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Updated: Oct 16, 2025

A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
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Serotonin type-3 receptor antagonists selectively kill melanoma cells through classical apoptosis, microtubule

Anita Barzegar-Fallah1, Houman Alimoradi1, Jessica L Dunlop1

  • 1Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.

Cell Biology and Toxicology
|October 16, 2021
PubMed

Insights

Serotonin type-3 (5-HT3) receptor antagonists, ondansetron and tropisetron, demonstrate selective anticancer effects on melanoma cells. These antiemetic drugs synergize with paclitaxel, inducing apoptosis and impairing microtubule formation.

Area of Science:

  • Pharmacology
  • Oncology
  • Cell Biology

Background:

  • Malignant melanoma is a metastatic and treatment-resistant cancer.
  • Serotonin type-3 (5-HT3) receptor antagonists (e.g., ondansetron, tropisetron) are antiemetic drugs.
  • Their potential anticancer effects, particularly in melanoma, are not fully understood.

Purpose of the Study:

  • To investigate the anticancer effects of ondansetron and tropisetron on melanoma cell lines.
  • To evaluate their synergistic potential with paclitaxel.
  • To elucidate the underlying mechanisms of action.

Main Methods:

  • Melanoma cell lines (WM-266-4, B16F10) were treated with drugs.
  • Cytotoxicity was assessed using MTT assay and IC50 curves.
  • Chou-Talalay analysis was performed for drug synergy.
  • Flow cytometry and fluorescent microscopy examined cell cycle and apoptosis.
  • Western blotting analyzed protein levels.
  • Molecular docking studied drug-target interactions.

Main Results:

  • Ondansetron and tropisetron exhibited selective, concentration-dependent cytotoxicity against melanoma cells.
  • A synergistic cytotoxic effect was observed when combined with paclitaxel.
  • The drugs induced classical apoptosis (subG1 DNA accumulation, cleaved caspase-3, mitochondrial permeabilization, phosphatidylserine exposure).
  • They enhanced cytosolic calcium levels, induced ERK1/2 phosphorylation, and inhibited NF-κB.
  • Microtubule formation was impaired, with docking studies suggesting binding to the tubulin colchicine-binding site.

Conclusions:

  • Ondansetron and tropisetron possess direct anticancer properties against melanoma cells.
  • These drugs can synergize with paclitaxel, enhancing its cytotoxic efficacy.
  • Their mechanism involves apoptosis induction and microtubule disruption.
  • Antiemetic drugs could potentially augment chemotherapy outcomes in melanoma treatment.
Keywords:
5-HT3AntagonistAntiemeticCytoskeletonSerotoninTubulin

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