title: Nanoparticle-Based Celecoxib and Plumbagin for the Synergistic Treatment of Melanoma.
abstract: Using multiple drugs to kill cancer cells can decrease drug resistance development. However, this approach is frequently limited by the bioavailability and toxicity of the combined agents and delivery at ratios to specific locations that synergistically kill cancer cells. Loading the individual agents into a nanoparticle that releases the drugs at synergizing ratios at a single location is one approach to resolve this concern. Celecoxib and plumbagin are two drugs that were identified from a screen to synergistically kill melanoma cells compared with normal cells. Combined use of these agents by traditional approaches was not possible due to poor bioavailability and toxicologic concerns. This study details the development of a nanoliposomal-based agent containing celecoxib and plumbagin, called CelePlum-777, which is stable and releases these drugs at an optimal ratio for maximal synergistic killing efficacy. CelePlum-777 was more effective at killing melanoma than normal cells and inhibited xenograft melanoma tumor growth by up to 72% without apparent toxicity. Mechanistically, the drug combination in CelePlum-777 led to enhanced inhibition of melanoma cell proliferation mediated by decreasing levels of key cyclins important for cancer cell proliferation and survival, which was not observed with the individual agents. Thus, a novel nanoparticle-based drug has been developed containing celecoxib and plumbagin that lacks toxicity and delivers the agents at a synergistically killing drug ratio to kill cancer cells.Mol Cancer Ther; 16(3); 440-52. ©2016 AACR.
authors.affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.|The Penn State Melanoma and Skin Cancer Center, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.|Penn State Melanoma Therapeutics Program, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.|Foreman Foundation for Melanoma Research, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
authors.forename: Raghavendra
authors.initials: R
authors.lastname: Gowda
authors.affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
authors.forename: Gregory
authors.initials: G
authors.lastname: Kardos
authors.affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
authors.forename: Arati
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. gpr11@psu.edu.|The Penn State Melanoma and Skin Cancer Center, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.|Penn State Melanoma Therapeutics Program, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.|Foreman Foundation for Melanoma Research, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.|Department of Pathology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.|Department of Dermatology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.|Department of Surgery, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Robertson
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry; D000068579:Celecoxib / Q000008:administration & dosage* / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage* / Q000737:chemistry; D004195:Disease Models, Animal; D004339:Drug Compounding; D004355:Drug Stability; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008081:Liposomes; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry; D009285:Naphthoquinones / Q000008:administration & dosage* / Q000737:chemistry; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D052246:Cyclooxygenase 2 Inhibitors; D008081:Liposomes; D009285:Naphthoquinones; D050796:STAT3 Transcription Factor; D000068579:Celecoxib; C014758:plumbagin