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

Abstract

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 24h of treatment. Antiproliferative effects were evaluated separately after a 72-hour incubation of the cells with the pharmacological substance. Subsequently, the IC50 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 (P<0.04). In addition, selumetinib and trametinib showed a significant inhibition of cell proliferation (P<0.05). Everolimus and erlotinib solely inhibited cell proliferation at the used concentrations (P<0.05). Besides an increase of necrotic cells after erufosine treatment (P<0.001), 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/mTOR 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.

Signaling Pathways mTOR and ERK as Therapeutic Targets in Sinonasal Intestinal-Type Adenocarcinoma

“…Our results on ITAC-3 cells showed a clear inhibitory effect with everolimus, even as a monotherapy at lower concentrations than described in similar studies on colon and breast cancer cell lines [39,40]. Exposure to selumetinib also caused an inhibition of cell growth as has been shown in cell lines of other cancer types [41,42]. However, a combination of both inhibitors showed the strongest growth reduction and was clearly superior to monotherapy, as has been shown for other cancer types [31].…”

Inhibition of EGFR attenuates EGF-induced activation of retinal pigment epithelium cell via EGFR/AKT signaling pathway

“…In previous studies, we have found that erlotinib inhibited the activation of EGFR/AKT signaling pathway [39] . Erlotinib was also proved to inhibit the cell proliferation [44] . In the present study, our data indicated that erlotinib significantly affected cell viability, proliferation, and migration.…”

Protein phosphatase 6 regulates trametinib sensitivity, a mitogen-activated protein kinase kinase (MEK) inhibitor, by regulating MEK1/2-ERK1/2 signaling in canine melanoma cells

“…It has been reported that mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) signaling and phosphoinositide-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways are activated in canine melanoma similar to human melanoma [ 27 ]. Therefore, molecularly targeted drugs that reduce the activity of MEK and Akt/mTOR are used in the treatment of both human and canine melanoma [ 13 , 26 ].…”