Celecoxib as a Valuable Adjuvant in Cutaneous Melanoma Treated with Trametinib

• Published in: International journal of molecular sciences 2021-04, Vol.22 (9), p.4387
• Main Authors: Tudor, Diana Valentina, Bâldea, Ioana, Olteanu, Diana Elena, Fischer-Fodor, Eva, Piroska, Virag, Lupu, Mihai, Călinici, Tudor, Decea, Roxana Maria, Filip, Gabriela Adriana
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Adjuvants, Pharmaceutic - pharmacology; AKT protein; Angiogenesis; Antineoplastic Agents - pharmacology; Apoptosis; Biotechnology; Caspase-3; Caspase-8; Celecoxib; Celecoxib - pharmacology; Cell activation; Cell culture; Cell death; Culture; Cyclooxygenase 2 Inhibitors - pharmacology; Dosage; Experiments; Fibroblasts; Flow cytometry; Humans; Immunoassay; Immunotherapy; Inflammation; Inflammation - prevention & control; Inhibitor drugs; Kinases; Low concentrations; MAP kinase; Melanoma; Melanoma - drug therapy; Melanoma - metabolism; Melanoma - pathology; Melanoma, Cutaneous Malignant; Metastases; Microphthalmia-associated transcription factor; Neovascularization, Pathologic - prevention & control; Proteins; Pyridones - pharmacology; Pyrimidinones - pharmacology; Rapamycin; Signal transduction; Signal Transduction - drug effects; Skin Neoplasms - drug therapy; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Software; Targeted cancer therapy; TOR protein; Tumor Cells, Cultured; Tyrosinase; Vascular endothelial growth factor
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22094387

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 (IC in nM range) could still preserve the chemopreventive effect on melanoma cells treated with trametinib. 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. Low-dose celecoxib significantly enhanced the melanoma response to trametinib. The therapeutic combination reduced nuclear transcription factor (NF)-kB ( < 0.0001) and caspase-8/caspase-3 activation ( < 0.0001), inhibited microphthalmia transcription factor (MITF) and tyrosinase ( < 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 ( < 0.0001). Low concentrations of celecoxib (IC in nM range) sufficed to exert antineoplastic capabilities and enhanced the therapeutic response of metastatic melanoma treated with trametinib.