The role of tricyclics drugs in selective triggering of mitochondrially mediated apoptosis in neoplastic glia: a therapeutic option in malignant glioma?

We have previously demonstrated that the tricyclic antidepressant, Clomipramine, exerts a concentration-dependant, tumour cell specific, pro-apoptotic effect on human glioma cells in vitro and that this effect is not mirrored in non-neoplastic human astrocytes. Moreover, the drug acts by triggering mitochondrially-mediated apoptosis by way of complex 3 of the respiratory chain. Here, through reduced reactive oxygen species and neoplastic cell specific, altered membrane potential, cytochrome c is released, thereby activating a caspase pathway to apoptosis. In addition, while we and others have shown that further antidepressants, including those of the selective serotonin reuptake inhibitor (SSRI) group, also mediate cancer cell apoptosis in both glioma and lymphoma, clomipramine appears to be most effective in this context. More recently, other groups have reported that clomipramine causes apoptosis, preceded by a rapid increase in p-c-Jun levels, cytochrome c release from mitochondria and increased caspase-3-like activity. In addition to clomipramine we have investigated the possible pro-apoptotic activity of a range of further tricyclic drugs. Only two such agents (amitriptyline and doxepin) showed a similar, or better, effect when compared with clomipramine. Since both orally administered clomipramine and amitriptyline are metabolised to desmethyl clomipramine (norclomipramine) and nortriptyline respectively it is necessary for testing at a tumour cell level to be carried out with both the parent tricyclic and the metabolic product. In addition, reversal of multidrug resistance in a number of solid cancers following treatment with both clomipramine and amitriptyline has been reported. This additional role for tricyclics may be of some significance in the treatment of primary and secondary brain tumours. Since a substantial number of patients with malignant glioma have already received and are receiving clomipramine, both anecdotally and within a clinical trial, we have carried out CYP (P450) gene expression studies and determined blood plasma levels of clomipramine and norclomipramine, in order to ascertain whether differences in individual patient metabolism influence clinical outcome. While the proapoptotic effect of norclomipramine appears to be inferior to that of the parent tricyclic, amitriptyline and nortriptyline share a similar propensity for eliciting apoptosis in neoplastic but not non-neoplastic astrocytes. The potential value of these agents as adjuvants in the management of patients with malignant glioma is apparent.