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Maslinic acid potentiates the antitumor activities of gemcitabine in vitro and in vivo by inhibiting NF-κB-mediated survival signaling pathways in human gallbladder cancer cells.

Abstract
Gemcitabine (GEM) is one of the first-line drugs in the treatment of gallbladder cancer (GBC), although the therapeutic effect is not sustained due to resistance to the drug over time. Maslinic acid (MA) has been shown to inhibit transcription factor nuclear factor-κB (NF-κB), resulting in the suppression of survival signaling. The authors of the present study investigated whether MA enhanced the antitumor activity of GEM in GBC. Anti-proliferative effects of MA, GEM and MA+GEM were assessed using the MTT assay. Apoptosis was assessed using Annexin V and by western blot analysis of various mediators of apoptosis. Xenograft tumors of EH-GB2 GBC cells were established in athymic nude mice and were monitored following treatment with MA, GEM and MA+GEM. Immunohistochemistry of the tumors was used to examine various survival proteins. MA inhibited the in vitro proliferation of various GBC cell lines and potentiated the apoptosis and cell invasion inhibition induced by GEM. Western blot analysis showed that the combination of MA and GEM inhibited constitutive NF-κB activation and NF-κB-regulated gene products, including cyclin D1, Bcl-2, Bax, MMP-2 and MMP-9, to a greater extent. In vivo, the group that was treated with MA+GEM showed significant reductions in tumor volume and a decreased expression of NF-κB-regulated gene products. In conclusion, the results suggest that MA potentiates the antitumor effects of GEM in human GBC cell lines by suppressing the activation of NF-κB and its dowstream gene products, which are involved in survival signaling.
AuthorsYong Yu, Jinghan Wang, Nianxin Xia, Bin Li, Xiaoqing Jiang
JournalOncology reports (Oncol Rep) Vol. 33 Issue 4 Pg. 1683-90 (Apr 2015) ISSN: 1791-2431 [Electronic] Greece
PMID25633045 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • NF-kappa B
  • Neoplasm Proteins
  • Triterpenes
  • Deoxycytidine
  • maslinic acid
  • Gemcitabine
Topics
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
  • Apoptosis (drug effects)
  • Carcinoma (drug therapy, pathology)
  • Cell Line, Tumor
  • Cell Movement (drug effects)
  • Deoxycytidine (administration & dosage, analogs & derivatives, pharmacology)
  • Drug Synergism
  • Gallbladder Neoplasms (drug therapy, pathology)
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • NF-kappa B (antagonists & inhibitors)
  • Neoplasm Invasiveness
  • Neoplasm Proteins (antagonists & inhibitors)
  • Random Allocation
  • Signal Transduction (drug effects)
  • Triterpenes (administration & dosage, pharmacology)
  • Xenograft Model Antitumor Assays
  • Gemcitabine

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