Abstract 5549: Efficacy and potential mechanisms of psychotropic drugs and statins in the treatment of glioblastoma.

Abstract

Abstract Background and Aims: Glioblastoma multiforme is an aggressive, highly invasive tumour with poor prognosis for patients with a median survival of less than 15 months. New treatment modalities are urgently required. Meta-analysis of cancer in schizophrenic patients suggests a lower incidence of some cancers leading to the hypothesis that antipsychotic drugs taken regularly by these patients may inhibit tumour growth. The aims of this study were to investigate the chemotherapeutic potential of antipsychotic drugs, alone and in combination with a statin, in cells lines and an animal model of gliboblastoma and to also determine their mechanism of action. Methods and Results: Drug efficacy was initially determined in U87MG and T98G cell lines using viability and clonogenic assays and demonstrated that the IC50 and LD50 values for the antipsychotic drugs (chlorpromazine, olanzapine and pimozide) are far lower than those for the current chemotherapeutic, temozolomide. These effects were enhanced when the drugs were used in combination with simvastatin. A novel rat model of glioblastoma that allows tumour monitoring via bioluminescence imaging following implantation of isogenic luciferase-tagged F98 cells was used to assess the in vivo potential of the drugs and indicated that treatment with olanzapine extended the life-span of the rats beyond that of temozolomide. We have previously investigated the mechanism of action of these drugs and determined that they affect intracellular cholesterol trafficking (Kristiana et al, 2010). Further studies using a yeast deletion library screen with the antipsychotic chlorpromazine revealed that it acts as a histone acetyltransferase inhibitor (HATi). Two representative members of other classes of phenothiazines, thioridazine and trifluoperazine, were investigated in HAT activity assays, and also shown to be HATi. Co-treatment with sodium butyrate, a histone deacetylase inhibitor, alleviated the detrimental effect on viability confirming that the HAT inhibitory activity was responsible for the cytotoxicity in cancer cells. Conclusions: While histone deacetylase inhibitors are increasingly being trialed as anti-cancer treatments, the phenothiazines could provide an important complement based on their HAT inhibitory activity. Our in vitro and in vivo studies indicate the potential of these drugs as candidates for the treatment of glioblastoma especially since they are able to cross the blood-brain barrier and, as they have been in clinical use for decades, their pharmacokinetics and toxicology are well-characterized. Kristiana I, Sharpe LJ, Catts VS, Lutze-Mann LH, Brown AJ (2010). Antipsychotic drugs upregulate lipogenic gene expression by disrupting intracellular trafficking of lipoprotein-derived cholesterol. Pharmacogenomics J 10, 396-407. Citation Format: Nirmani Wijenayake, Harvey R. Fernandez, Vibeke S. Catts, Noel J. Whitaker, Louise H. Lutze-Mann. Efficacy and potential mechanisms of psychotropic drugs and statins in the treatment of glioblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5549. doi:10.1158/1538-7445.AM2013-5549