title: Synergistic DNA-damaging effect in multiple myeloma with the combination of zalypsis, bortezomib and dexamethasone.
abstract: Despite new advances in multiple myeloma treatment and the consequent improvement in overall survival, most patients relapse or become refractory to treatment. This suggests that new molecules and combinations that may further inhibit important survival pathways for these tumor cells are needed. In this context, zalypsis is a novel compound, derived from marine organisms, with a powerful preclinical anti-myeloma effect based on the sensitivity of malignant plasma cells to DNA-damage induction; and it has already been tested in a phase I/II clinical trial in multiple myeloma. We hypothesized that the addition of this compound to the combination of bortezomib plus dexamethasone may improve efficacy with acceptable toxicity. The triple combination demonstrated strong synergy and higher efficacy compared with double combinations; not only in vitro, but also ex vivo and, especially, in in vivo experiments. The triple combination triggers cell death, mainly through a synergistic induction of DNA damage and a decrease in the nuclear localization of nuclear factor kappa B. Our findings support the clinical evaluation of this combination for relapsed and refractory myeloma patients.
authors.affiliation: University Hospital of Salamanca-IBSAL & Cancer Research Center-IBMCC (USAL-CSIC), Salamanca.
authors.forename: Ana-Alicia
authors.initials: AA
authors.lastname: López-Iglesias
authors.affiliation: University Hospital of Salamanca-IBSAL & Cancer Research Center-IBMCC (USAL-CSIC), Salamanca.
authors.forename: Lorena
authors.initials: L
authors.lastname: González-Méndez
authors.affiliation: University Hospital of Salamanca-IBSAL & Cancer Research Center-IBMCC (USAL-CSIC), Salamanca.
authors.forename: Laura
authors.initials: L
authors.lastname: San-Segundo
authors.affiliation: University Hospital of Salamanca-IBSAL & Cancer Research Center-IBMCC (USAL-CSIC), Salamanca.
authors.forename: Ana B
authors.initials: AB
authors.lastname: Herrero
authors.affiliation: University Hospital of Salamanca-IBSAL & Cancer Research Center-IBMCC (USAL-CSIC), Salamanca.
authors.forename: Susana
authors.initials: S
authors.lastname: Hernández-García
authors.affiliation: University Hospital of Salamanca-IBSAL & Cancer Research Center-IBMCC (USAL-CSIC), Salamanca.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Martín-Sánchez
authors.affiliation: University Hospital of Salamanca-IBSAL & Cancer Research Center-IBMCC (USAL-CSIC), Salamanca.
authors.forename: Norma C
authors.initials: NC
authors.lastname: Gutiérrez
authors.affiliation: University Hospital of Salamanca-IBSAL & Cancer Research Center-IBMCC (USAL-CSIC), Salamanca.
authors.forename: Teresa
authors.initials: T
authors.lastname: Paíno
authors.affiliation: PharmaMar SAU, Madrid, Center for Applied Medical Research (CIMA), IDISNA, Pamplona, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Avilés
authors.affiliation: University Hospital of Salamanca-IBSAL & Cancer Research Center-IBMCC (USAL-CSIC), Salamanca.
authors.forename: María-Victoria
authors.initials: MV
authors.lastname: Mateos
authors.affiliation: University Clinic of Navarra, Center for Applied Medical Research (CIMA), IDISNA, Pamplona, Spain.
authors.forename: Jesús F
authors.initials: JF
authors.lastname: San-Miguel
authors.affiliation: University Hospital of Salamanca-IBSAL & Cancer Research Center-IBMCC (USAL-CSIC), Salamanca.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Garayoa
authors.affiliation: University Hospital of Salamanca-IBSAL & Cancer Research Center-IBMCC (USAL-CSIC), Salamanca emocio@usal.es.
authors.forename: Enrique M
authors.initials: EM
authors.lastname: Ocio
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D000069286:Bortezomib / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology*; D004195:Disease Models, Animal; D004357:Drug Synergism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D016328:NF-kappa B; C500383:PM 00104; D044005:Tetrahydroisoquinolines; D000069286:Bortezomib; D003907:Dexamethasone; D020169:Caspases