Fluoxetine selectively induces p53-independent apoptosis in human colorectal cancer cells

Monika Marcinkute, Saeed Afshinjavid, Amos A. Fatokun, Farideh Javid

Research output: Contribution to journalArticle

Abstract

Fluoxetine has been shown to induce anti-tumour activity. The aim of this study was to determine the effect of fluoxetine on HCT116+/+ and p53 gene-depleted HCT116-/- human colorectal cancer cells and the mechanisms, including potential p53-dependence, of its action.
Fluoxetine-induced apoptosis was investigated by mitochondrial membrane potential assay, Annexin V assay, two-step cell cycle analysis using NC-3000™ system and pharmacological inhibition assays. Fluoxetine induced very selectively concentration-dependent apoptosis in human colorectal cancer cells by altering mitochondrial membrane potential and inducing translocation of phosphatidylserine to the outer membrane layer. Further evidence of the
preponderance of apoptosis in fluoxetine-induced cell death is provided by the finding that the cell death was not blocked by inhibitors of parthanatos, a form of cell death that results from overactivation of the enzyme poly (ADP-ribose) polymerase (PARP) but is different from apoptosis. Data obtained indicate fluoxetine caused cell cycle event at Sub-G1 and G0/G1 phases in both cell lines. In terms of apoptosis, there is no significant difference between the responses of the two cell lines to fluoxetine.
In conclusion, fluoxetine’s cytotoxicity induces mainly apoptosis and causes DNA fragmentation in human colorectal cancer cells, which seemed to be independent of the p53 protein, as no significant difference in death profiles in response to fluoxetine treatment was observed in both the p53-intact and the p53-deleted cell lines. Fluoxetine, therefore, has potential for being repurposed as a drug for the treatment of colon cancer and thus deserves further investigations in this context.
Original languageEnglish
Article number172441
JournalEuropean Journal of Pharmacology
Volume857
Early online date7 Jun 2019
DOIs
Publication statusPublished - 15 Aug 2019

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Fluoxetine
Colorectal Neoplasms
Apoptosis
Cell Death
Mitochondrial Membrane Potential
Cell Line
Cell Cycle
Cell Cycle Resting Phase
Poly(ADP-ribose) Polymerases
Annexin A5
Phosphatidylserines
p53 Genes
G1 Phase
DNA Fragmentation
Colonic Neoplasms
Pharmacology
Membranes

Cite this

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title = "Fluoxetine selectively induces p53-independent apoptosis in human colorectal cancer cells",
abstract = "Fluoxetine has been shown to induce anti-tumour activity. The aim of this study was to determine the effect of fluoxetine on HCT116+/+ and p53 gene-depleted HCT116-/- human colorectal cancer cells and the mechanisms, including potential p53-dependence, of its action.Fluoxetine-induced apoptosis was investigated by mitochondrial membrane potential assay, Annexin V assay, two-step cell cycle analysis using NC-3000™ system and pharmacological inhibition assays. Fluoxetine induced very selectively concentration-dependent apoptosis in human colorectal cancer cells by altering mitochondrial membrane potential and inducing translocation of phosphatidylserine to the outer membrane layer. Further evidence of thepreponderance of apoptosis in fluoxetine-induced cell death is provided by the finding that the cell death was not blocked by inhibitors of parthanatos, a form of cell death that results from overactivation of the enzyme poly (ADP-ribose) polymerase (PARP) but is different from apoptosis. Data obtained indicate fluoxetine caused cell cycle event at Sub-G1 and G0/G1 phases in both cell lines. In terms of apoptosis, there is no significant difference between the responses of the two cell lines to fluoxetine.In conclusion, fluoxetine’s cytotoxicity induces mainly apoptosis and causes DNA fragmentation in human colorectal cancer cells, which seemed to be independent of the p53 protein, as no significant difference in death profiles in response to fluoxetine treatment was observed in both the p53-intact and the p53-deleted cell lines. Fluoxetine, therefore, has potential for being repurposed as a drug for the treatment of colon cancer and thus deserves further investigations in this context.",
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Fluoxetine selectively induces p53-independent apoptosis in human colorectal cancer cells. / Marcinkute, Monika; Afshinjavid, Saeed; Fatokun, Amos A.; Javid, Farideh.

In: European Journal of Pharmacology, Vol. 857, 172441, 15.08.2019.

Research output: Contribution to journalArticle

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AU - Fatokun, Amos A.

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