Inhibition of phosphatidylinositide 3-kinase enhances gemcitabine-induced apoptosis in human pancreatic cancer cells.

摘要: Human pancreatic adenocarcinoma cell lines PK1 and PK8 are resistant to the clinically relevant chemotherapy agent gemcitabine. Cell cycle analysis demonstrated an accumulation of cells in early S phase during treatment with 20 microM gemcitabine, consistent its mode action as a DNA chain terminator. However, apoptosis was evident only small percentage cells. Similar cancers clinic, carry constitutively active Ki-Ras overexpress multiple receptor tyrosine kinases. Both genetic abnormalities may potentially up-regulate activity phosphatidylinositide 3-kinase (P13K)-protein kinase B (PKB)/Akt survival pathway. The current study examined relevance this pathway modulation drug resistance After exposure gemcitabine for 48 h continuous presence drug, P13K inhibitors wortmannin (50-200 nM) LY294002 (15-120 microM) 4 substantially enhanced concentration-dependent manner compared alone, determined by loss mitochondrial membrane potential increase propidium iodide uptake using flow cytometry. Furthermore, Western blotting showed that reduction phosphorylated PKB/Akt levels correlated enhancement gemcitabine-induced apoptosis, suggesting PI3K-PKB/Akt plays significant role mediating human cancer PI3K have therapeutic when combined cancers.