Serotonin type-3 receptor antagonists selectively kill melanoma cells through classical apoptosis, microtubule depolymerisation, ERK activation, and NF-κB downregulation

Malignant melanoma is a highly metastatic tumour, resistant to treatment. Serotonin type-3 (5-HT 3 ) 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 e...

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Veröffentlicht in:Cell biology and toxicology 2023-06, Vol.39 (3), p.1119-1135
Hauptverfasser: Barzegar-fallah, Anita, Alimoradi, Houman, Dunlop, Jessica L., Torbati, Elham, Baird, Sarah K.
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container_start_page 1119
container_title Cell biology and toxicology
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creator Barzegar-fallah, Anita
Alimoradi, Houman
Dunlop, Jessica L.
Torbati, Elham
Baird, Sarah K.
description Malignant melanoma is a highly metastatic tumour, resistant to treatment. Serotonin type-3 (5-HT 3 ) 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 IC 50 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- κ B 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.
doi_str_mv 10.1007/s10565-021-09667-0
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Serotonin type-3 (5-HT 3 ) 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 IC 50 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- κ B 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. 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Serotonin type-3 (5-HT 3 ) 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 IC 50 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- κ B 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. 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subjects Anticancer properties
Antiemetics
Antiemetics - adverse effects
Apoptosis
Binding sites
Biochemistry
Biomedical and Life Sciences
Calcium permeability
Caspase-3
Cell Biology
Cell cycle
Cell death
Chemotherapy
Colchicine
Cytoskeleton
Cytotoxicity
Data analysis
Depolymerization
Down-Regulation
Drugs
Extracellular signal-regulated kinase
Flow cytometry
Fluorescence
Humans
Life Sciences
Melanoma
Melanoma - drug therapy
Membrane permeability
Metastases
Microtubules
Mitochondrial DNA
Molecular docking
Molecular Docking Simulation
NF-kappa B
NF-κB protein
Ondansetron - adverse effects
Original Article
Paclitaxel
Paclitaxel - pharmacology
Pharmacology/Toxicology
Phosphatidylserine
Radiation therapy
Receptors
Serotonin
Serotonin - adverse effects
Serotonin S3 receptors
Skin cancer
Treatment resistance
Tropisetron - adverse effects
Tumor cell lines
Tumors
Variance analysis
Vomiting - chemically induced
Vomiting - drug therapy
Vomiting - prevention & control
Western blotting
title Serotonin type-3 receptor antagonists selectively kill melanoma cells through classical apoptosis, microtubule depolymerisation, ERK activation, and NF-κB downregulation
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