Celecoxib as a Valuable Adjuvant in Cutaneous Melanoma Treated with Trametinib

Abstract

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.

Low Doses of Celecoxib Might Promote Phenotype Switching in Cutaneous Melanoma Treated with Dabrafenib—Preliminary Study

“…Starting from viability tests we observed that melanoma cells manifested sustained resistance to usual doses of dabrafenib (1–100 nM—data not shown), therefore, we had to increase dabrafenib doses in order to achieve IC 50 (200–700 nM) [ 30 ]. Similar to our previous expertise, celecoxib did not alter cell viability as a single compound [ 14 ]. However, the celecoxib and dabrafenib combination induced a time and dose-dependent cytotoxic effect in both A375 and SK-MEL-28 cell lines.…”

“…Among them, phenotype switching, represented by a low MITF/AXL ratio, has gained a lot of attention [ 24 ]. In a previous work, we showed that low-dose celecoxib exerts antineoplastic effects in a melanoma co-culture treated with trametinib, by decreasing phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) resistance pathway activation [ 14 ]. Moreover, what is already known about the antineoplastic capabilities of celecoxib in melanoma, independent from COX-2/prostaglandin E2 (PgE 2 ) inhibition, is that it suppresses cancer cell growth and promotes apoptosis via Wnt/β-catenin and m-TOR (mechanistic target of rapamycin) substitutive pathway inhibition, and reduces the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and the signal transducer and activator of transcription 3 (STAT3) expression [ 25 , 26 , 27 , 28 ].…”

“…In a previous study, we showed that celecoxib and trametinib potentiated each other’s cytotoxic capabilities, proving a real antineoplastic synergism in an experimental melanoma model. Given the clinical use of dabrafenib and trametinib association in late stages of melanoma, it would be interesting to evaluate if this synergism is still preserved between celecoxib and dabrafenib [ 14 ].…”

A Combination of Celecoxib and Glucosamine Sulfate Has Anti-Inflammatory and Chondroprotective Effects: Results from an In Vitro Study on Human Osteoarthritic Chondrocytes

“…Different findings pointed out that GS seems to exert its effect on NF-κB-dependent transcription via an epigenetic mechanism, regulating the demethylation of specific CpG sites of DNA in the IL1β promoter, responsible for the aberrant expression of MMPs, ADAMTS, and IL-1β in human articular chondrocytes [37,54]. On the other hand, it is currently not completely defined how celecoxib mediates the activity of NF-κB, but it is possible to assume that it follows the PI3K/AKT/IKK/NF-kB pathway regulation, implicated in the regulation of apoptosis and cell proliferation, as demonstrated in different studies on cancer cell lines [59,60].…”

Celecoxib as an adjuvant to chemotherapy for patients with metastatic colorectal cancer

“…Preclinical ones revealed that, implication of celecoxib resulted in reduction of implanted cancer cell growth, decrease in angiogenesis, and fighting of metastases. 8 The clinical trials conducted recently to evaluate the role of celecoxib in enhancing the effect of chemotherapy showed either modest effect or lack of effect. 9 - 11 Thus, additional clinical trials on the anti-tumor efficacy of celecoxib are still required to provide results oriented clinical data.…”