Actions of Midostaurin as Cation Channel and Tyrosine Kinase Inhibitor in Diffuse Intrinsic Pontine Glioma Cell Lines

Tyrosine kinases (TKs) are drug targets in diffuse intrinsic pontine glioma (DIPG). Ion channels are emerging targets in cancer. TKIs targeting different kinases such as everolimus, crizotinib, dasatinib, erlotinib, lapatinib, perifosine and midostaurin (0.001-100 μM) were investigated on cell proliferation and ion channel currents. Methods: Cell viability assays in parallel with a patch-clamp study and Western blot of target proteins are performed in SU-DIPG-36 and SU-DIPG-50 cells. Results: Midostaurin is the most effective drug in different assays. Patch-clamp investigations show that the application of midostaurin reduced the inward and outward whole-cell cation channel currents vs. controls in the presence of low internal ATP. These currents were sensitive to the KATP channel inhibitors glibenclamide and repaglinide and were fully reduced by the unselective blocker TEA-BaCl₂. Midostaurin also reduced currents that are sensitive to TRPV1 channel blockers capsazepine and ruthenium-red. The IC₅₀ values of midostaurin as an antiproliferative drug and ion channel inhibitor in either cell line are in the sub-micromolar range. In SU-DIPG-36 cells midostaurin causes a concentration-dependent upregulation of autophagy markers. Conclusions: The inhibition of cation channel currents by midostaurin in SU-DIPG-36 and SU-DIPG-50 cells and the autophagy potentiation in SU-DIPG-36 cells can be novel mechanisms in DIPG.