Modulating effect of the PI3-kinase inhibitor LY294002 on cisplatin in human pancreatic cancer cells.
BACKGROUND
Chemoresistance is a serious problem in pancreatic cancer, but the mechanism of resistance and strategies against the resistance have not been elucidated. We examined the potential of the phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor LY294002 to enhance the anti-tumor effect of cisplatin and investigated the mechanism of chemoresistance in pancreatic cancer cells using a combination therapy of cisplatin and LY294002, both in vitro and in vivo.


METHODS
Cisplatin and LY294002, individually or in combination, were given to AsPC-1 and PANC-1 cell lines. Tumor growth, DNA fragments, and Akt phosphorylation were examined in vitro. To examine the therapeutic effect of cisplatin and LY294002, individually or combination an AsPC-1 tumor xenograft model was prepared for in vivo study.


RESULTS
Cisplatin induced growth inhibition and Akt phosphorylation in pancreatic cancer cells. LY294002 also inhibited cell proliferation but without showing Akt phosphorylation. However, the combination therapy markedly increased cleavage of caspase-3 and cytoplasmic histone-associated DNA fragments compared to the results with cisplatin alone. In the in vivo study, blocking the PI3K/Akt cascade with LY294002 increased the efficacy of cisplatin-induced inhibition of tumor growth in nude mice, suppressing half the tumor growth with cisplatin alone. There were no detectable side effects in mice treated with combination therapy.


CONCLUSIONS
Our studies suggest that the PI3K/Akt pathway plays an important role in cisplatin resistance of pancreatic cancer cells. The augmentation of cisplatin with PI3K/Akt inhibitor may resolve the chemoresistance problem of cisplatin, and this might be a plausible strategy for achieving tolerance for chemotherapeutic agents in pancreatic cancer therapy.
Fujiwara
Masao
M
Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University 1750-1, Miki, Kita, Kagawa 761-0793, Japan. mfuji@m51.sanuki.ne.jp
Izuishi
Kunihiko
K
Sano
Takanori
T
Hossain
Mohammad Akram
MA
Kimura
Shoji
S
Masaki
Tsutomu
T
Suzuki
Yasuyuki
Y
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D049109:Cell Proliferation; D002867:Chromones / Q000627:therapeutic use*; D002945:Cisplatin / Q000627:therapeutic use*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009025:Morpholines / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014407:Tumor Cells, Cultured
D002867:Chromones; D002945:Cisplatin; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one