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Yun-Ting Zhu,1,* Zan Teng,2,3,* Yi-Fan Zhang,1 Wei Li,1 Li-Xia Guo,1 Yun-Peng Liu,2,3 Xiu-Juan Qu,2,3 Quan-Ren Wang,4 Si-Yuan Mao,4 Xiao-Yan Chen,1 Da-Fang Zhong1 1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People’s Republic of China; 2Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, People’s Republic of China; 3Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, People’s Republic of China; 4Department of Clinical Research and Development, Jiangsu Hengrui Medicine Co., Ltd., Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi-Fan Zhang; Da-Fang ZhongState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, People’s Republic of ChinaTel/ Fax +86 21 50800738Email yfzhang@simm.ac.cn; dfzhong@simm.ac.cnBackground and Purpose: Apatinib is a small-molecule tyrosine kinase inhibitor for the treatment of recurrent or progressive advanced-stage gastric adenocarcinoma or gastroesophageal junction cancer. The in vitro inhibition studies suggested that apatinib exerted potent inhibition on CYP3A4 and CYP2C9. To evaluate the potential of apatinib as a perpetrator in CYP450-based drug–drug interactions in vivo, nifedipine and warfarin were, respectively, selected in the present study as the probe substrates of CYP3A4 and CYP2C9 for clinical drug–drug interaction studies. Since hypertension and thrombus are common adverse effects of vascular targeting anticancer agents, nifedipine and warfarin are usually coadministered with apatinib in clinical practice.Methods: A single-center, open-label, single-arm, and self-controlled trial was conducted in patients with advanced solid tumors. The patients received a single dose of 30 mg nifedipine on Day 1/14 and a single dose of 3 mg warfarin on Day 3/16. On Day 9– 21, the subjects received a daily dose of 750 mg apatinib, respectively. The pharmacokinetics of nifedipine and warfarin in the absence or presence of apatinib was, respectively, investigated.Results: Compared with the single oral administration, coadministration with apatinib contributed to the significant increases of AUC0– 48h and Cmax of nifedipine by 83% (90% confidence interval [CI] 1.46– 2.31) and 64% (90% CI 1.34– 2.01), respectively. Similarly, coadministration with apatinib contributed to the significant increases of AUC0-t and Cmax of S-warfarin by 92% (90% CI 1.68– 2.18) and 24% (90% CI 1.10– 1.39), respectively.Conclusion: Concomitant apatinib administration resulted in significant increases in systemic exposure to nifedipine and S-warfarin. Owing to the risk of pharmacokinetic drug–drug interactions based on CYP3A4/CYP2C9 inhibition by apatinib, caution is advised in the concurrent use of apatinib with either CYP2C9 or CYP3A4 substrates.Keywords: apatinib, drug-drug interaction, CYP3A4, CYP2C9, nifedipine, warfarin

Li-Bao Gong,1,2,* Chuang Zhang,1,2,* Ruo-Xi Yu,1,2 Ce Li,1,2 Yi-Bo Fan,1,2 Yun-Peng Liu,1,2 Xiu-Juan Qu1,2 1Department of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, People’s Republic of China; 2Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiu-Juan QuDepartment of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, People’s Republic of ChinaTel +86-24-83282312Fax +86-24-83282543Email xiujuanqu@yahoo.comPurpose: To explore the role of FKBP prolyl isomerase 10 (FKBP10) protein in the progression of gastric cancer.Methods: Four independent gastric cancer databases (GSE27342, GSE29272, GSE54129 and TCGA-STAD) were used to identify differentially expressed genes (DEGs). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was used to identify the abnormally active pathways in patients with gastric cancer. Univariate Cox regression analysis was used to identify genes with stable prognostic value in gastric cancer patients based on three independent gastric cancer databases (GSE15459, GSE62254, TCGA-STAD). Gene set enrichment analysis (GSEA) was used to explore the possible pathways related to FKBP10. The reverse transcription-polymerase chain reaction (RT-PCR) was employed to determine the expression of FKBP10 mRNA in the HGC-27 and MKN-7 cell lines. Adhesion assay was used to detect changes in cell adhesion ability. FKBP10, ITGA1, ITGA2, ITGA5, ITGAV, ITGA6, P-AKT473, P-AKT308, AKT, and β-actin were evaluated by Western blot (WB).Results: We first performed differential expression genes (DEGs) screening of four independent GC databases (GSE27342, GSE29272, GSE54129 and TCGA-STAD). Eighty-nine genes showed consistent up-regulation in GC, the results of pathway analysis showed that they were related to “Focal adhesion”. The prognostic value of these 89 genes was tested in three independent GC databases GSE15459, GSE62254 and TCGA-STAD cohort. Finally, 12 genes, in which the expression of FKBP10 was prominently increased in patients with lymph node metastasis (LNM), showed stable prognostic value. The following gene set enrichment analysis (GSEA) also showed that FKBP10 is mainly involved in cell adhesion process, while adhesion experiments confirmed that cell adhesion was down-regulated after silencing FKBP10 in GC cells, and adhesion-related molecules integrin αV and α 6 were down-regulated.Conclusion: FKBP10 may be used as a marker for lymph node metastasis of GC and could be used as a potential target for future treatment of GC.Keywords: FKBP10, GC, adhesion, lymph node metastasis, integrin

Wei Jing,1 Na Song,2,3 Yun-Peng Liu,2,3 Xiu-Juan Qu,2,3 Ya-Fei Qi,4 Ce Li,2,3 Ke-Zuo Hou,2,3 Xiao-Fang Che,2,3 Xiang-Hong Yang41The First Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China; 2Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, People’s Republic of China; 3Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, People’s Republic of China; 4Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of ChinaBackground: Although aberrant DNA methyltransferase 3a (DNMT3a) expression is important to the tumorigenesis of pancreatic ductal adenocarcinoma (PDAC), the role of DNMT3a in PDAC prognosis is not clarified yet due to the limited studies and lacking of underlying molecular mechanism.Methods: The expression of DNMT3a was examined by immunohistochemistry in PDAC tissues. Gene expression profiles assays were conducted to explore the impact of DNMT3a on biological processes and signal pathways. Cell cycle and apoptosis were measured by flow cytometry. Western blotting and real-time qPCR assays were used to explore the impact of DNMT3a on expression of protein and mRNA related to cell cycle, STAT3 signaling pathway and apoptosis.Results: DNMT3a was overexpressed and closely associated with poor outcomes of PDAC. DNMT3a knockdown restrained PDAC cell proliferation, induced cell cycle arrest and promoted apoptosis in vitro. Affymetrix GeneChip Human Transcriptome Array identified that the cell cycle-related process was most significantly associated with DNMT3a. DNMT3a knockdown induced G1-S phase transition arrest by decreasing the expression of cyclin D1, which was mediated by the reduction of IL8 and the subsequent inactivation of STAT3 signaling pathway. Furthermore, exogenous apoptosis was also promoted after DNMT3a knockdown, probably via up-regulation of DNA transcription and expression in CASP8.Conclusion: These findings indicate that DNMT3a plays an important role in PDAC progression. DNMT3a may serve as a prognostic biomarker and a therapeutic strategy candidate in PDAC.Keywords: DNA methyltransferase 3a, pancreatic ductal adenocarcinoma, prognosis, proliferation