title: Inhibition of Cell Proliferation in an NRAS Mutant Melanoma Cell Line by Combining Sorafenib and α-Mangostin.
abstract: α-Mangostin is a natural product commonly used in Asia for cosmetic and medicinal applications including topical treatment of acne and skin cancer. Towards finding new pharmacological strategies that overcome NRAS mutant melanoma, we performed a cell proliferation-based combination screen using a collection of well-characterized small molecule kinase inhibitors and α-Mangostin. We found that α-Mangostin significantly enhances Sorafenib pharmacological efficacy against an NRAS mutant melanoma cell line. The synergistic effects of α-Mangostin and Sorafenib were associated with enhanced inhibition of activated AKT and ERK, induced ER stress, and reduced autophagy, eventually leading to apoptosis. The structure of α-Mangostin resembles several inhibitors of the Retinoid X receptor (RXR). MITF expression, which is regulated by RXR, was modulated by α-Mangostin. Molecular docking revealed that α-Mangostin can be accommodated by the ligand binding pocket of RXR and may thereby compete with RXR-mediated control of MITF expression. In summary, these data demonstrate an unanticipated synergy between α-Mangostin and sorafenib, with mechanistic actions that convert a known safe natural product to a candidate combinatorial therapeutic agent.
authors.affiliation: Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|Cutaneous Biology Research Center, Massachusetts General Hospital, 149 Building 13th ST, Charlestown, Massachusetts, United States of America.
authors.forename: Yun
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, 149 Building 13th ST, Charlestown, Massachusetts, United States of America.|Clinical Laboratory, The Third Affiliated Hospital of Zhengzhou University, No.7 Front Kangfu ST, Zhengzhou 450052, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Departments of Biochemistry and Radiation Oncology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States of America.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Westover
authors.affiliation: Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Jiaming
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|Cutaneous Biology Research Center, Massachusetts General Hospital, 149 Building 13th ST, Charlestown, Massachusetts, United States of America.
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Chen
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, 149 Building 13th ST, Charlestown, Massachusetts, United States of America.
authors.forename: Jianming
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, 149 Building 13th ST, Charlestown, Massachusetts, United States of America.
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D011905:Genes, ras; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D018168:Receptors, Retinoic Acid / Q000187:drug effects; D000077157:Sorafenib; D044004:Xanthones / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D010671:Phenylurea Compounds; D018168:Receptors, Retinoic Acid; D044004:Xanthones; D009536:Niacinamide; D000077157:Sorafenib; C021053:mangostin