Tricyclic antidepressants protect against glioma and colorectal cancer
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
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
