Tricyclic antidepressants (TCA) are a class of drugs used primarily in the treatment of clinical depression and associated conditions. The primary mode of action of this group of compounds is the inhibition of re-uptake of the neurotransmitters serotonin and noradrenaline into nerve cells in the brain. As a consequence of this blockade of neurotransmitter re-uptake, extracellular levels of serotonin and noradrenaline are elevated, resulting in an alteration in mood that is beneficial to the treatment of depression.
Whilst TCAs have fallen somewhat out of fashion clinically in favour of newer classes of anti-depressant, they may have potential use in other areas. One such area is the prevention of certain cancers, including colorectal cancer and glioma.
A study funded by a grant to Dr. Timothy E. Bates from the Medical Research Council and published in the British Journal of Cancer [1] analysed 90,000 patients and control human subjects data gathered from the General Practice Research Database [GPRD] (an NHS-based database of anonymous clinical practice data) and in doing showed unequivocally using powerful validated statistical methodologies that the use of TCAs in patients with depression produced a dose-dependent and time-dependent protection from both colorectal cancer and glioma.
The mechanism of this protection in man was suggested to be that of an anti-mitochondrial, pro-apoptotic one, as the GPRD study was a follow on study to previous research by Dr. Bates group who showed that the TCA chlorimipramine specifically inhibits mitochondrial complex III activity [2], and decreases mitochondrial membrane potential resulting in death of several human cancer cell types by a mitochondrially mediated apoptotic mechanism
Of particular interest is a video produced Dr. Timothy E. Bates from the University of Lincoln, in which he demonstrates TCAs initiating apoptosis in lung cancer cells.
In this video we can see “blebbing”of the cancer cells’ plasma membrane followed by shrinkage and apoptosis. The footage is a time-lapse; condensing around two hours of video into a thirty second clip.
References and Further Reading
1 – Walker, A. J., Card, T., Bates, T. E., Muir, K. (2011) Tricyclic antidepressants and the incidence of certain cancers: a study using the GPRD. British Journal of Cancer 104 (link to article)
2 – Daley, E., Wilkie, D. & Loesch, A., et al. (2005) Chlorimipramine: A novel anticancer agent with a mitochondrial target. Biochemical and Biophysical Research Communications 328(2) (link to article)
3 – Dr. Timothy E. Bates University home page
Mitochondrial Me 