LY294002 enhances inhibitory effect of gemcitabine on proliferation of human pancreatic carcinoma PANC-1 cells

Abstract

Phosphatidylinositide 3-kinase (PI3K)/protein kinase B (PKB, Akt) pathway plays a major role in proliferation and survival of many types of cells. The inhibitory effect of LY294002, widely applied as an inhibitor of PI3K, in combination with gemcitabine on proliferation of PANC-1 cells was investigated. The expression of PI3K, phosphorylated Akt (p-Akt) and multidrug-resistance like protein (MRP) in normal pancreas tissues, chronic pancreatitis tissues and pancreatic carcinoma tissues was detected. The effects of LY294002 combined with gemcitabine on proliferation of PANC-1 cells and protein levels of p-Akt and MRP were detected. The results showed that the positive expression rate of PI3K, p-Akt and MRP in pancreatic carcinoma tissues was significantly higher than that in normal pancreas tissues and chronic pancreatitis tissues (P<0.01 and P<0.05 respectively). LY294002 could effectively enhance the inhibitory effect of gemcitabine on proliferation of PANC-1 cells. Furthermore, Western blotting revealed that LY294002 combined with gemcitabine reduced the protein levels of p-Akt and MRP, which contributed to the inhibition of proliferation. It is concluded that LY294002 in combination with gemcitabine may represent an alternative therapy for pancreatic carcinoma.

Keywords

pancreatic carcinoma / phosphatidylinositide 3-kinase / phosphorylated protein kinase B / multidrug-resistance like protein / LY294002

References

[1] DanoviD.S., WongH.H., LemoineN.R.. Targeted therapies for pancreatic cancer. Br Med Bull, 2008, 87(1): 97-130

[2] CascinuS., VerdecchiaL., ValeriN., et al.. New target therapies in advanced pancreatic cancer. Ann Oncol, 2006, 17(Suppl5): v148-152

[3] AlbertB.L., MaisonneuveP.. Epidemiology and prevention of pancreatic cancer. Jpn J Clin Oncol, 2004, 34(5): 238-244

[4] AntonioJ., ManuelH.. Molecular biomarkers: their increasing role in the diagnosis characterization, and therapy guidance in pancreatic cancer. Mol Cancer, 2006, 5(4): 787-796

[5] StollV., CallejaV., VassauxG., et al.. Dominant negative inhibitors of signalling through the phosphoinositol 3-kinase pathway for gene therapy of pancreatic cancer. Gut, 2005, 54(1): 109-116

[6] SimonP.O.Jr, McDunnJ.E., KashiwagiH., et al.. Targeting Akt with the proapoptotic peptide, TAT-CTMP: a novel strategy for the treatment of human pancreatic adenocarcinoma. Int J Cancer, 2009, 125(4): 942-951

[7] NgS.S.W., TsaoM.S., ChowS., et al.. Inhibition of phosphatidylinositide 3-kinase enhances gemcitabine-induced apoptosis in human pancreatic cancer Cells. Cancer Res, 2000, 60(19): 5451-5455

[8] HolcombB., Yip-SchneiderM.T., MatosJ.M., et al.. Pancreatic cancer cell genetics and signaling response to treatment correlate with efficacy of gemcitabine-based molecular targeting strategies. J Gastrointest Surg, 2008, 12(2): 288-296

[9] JunY., CuijuanQ.. Inhibition of Notch3 enhances sensitivity to gemcitabine in pancreatic cancer through an inactivation of PI3K/Akt-dependent pathway. Med Oncol, 2010, 27(3): 1017-1022

[10] TakedaA., OsakiM., AdachiK., et al.. Role of the phosphatidylinositol 3′-kinase-Akt signal pathway in the proliferation of human pancreatic ductal carcinoma cell lines. J Surg Res, 2010, 160(1): 90-101

