment of glioblastoma patients is the presence of blood brain barrier, which restricts the movement of the drugs to reach the brain. Penfluridol (PF) is known to cross blood brain barrier and is a clinically approved drug for schizophrenia patients. It is demonstrated and established by us that penfluridol suppresses the growth of metastasized breast cancer cells in brain giving us the rationale to evaluate it against glioblastoma (Alok Ranjan, Parul Gupta and Sanjay Srivastava, Cancer Research 2015). Penfluridol significantly reduced the viability of U87-MG, T98G and U251 MG glioblastoma cells with an IC50 of 6μM, 5.5μM and 9μM respectively after 24 h of treatment and induced apoptosis as exhibited by FITC/Annexin assay and cleavage of caspase 3 as well as PARP. It has been shown that GLI1, a transcription factor belonging to sonic hedgehog signaling is overexpressed in GBM and responsible for tumor progression. Our results demonstrated that penfluridol treatment reduced the expression of GLI1 in U87MG, T98G and U251 MG cells in concentration-dependent manner. In addition, overexpression of MGMT, a DNA repair enzyme has been linked to temozolomide (TMZ) resistance in GBM therapy. Combination of PF and TMZ induced more apoptosis and reduced the expression of GLI1 and MGMT as compared to PF or TMZ treatment alone. Our results further demonstrated that oral administration of PF inhibited the growth of GBM tumors by 66% and 72% in subcutaneous and intracranial GBM tumor model respectively. Immunohistochemical analysis of tumor tissue and western blot analysis of tumor lysate indicated down regulation of GLI1, MGMT and increase in cleavage of caspase 3, confirming in vitro finding. Apoptosis induction effect of PF treatment in tumor tissues was further confirmed by Tunel staining. Taken together, these results indicate that overall GBM tumor growth suppression by penfluridol was associated with inhibition of Gli1 and induction of apoptosis Citation Format: Alok Ranjan, Sanjay K. Srivastava. Penfluridol suppresses glioblastoma tumor growth by inhibiting sonic hedgehog signaling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2915.