Cytotoxic effects of antipsychotic drugs implicate cholesterol homeostasis as a novel

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1: Int J Cancer. 2009 Aug 6. [Epub ahead of print] Links

Cytotoxic effects of antipsychotic drugs implicate cholesterol homeostasis as a novel chemotherapeutic target.

Wiklund ED, Catts VS, Catts SV, Fong Ng T, Whitaker N, Brown AJ, Lutze-Mann LH.
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney NSW 2052.
The reported reduction in cancer risk in those suffering from schizophrenia may be because antipsychotic medications have anti-neoplastic effects. In this study, six antipsychotic agents with a range of structural and pharmacological properties (reserpine, chlorpromazine, haloperidol, pimozide, risperidone and olanzapine), were screened for their effect on the viability of cell lines derived from lymphoblastoma, neuroblastoma, non-small cell lung cancer and breast adenocarcinoma. We aimed to determine if antipsychotic drugs in general possess cancer-specific cytotoxic potential, and whether it can be attributed to a common mode of action. With the exception of risperidone, all drugs tested displayed selective inhibition of the viability of cancer cell lines compared to normal cells. Using Affymetrix expression microarrays and quantitative real time PCR (qRT-PCR), we found that for the antipsychotic drugs, olanzapine and pimozide, cytotoxicity appeared to be mediated via effects on cholesterol homeostasis. The role of cholesterol metabolism in the selective cytotoxicity of these drugs was supported by demonstration of their increased lethality when co-administered with a cholesterol synthesis inhibitor, mevastatin. Also, pimozide and olanzapine showed accelerating cytotoxic effects from 12 to 48 hours in time course studies, mirroring the time-dependent onset of cytotoxicity induced by the amphiphile, U18666A. Based on these results, we concluded that the class II cationic amphiphilic properties of antipsychotic drugs contribute to their cytotoxic effects by acting on cholesterol homeostasis and altering the biophysical properties of cellular membranes, and that drugs affecting membrane-related cholesterol pathways warrant further investigation as potential augmentors of standard cancer chemotherapy. (c) 2009 UICC.
PMID: 19662652 [PubMed - as supplied by publisher