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J Exp Clin Cancer Res. 2008 Nov 25;27:76. doi: 10.1186/1756-9966-27-76.

Modulating effect of the PI3-kinase inhibitor LY294002 on cisplatin in human pancreatic cancer cells.

Author information

1
Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University 1750-1, Miki, Kita, Kagawa 761-0793, Japan. mfuji@m51.sanuki.ne.jp

Abstract

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.

CONCLUSION:

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.

PMID:
19032736
PMCID:
PMC2607265
DOI:
10.1186/1756-9966-27-76
[Indexed for MEDLINE]
Free PMC Article

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