BACKGROUND: Melanoma patients stop responding to targeted therapies mainly due to mitogen activated protein kinase (MAPK) pathway re-activation, phosphoinositide 3 kinase/the mechanistic target of rapamycin (PI3K/mTOR) pathway activation or stromal cell influence. The future of melanoma treatment lies in combinational approaches. To address this, our in vitro study evaluated if lower concentrations of Celecoxib (IC50 in nM range) could still preserve the chemopreventive effect on melanoma cells treated with trametinib. MATERIALS AND METHODS: All experiments were conducted on SK-MEL-28 human melanoma cells and BJ human fibroblasts, used as co-culture. Co-culture cells were subjected to a celecoxib and trametinib drug combination for 72 h. We focused on the evaluation of cell death mechanisms, melanogenesis, angiogenesis, inflammation and resistance pathways. RESULTS: Low-dose celecoxib significantly enhanced the melanoma response to trametinib. The therapeutic combination reduced nuclear transcription factor (NF)-kB (p < 0.0001) and caspase-8/caspase-3 activation (p < 0.0001), inhibited microphthalmia transcription factor (MITF) and tyrosinase (p < 0.05) expression and strongly down-regulated the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) signaling pathway more significantly than the control or trametinib group (p < 0.0001). CONCLUSION: Low concentrations of celecoxib (IC50 in nM range) sufficed to exert antineoplastic capabilities and enhanced the therapeutic response of metastatic melanoma treated with trametinib.
BACKGROUND:Melanomapatients stop responding to targeted therapies mainly due to mitogen activated protein kinase (MAPK) pathway re-activation, phosphoinositide 3 kinase/the mechanistic target of rapamycin (PI3K/mTOR) pathway activation or stromal cell influence. The future of melanoma treatment lies in combinational approaches. To address this, our in vitro study evaluated if lower concentrations of Celecoxib (IC50 in nM range) could still preserve the chemopreventive effect on melanoma cells treated with trametinib. MATERIALS AND METHODS: All experiments were conducted on SK-MEL-28humanmelanoma cells and BJhuman fibroblasts, used as co-culture. Co-culture cells were subjected to a celecoxib and trametinib drug combination for 72 h. We focused on the evaluation of cell death mechanisms, melanogenesis, angiogenesis, inflammation and resistance pathways. RESULTS: Low-dose celecoxib significantly enhanced the melanoma response to trametinib. The therapeutic combination reduced nuclear transcription factor (NF)-kB (p < 0.0001) and caspase-8/caspase-3 activation (p < 0.0001), inhibited microphthalmia transcription factor (MITF) and tyrosinase (p < 0.05) expression and strongly down-regulated the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) signaling pathway more significantly than the control or trametinib group (p < 0.0001). CONCLUSION: Low concentrations of celecoxib (IC50 in nM range) sufficed to exert antineoplastic capabilities and enhanced the therapeutic response of metastatic melanoma treated with trametinib.
Authors: Claus Garbe; Teresa Amaral; Ketty Peris; Axel Hauschild; Petr Arenberger; Lars Bastholt; Veronique Bataille; Veronique Del Marmol; Brigitte Dréno; Maria Concetta Fargnoli; Jean-Jacques Grob; Christoph Höller; Roland Kaufmann; Aimilios Lallas; Celeste Lebbé; Josep Malvehy; Mark Middleton; David Moreno-Ramirez; Giovanni Pellacani; Philippe Saiag; Alexander J Stratigos; Ricardo Vieira; Iris Zalaudek; Alexander M M Eggermont Journal: Eur J Cancer Date: 2020-01-09 Impact factor: 9.162
Authors: Li Gong; Caroline F Thorn; Monica M Bertagnolli; Tilo Grosser; Russ B Altman; Teri E Klein Journal: Pharmacogenet Genomics Date: 2012-04 Impact factor: 2.089
Authors: Luigi Fattore; Susan Costantini; Debora Malpicci; Ciro Francesco Ruggiero; Paolo Antonio Ascierto; Carlo M Croce; Rita Mancini; Gennaro Ciliberto Journal: Oncotarget Date: 2017-03-28
Authors: Diana Valentina Tudor; Adrian Florea; Mihai Cenariu; Diana Elena Olteanu; Marius Farcaș; Andreea Hopârtean; Simona Valeria Clichici; Gabriela Adriana Filip Journal: J Clin Med Date: 2022-08-04 Impact factor: 4.964