Investigation of antitumor effects of synthetic epothilone analogs in human myeloma models in vitro and in vivo Academic Article uri icon

Overview

MeSH Major

  • Cell Proliferation
  • Epothilones
  • Multiple Myeloma

abstract

  • 26-Trifluoro-(E)-9,10-dehydro-12,13-desoxyepothilone B [Fludelone (Flu)] has shown broad antitumor activity in solid tumor models. In the present study, we showed, in vitro, that Flu significantly inhibited multiple myeloma (MM) cell proliferation (with 1-15 nM IC50), whereas normal human bone marrow stromal cells (HS-27A and HS-5 lines) were relatively resistant (10- to 15-fold higher IC50). Cell-cycle analysis demonstrated that Flu caused G2/M phase arrest and induced cell apoptosis. After Flu treatment, caspase-3, -8, and -9 were activated, cytochrome c and second mitochondrial-derived activator of caspase were released to the cytosol, and c-Jun N-terminal kinase was activated, indicating that mitochondria were involved in the apoptosis. Flu toxicity to human hematopoietic stem cells was evaluated by CD34+ cell-apoptosis measurements and hematopoietic-progenitor assays. There was no significant toxicity to noncycling human CD34+ cells. We compared the efficacy of Flu with the epothilone analog 12,13-desoxyepothilone B (dEpoB) in xenograft nonobese diabetic/severe combined immunodeficient mouse models with subcutaneous or disseminated MM. Flu caused tumor disappearance in RPMI 8226 subcutaneous xenografts after only five doses of the drug (20 mg/kg of body weight), with no sign of relapse after 100 d of observation. In a disseminated CAG MM model, mice treated with Flu had a significantly decreased tumor burden, as determined by bioluminescence imaging, and prolonged overall survival vs. mice treated with dEpoB or vehicle control, indicating that Flu may be a promising agent for MM therapy.

publication date

  • July 26, 2005

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC1180795

Digital Object Identifier (DOI)

  • 10.1073/pnas.0504512102

PubMed ID

  • 16030145

Additional Document Info

start page

  • 10640

end page

  • 5

volume

  • 102

number

  • 30