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ZSTK474, a PI3K inhibitor, suppresses proliferation and sensitizes human pancreatic adenocarcinoma cells to gemcitabine.

Abstract
The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is important in cell proliferation and survival, and it is frequently and aberrantly activated in pancreatic adenocarcinoma. Potential anti-tumor effect(s) of ZSTK474, a PI3K/Akt inhibitor, together with a key clinically relevant anti-tumor agent, gemcitabine (GEM), have been reported in a human pancreatic cancer xenograft mouse model. However, the precise molecular mechanism of these anti-tumor effects has not been well elucidated. In this study, we investigated the molecular mechanism of GEM plus ZSTK474 in reducing tumor cell survival in human pancreatic cancer cell lines. Our study showed that ZSTK474 inhibited cell growth by arresting cells at the G1 phase and by inducing apoptosis. ZSTK474 also inhibited the phosphorylation of Akt, GSK3β and BAD. The combination of GEM and ZSTK474 demonstrated synergistic anti-tumor effects on pancreatic cancer cells in both transient (3 days) and long-term (14 days) clonogenic assays. Thus, we elucidated the potential molecular mechanism leading to the enhanced anti-tumor effect when GEM and ZSTK474 are combined in treatment.
AuthorsHong-Quan Duong, Hee Jeong Kim, Hyo Jin Kang, Yeon-Sun Seong, Insoo Bae
JournalOncology reports (Oncol Rep) Vol. 27 Issue 1 Pg. 182-8 (Jan 2012) ISSN: 1791-2431 [Electronic] Greece
PMID21993922 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Phosphoinositide-3 Kinase Inhibitors
  • Triazines
  • ZSTK474
  • Deoxycytidine
  • Gemcitabine
Topics
  • Adenocarcinoma (metabolism, pathology)
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology)
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Deoxycytidine (administration & dosage, analogs & derivatives)
  • Drug Synergism
  • Flow Cytometry
  • Humans
  • Pancreatic Neoplasms (metabolism, pathology)
  • Phosphoinositide-3 Kinase Inhibitors
  • Triazines (administration & dosage)
  • Gemcitabine

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