Targeting phosphatidylinositol 4-kinase IIIα for radiosensitization: a potential model of drug repositioning using anti-HCV agent

Publication date: Available online 20 August 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Jeanny Kwon, Dan Hyo Kim, Ji Min Park, Young Hee Park, Yeo Hyun Hwang, Hong-Gyun Wu, Kyung Hwan Shin, In Ah Kim
PurposePhosphatidylinositol 4-kinase (PI4K) is responsible for the generation of PI4-phosphate (PI4P), a common upstream substrate of both the PLC/PKC and PI3K/Akt pathways. Inhibition of PI4K is expected to inactivate these PI4P-dependent pathways simultaneously. Therefore, we investigated that which isotype of PI4K may affect a radiosensitivity and examined whether anti-hepatitis C viral (HCV) agents, some of which have been shown to inhibit PI4K IIIα activity, could be repositioned or not as a radiosensitizer in human cancer cells.Methods and MaterialsU251, BT474, HepG2 cell lines and NHA were used. RNAi, clonogenic assays, western blotting, immunofluorescence, annexin V assay, lysotracker staining, and β-galactosidase assay were performed.ResultsOf the four PI4K isotypes, specific inhibition of IIIα increased the radiosensitivity. For pharmacologic inhibition of PI4K IIIα, we screened 9 anti-HCV agents by IC50 assay. Simeprevir was selected and its inhibition of PI4K IIIα activity was confirmed. Combination of simeprevir treatment and radiation significantly attenuated expression of p-PKC and p-Akt and increased radiation-induced cell death in tested cell lines. Pretreatment with simeprevir prolonged γH2AX foci formation and downregulation of p-DNA-PKcs, indicating impairment of nonhomologous end-joining repair. Cells pretreated with simeprevir exhibited mixed modes of cell death, including apoptosis and autophagy.ConclusionThese data demonstrate that targeting PI4K IIIα using an anti-HCV agent is a viable approach to enhance the therapeutic efficacy of radiotherapy in various human cancers, such as glioma, breast, and hepatocellular carcinoma.

Teaser

Targeting PI4K IIIα by siRNA showed a significant radiosensitizing effect on human cancer cells. The anti-HCV agent simeprevir had an inhibitory effect of PI4K IIIα, resulting in radiosensitization by inhibiting prosurvival signaling and DNA damage repair. Inhibition of PI4K IIIα via simeprevir represents an attractive approach for simultaneously inhibiting both the PI3K/Akt and PLC/PKC pathways and a viable approach to enhance the therapeutic efficacy of radiotherapy in various human cancers.


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