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Amiloride sensitizes human pancreatic cancer cells to erlotinib in vitro through inhibition of the PI3K/AKT signaling pathway

   
@article{APS9301,
	author = {Yuan-ting Zheng and Hui-ying Yang and Tao Li and Bei Zhao and Teng-fei Shao and Xiao-qiang Xiang and Wei-min Cai},
	title = {Amiloride sensitizes human pancreatic cancer cells to erlotinib  in vitro  through inhibition of the PI3K/AKT signaling pathway},
	journal = {Acta Pharmacologica Sinica},
	volume = {36},
	number = {5},
	year = {2017},
	keywords = {},
	abstract = {Aim: Blockade of EGFR by EGFR tyrosine kinase inhibitors such as erlotinib is insufficient for effective treatment of human pancreatic cancer due to independent activation of the Akt pathway, while amiloride, a potassium-sparing diuretic, has been found as a potential Akt inhibitor. The aim of this study was to investigate the anticancer effects of combined amiloride with erlotinib against human pancreatic cancer cells in vitro.
Methods: Cell proliferation, colony formation, cell cycle and apoptosis were analyzed in 4 human pancreatic cancer cell lines Bxpc-3, PANC-1, Aspc-1 and CFPAC-1 treated with erlotinib or amiloride alone, or in their combination. The synergistic analysis for the effects of combinations of amiloride and erlotinib was performed using Chou-Talalay’s combination index isobolographic method.
Results: Amiloride (10, 30, and 100 μmol/L) concentration-dependently potentiated erlotinib-induced inhibition of cell proliferation and colony formation in the 4 pancreatic cancer cell lines. Isobolographic analysis confirmed that combinations of amiloride and erlotinib produced synergistic cytotoxic effects. Amiloride significantly potentiated erlotinib-induced G0/G1 cell-cycle arrest and apoptosis in Bxpc-3 and PANC-1 cells. Amiloride inhibited EGF-stimulated phorsphorylation of AKT, and significantly enhanced erlotinib-induced downregulation of phorsphorylation of EGFR, AKT, PI3K P85 and GSK 3β in Bxpc-3 and PANC-1 cells.
Conclusion: Amiloride sensitizes human pancreatic cancer cells to erlotinib in vitro through inhibition of the PI3K/AKT signaling pathway. Treatment of pancreatic cancer patients with combination of erlotinib and amiloride merits further investigation.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/9301}
}