Paroxetine Induces Apoptosis of Human Breast Cancer MCF-7 Cells through Ca2+-and p38 MAP Kinase-Dependent ROS Generation

Abstract

Depression is more common in women with breast cancer than the general population. Selective serotonin reuptake inhibitors (SSRIs), a group of antidepressants, are widely used for the treatment of patients with depression and a range of anxiety-related disorders. The association between the use of antidepressant medication and breast cancer is controversial. In this study, we investigated whether and how SSRIs induce the death of human breast cancer MCF-7 cells. Of the antidepressants tested in this study (amitriptyline, bupropion, fluoxetine, paroxetine, and tianeptine), paroxetine most reduced the viability of MCF-7 cells in a time-and dose-dependent manner. The exposure of MCF-7 cells to paroxetine resulted in mitochondrion-mediated apoptosis, which is assessed by increase in the number of cells with sub-G1 DNA content, caspase-8/9 activation, poly (ADP-ribose) polymerase cleavage, and Bax/Bcl-2 ratio and a reduction in the mitochondrial membrane potential. Paroxetine increased a generation of reactive oxygen species (ROS), intracellular Ca2+ levels, and p38 MAPK activation. The paroxetine-induced apoptotic events were reduced by ROS scavengers and p38 MAPK inhibitor, and the paroxetine’s effect was dependent on extracellular Ca2+ level. Paroxetine also showed a synergistic effect on cell death induced by chemotherapeutic drugs in MCF-7 and MDA-MB-231 cells. Our results showed that paroxetine induced apoptosis of human breast cancer MCF-7 cells through extracellular Ca2+-and p38 MAPK-dependent ROS generation. These results suggest that paroxetine may serve as an anticancer adjuvant to current cancer therapies for breast cancer patients with or without depression.

Blockage of Autophagic Flux and Induction of Mitochondria Fragmentation by Paroxetine Hydrochloride in Lung Cancer Cells Promotes Apoptosis via the ROS-MAPK Pathway

“…Paxil, a widely used antidepressant, showed anti-cancer activity in various types of cancer cells such as colon cancer cells and breast cancer cells (Cho et al, 2019;Jang et al, 2019). The major kinases of MAPK pathways such as p38, JNK was proposed to mediate the drug-induced apoptosis.…”

<p>Histone deacetylase 6 is overexpressed and promotes tumor growth of colon cancer through regulation of the MAPK/ERK signal pathway</p>

“…Accumulating evidence suggests that an increase in reactive oxygen species initiates the p38 MAPK signaling pathway and triggers the apoptosis cascade in colon cancer. Therefore, treatment with ROS scavengers or MAPK inhibitors would abolish this effect in cancer cells 35–38. Altogether, measures that target the ROS-induced activation of p38 MAPK provide new insights into the molecular mechanisms that may be of therapeutic interest for the treatment of colon cancer.…”

Dipeptide YA is Responsible for the Positive Effect of Oyster Hydrolysates on Alcohol Metabolism in Single Ethanol Binge Rodent Models

“…Chang liver cells were plated in a poly-L-lysine-coated confocol image dish and incubated with 5 μM H 2 DCFDA at 37 °C for 30 min in the dark. As previously mentioned, the measurement of ROS levels was performed [ 52 ].…”