Zalypsis: a novel marine-derived compound with potent antimyeloma activity that reveals high sensitivity of malignant plasma cells to DNA double-strand breaks.
Multiple myeloma (MM) remains incurable, and new drugs with novel mechanisms of action are still needed. In this report, we have analyzed the action of Zalypsis, an alkaloid analogous to certain natural marine compounds, in MM. Zalypsis turned out to be the most potent antimyeloma agent we have tested so far, with IC(50) values from picomolar to low nanomolar ranges. It also showed remarkable ex vivo potency in plasma cells from patients and in MM cells in vivo xenografted in mice. Besides the induction of apoptosis and cell cycle arrest, Zalypsis provoked DNA double-strand breaks (DSBs), evidenced by an increase in phospho-histone-H2AX and phospho-CHK2, followed by a striking overexpression of p53 in p53 wild-type cell lines. In addition, in those cell lines in which p53 was mutated, Zalypsis also provoked DSBs and induced cell death, although higher concentrations were required. Immunohistochemical studies in tumors also demonstrated histone-H2AX phosphorylation and p53 overexpression. Gene expression profile studies were concordant with these results, revealing an important deregulation of genes involved in DNA damage response. The potent in vitro and in vivo antimyeloma activity of Zalypsis uncovers the high sensitivity of tumor plasma cells to DSBs and strongly supports the use of this compound in MM patients.
Ocio
Enrique M
EM
Centro de Investigación del Cáncer, Instituto de Biologia Molecular y Celular del Cancer/Centro de Superior de Investigaciones Cientificas-Universidad de Salamanca, Spain. emocio@usal.es
Maiso
Patricia
P
Chen
Xi
X
Garayoa
Mercedes
M
Alvarez-Fernández
Stela
S
San-Segundo
Laura
L
Vilanova
David
D
López-Corral
Lucía
L
Montero
Juan C
JC
Hernández-Iglesias
Teresa
T
de Alava
Enrique
E
Galmarini
Carlos
C
Avilés
Pablo
P
Cuevas
Carmen
C
San-Miguel
Jesús F
JF
Pandiella
Atanasio
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016923:Cell Death; D064447:Checkpoint Kinase 2; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D010950:Plasma Cells / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C468783:H2AX protein, human; D006657:Histones; C500383:PM 00104; C495901:TP53 protein, human; D044005:Tetrahydroisoquinolines; D016159:Tumor Suppressor Protein p53; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases