Title | Investigation of antitumor effects of synthetic epothilone analogs in human myeloma models in vitro and in vivo. |
Publication Type | Journal Article |
Year of Publication | 2005 |
Authors | Da Wu K-, Cho YShin, Katz J, Ponomarev V, Chen-Kiang S, Danishefsky SJ, Moore MAS |
Journal | Proc Natl Acad Sci U S A |
Volume | 102 |
Issue | 30 |
Pagination | 10640-5 |
Date Published | 2005 Jul 26 |
ISSN | 0027-8424 |
Keywords | Animals, Annexin A5, Apoptosis, Bone Marrow Cells, Caspase 8, Caspase 9, Caspases, Cell Cycle, Cell Line, Cell Proliferation, Dose-Response Relationship, Drug, Epothilones, Immunoblotting, Inhibitory Concentration 50, JNK Mitogen-Activated Protein Kinases, Mice, 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. |
DOI | 10.1073/pnas.0504512102 |
Alternate Journal | Proc Natl Acad Sci U S A |
PubMed ID | 16030145 |
PubMed Central ID | PMC1180795 |
Related Faculty:
Selina Chen-Kiang, Ph.D.