Aplidin, a marine organism-derived compound with potent antimyeloma activity in vitro and in vivo.
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.
Mitsiades
Constantine S
CS
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Constantine_Mitsiades@dfci.harvard.edu
Ocio
Enrique M
EM
Pandiella
Atanasio
A
Maiso
Patricia
P
Gajate
Consuelo
C
Garayoa
Mercedes
M
Vilanova
David
D
Montero
Juan Carlos
JC
Mitsiades
Nicholas
N
McMullan
Ciaran J
CJ
Munshi
Nikhil C
NC
Hideshima
Teru
T
Chauhan
Dharminder
D
Aviles
Pablo
P
Otero
Gabriel
G
Faircloth
Glynn
G
Mateos
M Victoria
MV
Richardson
Paul G
PG
Mollinedo
Faustino
F
San-Miguel
Jesus F
JF
Anderson
Kenneth C
KC
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
D000970:Antineoplastic Agents; D047630:Depsipeptides; D015850:Interleukin-6; D010456:Peptides, Cyclic; D007334:Insulin-Like Growth Factor I; C098980:plitidepsin