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

Wiklund, Erik D., Catts, Vibeke S., Catts, Stanley V., Ng, Teng Fong, Whitaker, Noel J., Brown, Andrew J. and Lutze-Mann, Louise H. (2010) Cytotoxic effects of antipsychotic drugs implicate cholesterol homeostasis as a novel chemotherapeutic target. International Journal of Cancer, 126 1: 28-40. doi:10.1002/ijc.24813

Author Wiklund, Erik D.
Catts, Vibeke S.
Catts, Stanley V.
Ng, Teng Fong
Whitaker, Noel J.
Brown, Andrew J.
Lutze-Mann, Louise H.
Title Cytotoxic effects of antipsychotic drugs implicate cholesterol homeostasis as a novel chemotherapeutic target
Journal name International Journal of Cancer   Check publisher's open access policy
ISSN 1097-0215
Publication date 2010-01
Year available 2009
Sub-type Article (original research)
DOI 10.1002/ijc.24813
Volume 126
Issue 1
Start page 28
End page 40
Total pages 13
Editor H. zur Hausen
Place of publication New York , U. S. A.
Publisher Wiley InterScience
Collection year 2010
Language eng
Subject C1
060101 Analytical Biochemistry
111201 Cancer Cell Biology
920410 Mental Health
920102 Cancer and Related Disorders
Abstract The reported reduction in cancer risk in those suffering from schizophrenia may be because antipsychotic medications have antineoplastic effects. In this study, 6 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 with normal cells. Using Affymetrix expression microarrays and quantitative real-time polymerase chain reaction, 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 coadministered with a cholesterol synthesis inhibitor, mevastatin. Also, pimozide and olanzapine showed accelerating cytotoxic effects from 12 to 48 hr in time course studies, mirroring the time-dependent onset of cytotoxicity induced by the amphiphile, U18666A. On the basis of 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.
Keyword cholesterol
Q-Index Code C1
Q-Index Status Confirmed Code

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2010 Higher Education Research Data Collection
School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 33 times in Thomson Reuters Web of Science Article | Citations
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Created: Sun, 20 Dec 2009, 00:02:50 EST