title: Antitumor activity of gemcitabine can be potentiated in pancreatic cancer through modulation of TLR4/NF-κB signaling by 6-shogaol.
abstract: Advanced pancreatic cancer still has a poor prognosis, even with the approval of several drugs, such as gemcitabine. Therefore, developing effective and safe antitumor agents is urgently needed. 6-Shogaol, a phenol extracted from ginger, has been linked to suppression of proliferation and survival of cancer with different mechanisms. In the present study, we investigated whether 6-shogaol could suppress pancreatic cancer progress and potentiate pancreatic cancer to gemcitabine treatment in vitro and in vivo. We found that 6-shogaol prevented the activation of toll like receptor 4 (TLR4)/NF-κB signaling. The modulation of NF-κB signaling by 6-shogaol was ascertained by electrophoretic mobility shift assay and western blot analysis. The suppression of NF-κB signaling and key cell survival regulators including COX-2, cyclinD1, survivin, cIAP-1, XIAP, Bcl-2, and MMP-9 brought the anti-proliferation effects in pancreatic cancer cells and sensitized them to gemcitabine treatment. Furthermore, in a pancreatic cancer xenograft model, we found a decreased proliferation index (Ki-67) and increased apoptosis by TUNEL staining in 6-shogaol treated tumors. It was also shown that 6-shogaol combined with gemcitabine treatment was more effective than drug alone, consistent with the downregulation of NF-κB activity along with its target genes COX-2, cyclinD1, survivin, cIAP-1, and XIAP. Overall, our results suggest that 6-shogaol can inhibit the growth of human pancreatic tumors and sensitize them to gemcitabine by suppressing of TLR4/NF-κB-mediated inflammatory pathways linked to tumorigenesis.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing, 210009, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhou
authors.forename: Lianwen
authors.initials: L
authors.lastname: Qi
authors.forename: Lifeng
authors.initials: L
authors.lastname: Jiang
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.forename: Jiang
authors.initials: J
authors.lastname: Ma
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Xu
authors.forename: Ping
authors.initials: P
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002396:Catechols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D002396:Catechols; D016328:NF-kappa B; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D003841:Deoxycytidine; C040115:shogaol; D000093542:Gemcitabine