Malignant melanoma is a highly metastatic tumour, resistant to treatment.
Serotonin type-3 (5-HT3) receptor antagonists, such as
tropisetron and
ondansetron, are well-tolerated
antiemetic drugs commonly used to prevent
nausea caused by
chemotherapy or
radiotherapy. We investigated the anticancer effects of these drugs on
melanoma cancer cell lines WM-266-4 and B16F10 with or without
paclitaxel. We constructed IC50 curves and performed Chou-Talalay analysis, using data obtained with the MTT assay. Flow cytometry and fluorescent microscopy were used to examine characteristics of the cell cycle, cell death and cytoskeleton changes.
Protein levels and activation were analysed by western blotting and molecular docking studies carried out. Data were analysed by one way ANOVA and post hoc testing.
Ondansetron and
tropisetron showed selective concentration-dependent cytotoxicity in
melanoma cell lines WM-266-4 and B16F10. The effect in combination with
paclitaxel was synergistic. The drugs did not cause cell cycle arrest but did promote characteristics of classical apoptosis, including accumulation of subG1
DNA, cleaved
caspase-3, mitochondrial membrane permeability and
phosphatidylserine exposure. As well, the cytosolic
calcium level in the
melanoma cells was enhanced, phosphorylated ERK1/2 induced and NF-κB inhibited. Finally, the formation of microtubules was shown to be impaired in
melanoma cells treated with
ondansetron or
tropisetron. Docking studies were used to predict that these drugs could bind to the
colchicine binding site on the
tubulin molecule.
Antiemetic drugs, already given in combination with
chemotherapy, may enhance the cytotoxic effect of
chemotherapy, following successful delivery to the tumour site.