title: Targeting multiple key signaling pathways in melanoma using leelamine.
abstract: Melanoma is a highly drug-resistant cancer with resistance developing to agents targeting single proteins. To circumvent this problem, a new class of agent inhibiting multiple key pathways important in this disease is being developed to reduce the likelihood of developing resistant disease. The phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), and STAT3 pathways are constitutively activated in 50% to 70% of melanomas, promoting disease development. To identify a drug simultaneously targeting the PI3K, MAPK, and STAT3 cascades, a natural product library was screened to identify leelamine as a potential inhibitor. Leelamine was 4.5-fold more effective at inhibiting cultured melanoma cell survival than normal cells, with average IC(50) values of 2 and 9.3 μmol/L, respectively. It inhibited cellular proliferation at a concentration of 2.5 μmol/L by 40% to 80% and longer exposure increased apoptosis 600%. Leelamine inhibited the growth of preexisting xenografted melanoma tumors by an average of 60% by targeting the PI3K, MAPK, and STAT3 pathways without affecting animal body weight or blood markers of major organ function. The mechanism of action of leelamine is mediated by disruption of cholesterol transport, causing decreased cellular proliferation and consequently leading to increased tumor cell apoptosis as well as decreased tumor vascularization. Thus, a unique agent and novel mechanism of action has been identified for the treatment of melanoma that acts by inhibiting the activity of three major signaling pathways regulating the development of this disease.
authors.affiliation: Authors' Affiliations: Departments of Pharmacology, Penn State Hershey Melanoma Center, Penn State Melanoma Therapeutics Program.
authors.forename: Raghavendra
authors.initials: R
authors.lastname: Gowda
authors.affiliation: Authors' Affiliations: Departments of Pharmacology.
authors.forename: SubbaRao V
authors.initials: SV
authors.lastname: Madhunapantula
authors.affiliation: Authors' Affiliations: Departments of Pharmacology, Penn State Hershey Melanoma Center.
authors.forename: Omer F
authors.initials: OF
authors.lastname: Kuzu
authors.affiliation: Authors' Affiliations: Departments of Pharmacology, Penn State Hershey Melanoma Center, Penn State Melanoma Therapeutics Program.
authors.forename: Arati
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Authors' Affiliations: Departments of Pharmacology, Pathology, Dermatology, and Surgery, Penn State Hershey Melanoma Center, Penn State Melanoma Therapeutics Program, The Foreman Foundation for Melanoma Research, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania gprobertson@psu.edu.
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Robertson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D004224:Diterpenes