title: Synergistic inhibitory effects of Celecoxib and Plumbagin on melanoma tumor growth.
abstract: 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.
authors: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United states; The Penn State Melanoma Center, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United states; Penn State Melanoma Therapeutics Program, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United states; Foreman Foundation for Melanoma Research, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United states.
authors: Raghavendra
authors: R
authors: Gowda
authors: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United states.
authors: Arati
authors: A
authors: Sharma
authors: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United states; Department of Pathology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United states; Department of Dermatology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United states; Department of Surgery, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United states; The Penn State Melanoma Center, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United states; Penn State Melanoma Therapeutics Program, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United states; Foreman Foundation for Melanoma Research, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United states. Electronic address: gprobertson@psu.edu.
authors: Gavin P
authors: GP
authors: Robertson
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000068579:Celecoxib / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D016213:Cyclins / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008819:Mice, Nude; D009285:Naphthoquinones / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016213:Cyclins; D052246:Cyclooxygenase 2 Inhibitors; D009285:Naphthoquinones; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000068579:Celecoxib; C014758:plumbagin
keywords: COX-2; Celecoxib; Plumbagin; STAT3; Synergy; Tumor development