title: A Novel Plant Sesquiterpene Lactone Derivative, DETD-35, Suppresses BRAFV600E Mutant Melanoma Growth and Overcomes Acquired Vemurafenib Resistance in Mice.
abstract: Acquired resistance to vemurafenib develops through reactivation of RAF/MEK/ERK signaling or bypass mechanisms. Recent combination therapies such as a MEK inhibitor combined with vemurafenib show improvement in major clinical end points, but the percentage of patients with adverse toxic events is higher than with vemurafenib monotherapy and most patients ultimately relapse. Therefore, there is an urgent need to develop new antimelanoma drugs and/or adjuvant agents for vemurafenib therapy. In this study, we created a novel semiorganically modified derivative, DETD-35, from deoxyelephantopin (DET), a plant sesquiterpene lactone demonstrated as an anti-inflammatory and anti-mammary tumor agent. Our results show that DETD-35 inhibited proliferation of a panel of melanoma cell lines, including acquired vemurafenib resistance A375 cells (A375-R) established in this study, with superior activities to DET and no cytotoxicity to normal melanocytes. DETD-35 suppressed tumor growth and reduced tumor mass as effectively as vemurafenib in A375 xenograft study. Furthermore, DETD-35 also reduced tumor growth in both acquired (A375-R) and intrinsic (A2058) vemurafenib resistance xenograft models, where vemurafenib showed no antitumor activity. Notably, the combination of DETD-35 and vemurafenib exhibited the most significant effects in both in vitro and in vivo xenograft studies due to synergism of the compound and the drug. Mechanistic studies suggested that DETD-35 overcame acquired vemurafenib resistance at least in part through deregulating MEK-ERK, Akt, and STAT3 signaling pathways and promoting apoptosis of cancer cells. Overall, our results suggest that DETD-35 may be useful as a therapeutic or adjuvant agent against BRAF(V600E) mutant and acquired vemurafenib resistance melanoma. Mol Cancer Ther; 15(6); 1163-76. ©2016 AACR.
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan. Institute of Plant Biology, College of Life Science, National Taiwan University, Taipei, Taiwan.
authors.forename: Jia-Hua
authors.initials: JH
authors.lastname: Feng
authors.affiliation: College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan. Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nakagawa-Goto
authors.affiliation: Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan. PhD Program in Translational Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. lfshyur@ccvax.sinica.edu.tw.
authors.forename: Lie-Fen
authors.initials: LF
authors.lastname: Shyur
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000494:pharmacology; D007783:Lactones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D015394:Molecular Structure; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics; D013449:Sulfonamides / Q000008:administration & dosage* / Q000494:pharmacology; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D007211:Indoles; D007783:Lactones; D012717:Sesquiterpenes; D013449:Sulfonamides; C528427:deoxyelephantopin; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf