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Oncotarget. 2016 Apr 12;7(15):19897-909. doi: 10.18632/oncotarget.7658.

ZSTK474, a specific class I phosphatidylinositol 3-kinase inhibitor, induces G1 arrest and autophagy in human breast cancer MCF-7 cells.

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Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China.
Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Nankai Dsitrict, Tianjin 300193, China.


Multifaceted activities of class I phosphatidylinositol 3-kinase (PI3K) inhibitor ZSTK474 were investigated on human breast cancer cell MCF-7. ZSTK474 inhibited proliferation of MCF-7 cells potently. Flow cytometric analysis indicated that ZSTK474 induced cell cycle arrest at G1 phase, but no obvious apoptosis occurred. Western blot analysis suggested that blockade of PI3K/Akt/GSK-3β/cyclin D1/p-Rb pathway might contribute to the G1 arrest induced. Moreover, we demonstrated that ZSTK474 induced autophagy in MCF-7 cells by use of various assays including monodansylcadaverine (MDC) staining, transmission electron microscopy (TEM), tandem mRFP-GFP-LC3 fluorescence microscopy, and western blot detection of the autophagy protein markers of LC3B II, p62 and Atg 5. Inhibition of class I PI3K and the downstream mTOR might be involved in the autophagy-inducing effect. Combinational use of ZSTK474 and autophagy inhibitors enhanced cell viability, suggesting ZSTK474-induced autophagy might contribute to the antitumor activity. Our report supports the application of ZSTK474, which is being evaluated in clinical trials, for breast cancer therapy.


G1 arrest; MCF-7; PI3K inhibitor; ZSTK474; autophagy

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