title: Aplidin, a marine organism-derived compound with potent antimyeloma activity in vitro and in vivo.
abstract: Despite recent progress in its treatment, multiple myeloma (MM) remains incurable, thus necessitating identification of novel anti-MM agents. We report that the marine-derived cyclodepsipeptide Aplidin exhibits, at clinically achievable concentrations, potent in vitro activity against primary MM tumor cells and a broad spectrum of human MM cell lines, including cells resistant to conventional (e.g., dexamethasone, alkylating agents, and anthracyclines) or novel (e.g., thalidomide and bortezomib) anti-MM agents. Aplidin is active against MM cells in the presence of proliferative/antiapoptotic cytokines or bone marrow stromal cells and has additive or synergistic effects with some of the established anti-MM agents. Mechanistically, a short in vitro exposure to Aplidin induces MM cell death, which involves activation of p38 and c-jun NH(2)-terminal kinase signaling, Fas/CD95 translocation to lipid rafts, and caspase activation. The anti-MM effect of Aplidin is associated with suppression of a constellation of proliferative/antiapoptotic genes (e.g., MYC, MYBL2, BUB1, MCM2, MCM4, MCM5, and survivin) and up-regulation of several potential regulators of apoptosis (including c-JUN, TRAIL, CASP9, and Smac). Aplidin exhibited in vivo anti-MM activity in a mouse xenograft model. The profile of the anti-MM activity of Aplidin in our preclinical models provided the framework for its clinical testing in MM, which has already provided favorable preliminary results.
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Constantine_Mitsiades@dfci.harvard.edu
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
authors.forename: Enrique M
authors.initials: EM
authors.lastname: Ocio
authors.forename: Atanasio
authors.initials: A
authors.lastname: Pandiella
authors.forename: Patricia
authors.initials: P
authors.lastname: Maiso
authors.forename: Consuelo
authors.initials: C
authors.lastname: Gajate
authors.forename: Mercedes
authors.initials: M
authors.lastname: Garayoa
authors.forename: David
authors.initials: D
authors.lastname: Vilanova
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Montero
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitsiades
authors.forename: Ciaran J
authors.initials: CJ
authors.lastname: McMullan
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.forename: Pablo
authors.initials: P
authors.lastname: Aviles
authors.forename: Gabriel
authors.initials: G
authors.lastname: Otero
authors.forename: Glynn
authors.initials: G
authors.lastname: Faircloth
authors.forename: M Victoria
authors.initials: MV
authors.lastname: Mateos
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Faustino
authors.initials: F
authors.lastname: Mollinedo
authors.forename: Jesus F
authors.initials: JF
authors.lastname: San-Miguel
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D047630:Depsipeptides / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010456:Peptides, Cyclic; D012623:Seawater; D017154:Stromal Cells / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D016896:Treatment Outcome; D014561:Urochordata / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D015850:Interleukin-6; D010456:Peptides, Cyclic; D007334:Insulin-Like Growth Factor I; C098980:plitidepsin