|Institution:||University of New South Wales|
|Department:||Faculty of Science|
|Keywords:||psychotropic drugs; glioblastoma; cancer; statins|
|Full text PDF:||http://handle.unsw.edu.au/1959.4/53955|
Glioblastoma is an aggressive, highly invasive tumour with poor prognosis for patients with a median survival of less than 15 months. In most cases, surgical resection is usually followed by radiotherapy and chemotherapy with temozolomide, one of the few approved drugs for the treatment of glioblastoma. Unfortunately, most tumours develop resistance against temozolomide and therefore, 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 psychotropic drugs, alone and in combination with a statin, in cell lines and an animal model of glioblastoma and to also determine their mechanism of action. Drug efficacy was initially determined in U87MG and T98G cell lines using viability and clonogenic assays. These demonstrated lower IC50 and LD50 values for the psychotropic drugs and statins compared to temozolomide. These effects were enhanced when the psychotropic drugs were used in combination with simvastatin. A rat model of glioblastoma 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. Investigation of the mechanism of action of these drugs indicated that they affect intracellular cholesterol trafficking and the intermediates of the cholesterol synthesis pathway. Furthermore, simvastatin prevented cell migration and seemed to cause cell death through apoptosis. 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. These drugs have been in clinical use for decades and their pharmacokinetics and toxicology are well characterized, increasing their potential.