The antidepressant sertraline downregulates Akt and has activity against melanoma cells

Abstract

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.

Effect of high-fat diet-induced obesity on the Akt/FoxO/Smad signaling pathway and the follicular development of the mouse ovary

“…John et al (12) reported that as the downstream of PI3K/Akt, hyperphosphorylation of FoxO3a induced over-activation of primordial follicules (8,26,28). As previous studies have systematically reported that maintaining optimal activities of PI3K/Akt signaling pathway is essential for normal ovarian function, which not only regulates the balance between survival and activation of primordial follicles, but also is vital for the proliferation and differentiation of GCs (26)(27)(28). These studies suggested that regulation of the optimal expression level of FoxO3a is important spatially and temporally during follicular development.…”

“…Previous studies have systematically reported that maintaining optimal activity of Akt serine/threonine kinase 1 (Akt) signaling is essential for normal ovarian function, which regulates the balance between survival and activation of primordial follicles, and also is important for proliferation and differentiation of GCs (26)(27)(28). FoxO3a is also a substrate of Akt, thus, the present study also examined the expression of Akt ovaries.…”

The Akt signaling pathway

“…Being a member of the selective serotonin reuptake inhibitor class of anti-depressants, sertraline possesses Akt inhibitory activity and acts as a serotonin transporter antagonist. 126 Human melanoma cells treated with sertraline exhibited low pAkt and phosphorylated p70 S6 kinase activities. 126 In addition, sertraline treatment induced endoplasmic reticulum stress triggering cellular apoptosis.…”

“…126 Human melanoma cells treated with sertraline exhibited low pAkt and phosphorylated p70 S6 kinase activities. 126 In addition, sertraline treatment induced endoplasmic reticulum stress triggering cellular apoptosis. In animals, intraperitoneal administration of 1 mg/day setraline inhibited xenografted A375 tumor development.…”

“…In animals, intraperitoneal administration of 1 mg/day setraline inhibited xenografted A375 tumor development. 126 Although this antidepressant inhibited melanoma tumor development, further investigation in preclinical as well as clinical models are warranted to establish its activity against melanoma, mechanism of action for tumor inhibition and potential toxicity.…”