title: Sclareolide enhances gemcitabine‑induced cell death through mediating the NICD and Gli1 pathways in gemcitabine‑resistant human pancreatic cancer.
abstract: Pancreatic cancer is a type of cancer, which rapidly develops resistance to chemotherapy. Gemcitabine is the treatment used clinically, however, gemcitabine resistance leads to limited efficacy and patient survival rates of only a few months following diagnosis. The aim of the present study was to investigate the mechanisms underlying gemcitabine resistance in pancreatic cancer and to select targeted agents combined with gemcitabine to promote the treatment of pancreatic cancer. Panc‑1 and ASPC‑1 human pancreatic cancer cells (HPCCs) were used to establish the experimental model, and HPCCs were exposed to gemcitabine of serially increased concentrations to generate gemcitabine‑resistant cells (GR‑HPCCs). The anticancer effect of gemcitabine combined with sclareolide was then assessed. Epithelial to mesenchymal transition (EMT), human equilibrative nucleoside transporter 1 (hENT1) and ribonucleoside diphosphate reductase 1 (RRM1) were detected in the HPCCs and GR‑HPCCs, and the mechanisms were investigated. Sclareolide resensitized the GR‑HPCCs to gemcitabine. The expression levels of hENT1 and RRM1 were lower and higher, respectively, in GR‑HPCCs, compared with HPCCs. Sclareolide upregulated hENT1, downregulated RRM1 and inhibited gemcitabine‑induced EMT through the TWIST1/Slug pathway in the GR‑HPCCs. In addition, sclareolide mediated the NOTCH 1 intracellular cytoplasmic domain (NICD)/glioma‑associated oncogene 1 (Gli1) pathway, which triggered TWIST1/Slug‑hENT1/RRM1 signaling and resensitized GR‑HPCCs to gemcitabine. Finally, sclareolide resensitized GR‑HPCCs to gemcitabine through inducing apoptosis; in vivo, the co‑administraion of sclareolide and gemcitabine effectively suppressed tumor growth. Sclareolide may be a novel agent in combination with gemcitabine for the treatment of gemcitabine‑resistant pancreatic cancer, which resensitizes GR‑HPCCs to gemcitabine through mediating NICD and Gli1.
authors.affiliation: Department of General Surgery, The General Hospital of the PLA Rocket Force, Beijing 100088, P.R. China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Pathology, China‑Japan Friendship Hospital, Beijing 100029, P.R. China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of General Surgery, The General Hospital of the PLA Rocket Force, Beijing 100088, P.R. China.
authors.forename: Wen-Long
authors.initials: WL
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, The General Hospital of the PLA Rocket Force, Beijing 100088, P.R. China.
authors.forename: Mao-Sheng
authors.initials: MS
authors.lastname: Dong
authors.affiliation: Department of General Surgery, The General Hospital of the PLA Rocket Force, Beijing 100088, P.R. China.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004224:Diterpenes / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D033721:Equilibrative Nucleoside Transporter 1 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D010641:Phenotype; D051880:Receptors, Notch / Q000378:metabolism*; D012262:Ribonucleoside Diphosphate Reductase; D015398:Signal Transduction / Q000187:drug effects*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000071676:Zinc Finger Protein GLI1 / Q000378:metabolism*; D000093542:Gemcitabine
chemical_list: D004224:Diterpenes; D033721:Equilibrative Nucleoside Transporter 1; C400551:GLI1 protein, human; D051880:Receptors, Notch; C438649:SLC29A1 protein, human; D025521:Tumor Suppressor Proteins; D000071676:Zinc Finger Protein GLI1; D003841:Deoxycytidine; C109395:sclareolide; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; D000093542:Gemcitabine