TY  - JOUR
A1  - Pastukhov, Oleksandr
A1  - Schwalm, Stephanie
A1  - Zangemeister-Wittke, Uwe
A1  - Fabbro, Doriano
A1  - Bornancin, Frederic
A1  - Japtok, Lukasz
A1  - Kleuser, Burkhard
A1  - Pfeilschifter, Josef
A1  - Huwiler, Andrea
T1  - The ceramide kinase inhibitor NVP-231 inhibits breast and lung cancer cell proliferation by inducing M phase arrest and subsequent cell death
JF  - British journal of pharmacology : journal of The British Pharmacological Society
N2  - Background and PurposeCeramide kinase (CerK) catalyzes the generation of ceramide-1-phosphate which may regulate various cellular functions, including inflammatory reactions and cell growth. Here, we studied the effect of a recently developed CerK inhibitor, NVP-231, on cancer cell proliferation and viability and investigated the role of cell cycle regulators implicated in these responses.
 Experimental ApproachThe breast and lung cancer cell lines MCF-7 and NCI-H358 were treated with increasing concentrations of NVP-231 and DNA synthesis, colony formation and cell death were determined. Flow cytometry was performed to analyse cell cycle distribution of cells and Western blot analysis was used to detect changes in cell cycle regulator expression and activation.
 Key ResultsIn both cell lines, NVP-231 concentration-dependently reduced cell viability, DNA synthesis and colony formation. Moreover it induced apoptosis, as measured by increased DNA fragmentation and caspase-3 and caspase-9 cleavage. Cell cycle analysis revealed that NVP-231 decreased the number of cells in S phase and induced M phase arrest with an increased mitotic index, as determined by increased histone H3 phosphorylation. The effect on the cell cycle was even more pronounced when NVP-231 treatment was combined with staurosporine. Finally, overexpression of CerK protected, whereas down-regulation of CerK with siRNA sensitized, cells for staurosporine-induced apoptosis.
 Conclusions and ImplicationsOur data demonstrate for the first time a crucial role for CerK in the M phase control in cancer cells and suggest its targeted inhibition, using drugs such as NVP-231, in combination with conventional pro-apoptotic chemotherapy.
Y1  - 2014
U6  - https://doi.org/10.1111/bph.12886
SN  - 0007-1188
SN  - 1476-5381
VL  - 171
IS  - 24
SP  - 5829
EP  - 5844
PB  - Wiley-Blackwell
CY  - Hoboken
ER  -