DNA repair proteins as the targets for paroxetine to induce cytotoxicity in gastric cancer cell AGS.

To evaluate the potential anticancer effects of 1175 FDA-approved drugs, cell viability screening was performed using 25 human cancer cell lines covering 14 human cancer types. Here, we focus on the action of paroxetine, which demonstrated greater toxicity toward human gastric adenocarcinoma cell-line AGS cells compared with the other FDA-approved drugs, exhibiting an IC50 value lower than 10 µM. Evaluation of the underlying novel mechanisms revealed that paroxetine can enhance DNA damage in gastric cancer cells and involves downregulation of Rad51, HR23B and ERCC1 expression and function, as well as nucleotide shortage. Enhancement of autophagy counteracted paroxetine-induced apoptosis but did not affect paroxetine-induced DNA damage. Paroxetine also enhanced ROS generation in AGS cells, but a ROS scavenger did not improve paroxetine-mediated DNA damage, apoptosis, or autophagy, suggesting ROS might play a minor role in paroxetine-induced cell toxicity. In contrast, paroxetine did not enhance DNA damage, apoptosis, or autophagy in another insensitive gastric adenocarcinoma cell-line MKN-45 cells. Interestingly, co-administration of paroxetine with conventional anticancer agents sensitized MKN-45 cells to these agents: co-treated cells showed increased apoptosis relative to MKN-45 cells treated with the anticancer agent alone. Unequivocally, these data suggest that for the first time that paroxetine triggers cytotoxicity and DNA damage in AGS cells at least partly by reducing the gene expression of Rad51, HR23B, and ERCC1. Our findings also suggest that paroxetine is a promising candidate anticancer agent and/or chemosensitizing agent for use in combination with other anticancer drugs in cancer therapy. The molecular mechanisms underlying the anticancer activity of co-treatment with paroxetine and chemotherapy appear to be complex and are worthy of further investigation.

MEK2 is a critical modulating mechanism to down-regulate GCIP stability and function in cancer cells.

Loss of tumor suppressor activity and upregulation of oncogenic pathways simultaneously contribute to tumorigenesis. Expression of the tumor suppressor, GCIP (Grap2- and cyclin D1-interacting protein), is usually reduced or lost in advanced cancers, as seen in both mouse tumor models and human cancer patients. However, no previous study has examined how cancer cells down-regulate GCIP expression. In this study, we first validate the tumor suppressive function of GCIP using clinical gastric cancer tissues and online database analysis. We then reveal a novel mechanism whereby MEK2 directly interacts with and phosphorylates GCIP at its Ser313 and Ser356 residues to promote the turnover of GCIP by ubiquitin-mediated proteasomal degradation. We also reveal that decreased GCIP stability enhances cell proliferation and promotes cancer cell migration and invasion. Taken together, these findings provide a more comprehensive view of GCIP in tumorigenesis and suggest that the oncogenic MEK/ERK signaling pathway negatively regulates the protein level of GCIP to promote cell proliferation and migration.

Use dose bricks concept to implement nasopharyngeal carcinoma treatment planning.

PURPOSE: A "dose bricks" concept has been used to implement nasopharyngeal carcinoma treatment plan; this method specializes particularly in the case with bell shape nasopharyngeal carcinoma case. MATERIALS AND METHODS: Five noncoplanar fields were used to accomplish the dose bricks technique treatment plan. These five fields include (a) right superior anterior oblique (RSAO), (b) left superior anterior oblique (LSAO), (c) right anterior oblique (RAO), (d) left anterior oblique (LAO), and (e) superior inferior vertex (SIV). Nondivergence collimator central axis planes were used to create different abutting field edge while normal organs were blocked by multileaf collimators in this technique. RESULTS: The resulting 92% isodose curves encompassed the CTV, while maximum dose was about 115%. Approximately 50% volume of parotid glands obtained 10-15% of total dose and 50% volume of brain obtained less than 20% of total dose. Spinal cord receives only 5% from the scatter dose. CONCLUSIONS: Compared with IMRT, the expenditure of planning time and costing, "dose bricks" may after all be accepted as an optional implementation in nasopharyngeal carcinoma conformal treatment plan; furthermore, this method also fits the need of other nonhead and neck lesions if organ sparing and noncoplanar technique can be executed.