Title : Cytotoxic And Neuroprotective Activity of Serotonin Transporter Inhibitors and Serotonin Receptor Ligands With Antidepressant Activity
Serotonin exhibits multiple non-neural functions involved in essential hypertension, early embryogenesis, follicle maturation and behaviour. Growth stimulatory effects of the neurotransmitter have been described for a variety cell types. 5-HT was found to induce migration of the human prostate cancer cell lines - PC-3 and Du145 - and several 5-HT1A antagonists and serotonin reuptake inhibitors were reported to inhibit the growth of different tumor cell lines in vitro. SSRIs are among the most commonly used antidepressant drugs. It has been shown that some antidepressant drugs and some serotonin 5-HT1A receptor ligands may exhibit neuroprotective activity, which could be connected to their antidepressant activity. On the other hand, it was reported that the very same group of compounds may induce apoptosis in some cancer cell lines. This activity could be connected to the compounds serotonergic activity since it was found that 5-HT induced proliferation and migration of PC-3 and DU-145 cells (but not androgen-dependent LNCaP cells). The action of 5-HT was inhibited to varying degrees by the inhibition of MAPK and PI3K as well as by a 5-HT1A receptor antagonist.
In the present paper the literature available data concerning the cytoprotective and proapoptotic activity of several SERT inhibitors and serotonin receptor ligands will be summarized and discussed. Additionally, the cytotoxic activity of several SERT inhibitors and 5-HT1A receptor ligands in some neuroblastoma and prostate cancer cell lines as well as their propensity to influence cAMP, ERK1/2 and Akt biochemical transduction pathways will be discussed. It is suggested that one should not expect a straightforward relationship between the activation of particular serotonergic pathways by the examined compounds (SSRIs and 5-HT1A receptor ligands) and their cytotoxic or cytoprotective activity.