Wortmannin potentiates roscovitine-induced growth inhibition in human solid tumor cells by repressing PI3K/Akt pathway.

Feng Zhang, Tao Zhang, Tao Jiang, Rong Zhang, Zeng-hui Teng, Chen Li, Zhong-Ping Gu, Qibing Mei

Department of Pharmacology, The Fourth Military Medical University, Xi'an 710032, China.

Cancer letters 2009 Dec 28

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Roscovitine has been reported to have anti-tumor effects in some cancer cell lines. The phosphatidylinositol-3-kinase (PI3K) signaling, which activates protein kinase B (PKB)/Akt, is known to mediate cell survival. The current study examined the role of wortmannin, a PI3K inhibitor, as a chemosensitizer for roscovitine and its proposed mechanism of action. The results showed that wortmannin significantly chemosensitized three human tumor cell lines (A549, HCT116 and HeLa cells). In A549 cells, wortmannin increased roscovitine-induced apoptosis in a dose-dependent manner, which was correlated with the inhibition of phosphorylated PKB/Akt level. Wortmannin enhanced the effects of roscovitine by causing pronounced reduction of mitochondrial transmembrane potential (MMP) and increases of cytochrome c release and active caspase-3, as well as enhanced activation of Bax and Bad, including Bax oligomerization and mitochondrial translocation of Bax and Bad. Taken together, these results provide evidence for the potential application of roscovitine/wormannin combination in clinical treatment for solid tumors.

Citation

Feng Zhang, Tao Zhang, Tao Jiang, Rong Zhang, Zeng-hui Teng, Chen Li, Zhong-Ping Gu, Qibing Mei. Wortmannin potentiates roscovitine-induced growth inhibition in human solid tumor cells by repressing PI3K/Akt pathway. Cancer letters. 2009 Dec 28;286(2):232-9