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The antidepressant sertraline downregulates Akt and has activity against melanoma cells
Author(s) -
Reddy Kalpana K.,
Lefkove Benjamin,
Chen Lan Bo,
Govindarajan Baskaran,
Carracedo Arkaitz,
Velasco Guillermo,
Carrillo Carol O.,
Bhandarkar Sulochana S.,
Owens Michael J.,
MechtaGrigoriou Fatima,
Arbiser Jack L.
Publication year - 2008
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/j.1755-148x.2008.00481.x
Subject(s) - protein kinase b , sertraline , melanoma , medicine , pharmacology , cancer research , pi3k/akt/mtor pathway , antidepressant , phosphorylation , signal transduction , biology , microbiology and biotechnology , hippocampus
Summary Melanoma is a common malignancy which is poorly responsive to chemotherapy and radiation. One of the major reasons melanoma responds poorly to these modalities is constitutive expression of Akt, which protects against apoptosis. The antidepressant sertraline was found to be a potent cytotoxic agent against A375 human melanoma. To determine the mechanism by which sertraline kills melanoma cells, Western blot analysis of signaling molecules, including phosphorylated Akt, caspase 9 and phospho‐p70 S6 kinase was performed. Finally, the effects of sertraline on A375 xenografts in mice were assessed. Sertaline potently inhibited the phosphorylation of Akt, and caused cell death through induction of endoplasmic reticulum in vitro. Sertraline monotherapy demonstrated activity against A375 xenografts in vivo. Akt is a major cause of resistance of melanoma to current therapy. Antidepressants are commonly used to prevent interferon‐induced depression. Use of antidepressants that decrease Akt may improve the efficacy of interferon and other therapies against melanoma. Further studies are needed to elucidate whether sertraline acts as an Akt inhibitor in melanoma.