Tricyclic antidepressants protect against glioma and colorectal cancer


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Alex Walker1, Kenneth Muir2, Timothy Bates3, Timothy Card1

1The University of Nottingham, UK, 2Royal College of Medicine, London, UK, 3New-Use Therapeutics Limited, Nottingham, UK

Abstract

Proffered paper presentation

Background
Previous studies have shown that tricyclic antidepressants (TCAs) can inhibit mitochondrial electron transport chain (ETC) enzyme activity, and induce mitochondrially mediated apoptosis in human glioma cells, but not normal glial cells (Daley et al, 2005). There is also evidence of TCAs killing CRC cell lines (Arimochi et al, 2006). We therefore investigated whether this activity translates to a protective effect against several cancer types.

Methods
A case-control study was carried out using the General Practice Research Database. We examined whether prior tricyclic usage was associated with a reduction in incidence of nervous system (with glioma as a sub-category), breast, colorectal, lung and prostate cancers. Conditional logistic regression was used to correct for age, sex, general practice, smoking status, body mass index, alcohol use and non-steroidal anti-inflammatory drug use.

Results
31,953 cancer cases were identified, each matched to up to 2 controls. The data for glioma show a significant reduction in the odds ratio in patients taking TCAs, in cases relative to controls (Odds Ratio (OR) =0.601, 95% Confidence Interval (CI)=0.392-0.920). A similar reduction was observed in CRC (OR=0.857, 95% CI=0.759-0.967). This effect appeared dose- and time-dependant, most notably in glioma patients with >50 prescriptions (OR=0.480, 95% CI=0.257-0.897), and CRC patients whose treatment began >10 years before cancer diagnosis (OR=0.776, 95% CI=0.649-0.928). This effect was selective depending on cancer type with lung, breast and prostate cancers unaffected by antidepressant use.

Conclusion
This is the first human study to demonstrate chemo-protection against glioma and CRC using tricyclics in vivo.

References
Daley, E., et al., Chlorimipramine: a novel anticancer agent with a mitochondrial target. Biochemical & Biophysical Research Communications, 2005. 328(2): p.623-32.

Arimochi, H. and K. Morita, Characterization of cytotoxic actions of tricyclic antidepressants on human HT29 colon carcinoma cells. European Journal of Pharmacology, 2006. 541(1-2): p.17-23