[11] MaJ., SawaiH., MatsuoY., et al.. IGF-1 mediates PTEN suppression and enhances cell invasion and proliferation via activation of the IGF-1/PI3K/Akt signaling pathway in pancreatic cancer cells. J Surg Res, 2010, 160(1): 90-101

[12] StollV., CallejaV., VassauxG., et al.. Dominant negative inhibitors of signaling through the phosphoinositol 3-kinase pathway for gene therapy of pancreatic cancer. Gut, 2005, 54(1): 109-116

[13] WorkmanP., ClarkeP.A., RaynaudF.I., et al.. Drugging the PI3 kinome: from chemical tools to drugs in the clinic. Cancer Res, 2010, 70(6): 2146-2157

[14] O’DriscollL., WalshN., LarkinA., et al.. MDR1/P-glycop-rotein and MRP-1 drug efflux pumps in pancreatic carcinoma. Anticancer Res, 2007, 27(4B): 2115-2120

[15] BergmanA.M., PinedoH.M., TalianidisI., et al.. Increased sensitivity to gemcitabine of P-glycoprotein and multidrug resistance-associated protein-overexpressing human cancer cell lines. Br J Cancer, 2003, 88(12): 1963-1970

[16] LeeJ.T.Jr, SteelmanL.S., McCubreyJ.A.. Phosphatidylinositol 3′-kinase activation leads to multidrug resistance protein-1 expression and subsequent chemoresistance in advanced prostate cancer cells. Cancer Res, 2004, 64(22): 8397-8404

[17] YauC.Y., WheelerJ.J., SuttonK.L., et al.. Inhibition of integrin-linked kinase by a selective small molecule inhibitor, QLT0254, inhibits the PI3K/PKB/mTOR, Stat3, and FKHR pathways and tumor growth, and enhances gemcitabine-induced apoptosis in human orthotopic primary pancreatic cancer xenografts. Cancer Res, 2005, 65(4): 1497-1504

[18] EdgeS.B., ComptonC.C.. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol, 2010, 17(6): 1471-1474

[19] ChuaY.J., CunninghamD.. Chemotherapy for advanced pancreatic cancer. Best Pract Res Clin Gastroenterol, 2006, 20(2): 327-348

[20] ReichertM., SaurD., HamacherR., et al.. Phosphoinositide-3-kinase signaling controls S-phase kinase-associated protein 2 transcription via E2F1 in pancreatic ductal adenocarcinoma cells. Cancer Res, 2007, 67(9): 4149-4156

[21] EdlingC.E., SelvaggiF., BuusR., et al.. Key role of phosphoinositide 3-kinase class IB in pancreatic cancer. Clin Cancer Res, 2010, 16(20): 4928-4937

[22] BondarV.M., Sweeney GotschB., AndreeffM., et al.. Inhibition of the phosphatidylinositol 3′-kinase (PI3K)-Akt pathway induces apoptosis in pancreatic carcinoma cells in vitro and in vivo. Mol Cancer Ther, 2002, 1(12): 989-997

[23] YamasakiF., JohansenM.J., ZhangD.W., et al.. Acquired resistance to erlotinib in A-431 epidermoid cancer cells requires down-regulation of MMAC/PTEN and up-regulation of phosphorylated Akt. Cancer Res, 2007, 67(12): 5779-5788

[24] XiaS., YuS., FuQ., et al.. Inhibiting PI3K/Akt pathway increases DNA damage of cervical carcinoma heLa cells by drug radiosensitization. J Huazhong Univ Sci Technol [Med Sci], 2010, 30(3): 360-364

[25] Yip-SchneiderM.T., WiesenauerC.A., SchmidtC.M.. Inhibition of the phosphatidylinositol 3′-kinase signaling pathway increases the responsiveness of pancreatic carcinoma cells to sulindac. J Gastrointest Surg, 2003, 7(3): 354-363

[26] KongD., YamoriT.. Phosphatidylinositol 3-kinase inhibitors: promising drug candidates for cancer therapy. Cancer Sci, 2008, 99(9): 1734-1740