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Overexpression of pyruvate dehydrogenase kinases (PDKs) has been widely noticed in a variety of human solid tumors, which could be regarded as an attractive therapeutic target for cancer therapy. In this paper, we present an enzymatic screening assay and multiple biological evaluations for the identification of potential PDKs, especially PDK1 inhibitors. We identified 9 potential PDKs inhibitors from the screening of an in-house small molecule library, all of the identified inhibitors reduced pyruvate dehydrogenase (PDH) complex phosphorylation. Among which, 4, 5, and 9 displayed the most potent PDKs inhibitory activities, with EC 50 values of 0.34, 1.4, and 1.6 μM in an enzymatic assay, respectively. A kinase inhibition assay suggested that 4, 5, and 9 were pan-isoform PDK inhibitors, but more sensitive to PDK1. Meanwhile, the three compounds inhibited HSP90, with IC 50 values of 0.78, 3.58, and 2.70 μM, respectively. The cell viability assay indicated that 4 inhibited all of the tested cancer cells proliferation, with a GC 50 value of 2.3 μM against NCIH1975 cell, but has little effect on human normal lung cell BEAS-2B cell. In the NCIH1975 xenograft models, 4 displayed strong antitumor activities at a dose of 10 and 20 mg/kg, but with no negative effect on the mice weight. In addition, 4 decreased the ECAR and lactate formation, increased OCR and ROS level in NCIH1975 cancer cell, which could be used as a promising modulator to reprogram the glucose metabolic pathways in NCIH1975 cancer cells., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

The purpose of this study was to explore the role by which the DNA-dependent protein kinase complex catalytic subunit (DNA-PKcs) influences osteosarcoma MG-63 cell apoptosis, proliferation, migration and invasion. Osteosarcoma tissues and adjacent normal tissues were obtained from 57 osteosarcoma patients. Human osteosarcoma MG-63 cells were assigned into designated groups including the blank, siRNA-negative control (NC) and siRNA-DNA-PKcs groups. RT-qPCR and Western blotting methods were employed to evaluate the mRNA and protein expressions of DNA-PKcs. A cell counting kit-8 (CCK-8) assay was performed to assess cell viability. The evaluation of cell migration and invasion were conducted by means of Scratch test and Transwell assay. Flow cytometry with PI and annexin V/PI double staining was applied for the analysis of the cell cycle and apoptosis. Twenty-Four Balb/c nude mice were recruited and randomly divided into the blank, siRNA-NC and siRNA-DNA-PKcs groups. Tumorigenicity of the Balb/c nude mice was conducted to evaluate the rate of tumor formation, as well as for the assessment of tumor size and weight, and confirm the number of lung metastatic nodules in the mice post transfection. Osteosarcoma tissues were found to possess greater expression of DNA-PKcs than that of the adjacent normal tissues. DNA-PKcs expression in osteosarcoma tissues were correlated with the clinical stage and metastasis. Compared with the blank and siRNA-NC groups, proliferation, miration, as well as the invasion abilities of the MG-63 cells increased. Furthermore, an increase in apoptosis and cells at the G1 stage in the MG-63 cells was observed, while there were reductions in the cells detected at the S stage. The mRNA and protein expressions of CyclinD1, PCNA, Bcl-2 decreased while those of Bax increased in the siRNA-DNA-PKcs group. The tumor formation rate, tumor diameter, weight and lung metastatic nodules among the nude mice in the siRNA-DNA-PKcs group were all lower than those in the blank and siRNA-NC groups. The observations and findings of the study suggested that the silencing of DNA-PKcs inhibits the proliferation, migration and invasion, while acting to promote cell apoptosis in MG-63 cells and osteosarcoma growth in nude mice., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Objectives: During this study, we aimed to analyze the correlation between dosages of dexmedetomidine (DEX) and the p38MAPK/NF-κB signaling pathway, and their effects on immune function and tumor growth in rats with ovarian cancer (OC)., Methods: A total of 100 rats were selected for the purposes of the study. The normal group consisted of 20 rats, while the remaining 80 rats were utilized for OC model establishment purposes, and further assigned into the model, 0.2 DEX, 1 DEX and 5 DEX groups (based on respective dosages of DEX, n=20 per group). The tumor inhibition rate was calculated. Positive expressions of p38 and NF-κB in ovarian tissues were examined by means of immunohistochemical staining. Cell transformation as well as lymphocyte proliferation rates were measured using MTT. Cell cycle and apoptosis of CD4 + and CD8 + cells were determined by flow cytometry. Serum levels of IL-2 and TNF-α were detected using ELISA, while qRT-PCR and western blotting methods were used to analyze mRNA and protein expressions of p38 and NF-κB., Results: Compared with the normal group, the other four groups exhibited up-regulated IL-2, TNF-α serum levels as well as up regulated expressions of p38, NF-κB65 mRNA and protein; while the respective percentages of both CD4 + and CD8 + T cells exhibited down-regulated rates. The other four groups displayed increases in tumor weight and cell apoptosis, as well as decreased levels of cell proliferation and transformation rates. The aforementioned findings of the study ultimately highlighted a greater tendency among the three DEX groups in comparison to the model group., Conclusion: The findings of the study suggest that a particular dosage of DEX may act to enhance the immune function of rats with OC by inhibiting the p38MAPK/NF-κB signaling pathway., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. Concern was raised about the reliability of the Western blot results in Figures 3A, 5C and 7A which appear to have a similar phenotype as many other publications, as detailed here: https://pubpeer.com/publications/7D9475A7397928053FFE9442F8E943; and here: https://docs.google.com/spreadsheets/d/1r0MyIYpagBc58BRF9c3luWNlCX8VUvUuPyYYXzxWvgY/edit#gid=262337249. Several additional suspected image duplication issues were also identified in Figures 3A, 5A, and 7A. The journal requested the corresponding authors comment on these concerns and provide the raw data. The authors were unable to provide a satisfactory explanation or the raw data. The Supervision Committee of the National Natural Science Foundation of China launched an investigation into several papers of Jiangsu Normal University, including this one, and found evidence of "Falsification of pictures or data, fabrication of research process, use of others' signatures without consent, and false information in project final reports", as detailed here: https://www.nsfc.gov.cn/publish/portal0/tab442/info85495.htm. The Academic Committee at Jiangsu Normal University requested retraction of the article. The Editor-in-Chief assessed the case and decided to retract the article., (Copyright © 2017. Published by Elsevier Masson SAS.)