Synergistic inhibitory effects of Celecoxib and Plumbagin on melanoma tumor growth

Melanoma is a highly drug resistant cancer. To circumvent this problem, a class of synergistically acting drug combinations, which inhibit multiple key pathways in melanoma cells, could be used as one approach for long-term treatment of this deadly disease. A screen has been undertaken on cell lines to identify those that could be combined to synergistically kill melanoma cells. Plumbagin and Celecoxib are two agents that were identified to synergistically kill melanoma cells by inhibiting the COX-2 and STAT3 pathways, which are constitutively activated in up to 70% of melanomas. The combination of these two drugs was more effective at killing melanoma cells than normal cells and decreased cellular proliferation as well as induced apoptosis of cultured cells. The drug combination inhibited development of xenograft melanoma tumors by up to 63% without affecting animal weight or blood biomarkers of organ function, suggesting negligible toxicity. Mechanistically, combination of Celecoxib and Plumbagin decreased melanoma cell proliferation and retarded vascular development of tumors mediated by inhibition of COX-2 and STAT3 leading to decreased levels of key cyclins key on which melanoma cell were dependent for survival.