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Inhibition of Phosphatidylinositide 3-Kinase Enhances Gemcitabine-induced Apoptosis in Human Pancreatic Cancer Cells¹

Divisions of Experimental Therapeutics [S. S. W. N., D. W. H.] and Molecular & Cellular Biology [M-S. T.], Ontario Cancer Institute, and Departments of Medical Oncology & Hematology [D. W. H.], Laboratory Medicine & Pathobiology [M-S. T., S. C.] and Medical Biophysics [S. S. W. N., M-S. T., D. W. H.], Princess Margaret Hospital and University of Toronto, Toronto, Ontario, M5G 2M9 Canada

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

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