Pharmacological drug screening to inhibit uveal melanoma metastatic cells either via EGF-R, MAPK, mTOR or PI3K

作     者：Stefan Kassumeh Sebastian Arrow AndréKafka Nikolaus Luft Siegfried G.Priglinger Armin Wolf Kirsten Eibl-Lindner Christian M.Wertheimer 

作者机构：Department of OphthalmologyUniversity HospitalLMU MunichMunich 80336Germany Department of OphthalmologyUniversity HospitalUniversity UlmUlm 89075Germany 

出 版 物：《International Journal of Ophthalmology(English edition)》 (国际眼科杂志（英文版）)

年 卷 期：2022年第15卷第10期

页      面：1569-1576页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

主　　题：uveal melanoma selumetinib trametinib erufosine erlotinib 

摘      要：AIM: To screen five potential pharmacological substances specifically targeting EGF-R, MAPK, mTOR, or PI3K for their antiproliferative effects, possible impact on cell viability, as well as cell death rates on three different uveal melanoma metastasis cell lines in vitro. METHODS: Three different uveal melanoma metastasis cell lines(OMM2.5, OMM2.3, and OMM1), that originated from human hepatic and subcutaneous metastasis, were exposed to inhibitors of different targets: erlotinib(EGF-R), everolimus(mTOR), selumetinib(MAPK), trametinib(MAPK) or the alkylphosphocholine erufosine(PI3K). Cell viability was assessed with a 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide(XTT) dye reduction assay after 24 h of treatment. Antiproliferative effects were evaluated separately after a 72-hour incubation of the cells with the pharmacological substance. Subsequently, the IC_(50) was calculated. Tumor cell death was investigated using a double stain apoptosis detection assay. RESULTS: Selumetinib, trametinib, and erufosine significantly decreased cell viability of all OMM cell lines(P0.04). In addition, selumetinib and trametinib showed a significant inhibition of cell proliferation(P0.05). Everolimus and erlotinib solely inhibited cell proliferation at the used concentrations(P0.05). Besides an increase of necrotic cells after erufosine treatment(P0.001), no changes in the number of dead cells for the other substances were observed.CONCLUSION: The preliminary drug screening demonstrates five new candidates, successfully targeting the canonical MAPK/ERK and PI3K/AKT/m TOR pathways in uveal melanoma metastasis cells in vitro. Hence, these findings provide an experimental basis to explore future single or combined therapy strategies for metastatic uveal melanoma.