5HT3 receptor antagonists selectively kill melanoma cells

Date 24 November 2018
Event ESMO Asia 2018 Congress
Session Poster display - Cocktail
Topics Melanoma
Translational Research
Presenter Anita Barzegar Fallah
Citation Annals of Oncology (2018) 29 (suppl_9): ix105-ix108. 10.1093/annonc/mdy439
Authors A. Barzegar Fallah, H. Alimoradi, S.K. Baird
  • Department Of Pharmacology And Toxicology, University of Otago, 9016 - Dunedin/NZ

Abstract

Background

Malignant melanoma is a highly metastatic tumor, resistant to chemotherapy and radiotherapy. 5-HT3 receptor antagonists, such as tropisetron and ondansetron are well tolerated antiemetic drugs which are commonly used in the prevention of nausea and emesis. Here, we investigated the anticancer effects of these drugs on melanoma cancer cells with or without paclitaxel.

Methods

Cellular toxicity of tropisetron and ondansetron was determined by MTT, cell cycle analysis, annexin V/PI staining and determination of mitochondrial membrane permeability and cytosolic calcium level, the expression of cleaved caspase-3, cleaved PARP and phosphorylated ERK1/2 and the localization of NF-κB in the nucleus.

Results

Here, we established that tropisetron and ondansetron (at the concentrations which are safe to normal human dermal fibroblasts) showed potent dose-dependent cytotoxicity on two melanoma cell lines, WM-266-4 and B16F10. In addition, when they were combined with paclitaxel, they significantly enhanced the cytotoxicity of paclitaxel in the cancer cells. They arrested cancer cell cycle in the G0 phase and produced programmed cell death by apoptosis. Western blot analysis showed treatment of the cancer cells with ondansetron or tropisetron enhanced the expression of cleaved PARP and cleaved caspase-3. The drugs impaired the integrity of the mitochondria membrane and enhanced the cytosolic calcium level in cancer cells, induced phosphorylated ERK1/2 and inhibited NF-κB localization in nuclei which consequently direct the cells toward apoptosis and necrosis.

Conclusions

Tropisetron and ondansetron showed selective cytotoxicity in melanoma cells through increasing mitochondrial membrane permeability, cytosolic calcium level and ERK1/2 and NF-κB pathways. The study provides a basis for future research projects to determine the mechanism through which ondansetron and tropisetron selectively kill the cancer cells and develop new selective anticancer drugs.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

University of Otago.

Funding

University of Otago.

Disclosure

All authors have declared no conflicts of interest.