Subscribe to RSS
DOI: 10.1055/s-0036-1592710
Novel drug OTSSP167 inhibits proliferation and induces apoptosis selectively in high-grade serous ovarian cancer cells
Introduction: Our previous transcriptomic analysis identified MELK (maternal embryonic leucine-zipper kinase), suggested to play a key role in carcinogenesis, to be overexpressed in epithelial ovarian cancer. MELK is elevated and correlates with poor prognosis also in basal-like breast cancer and its inhibition by OTSSP167 induced apoptosis in these cells. We analyzed MELK expression in high-grade serous ovarian cancer (HGSOC) and determined the effect of MELK-inhibition in ovarian cancer cells and drug-resistant cells.
Material and methods: Data base analysis was performed using public data sets via Gene Expression Omnibus; proliferation and colony formation inhibition by MTT- and clonogenic assay; MELK expression and apoptosis by Western-blotting; cell cycle analysis by flow cytometry; MELK knock-down by doxycycline-inducible shRNA; drug resistance acquisition by repeated cycles of drug exposures.
Results: Bioinformatical analysis revealed elevated MELK expression preferentially in HGSOC (compared to controls) with increasing histological grade. HGSOC patients with high MELK expression had a shorter progression-free survival. MELK-inhibitor OTSSP167 induced apoptosis in all investigated HGSOC cell lines. OTSSP167 inhibited proliferation of IGROV1 and OVCAR3 cells associated with G2/M cell cycle arrest and retained its anti-proliferative effect also in Paclitaxel- and Carboplatin-resistant IGROV1 cells. Colony formation was also inhibited by OTSSP167 and in cells with shRNA-silenced MELK. All these effects were not observed in normal (ovarian surface and fallopian tube epithelium) and non-serous ovarian cancer cells.
Conclusion: The preference for elevated MELK expression in HGSOC predicts a more aggressive phenotype. The selective potency of OTSSP167 makes MELK a drugable target in patients with (resistant) HGSOC.