Investigation of antitumor effects of synthetic epothilone analogs in human myeloma models in vitro and in vivo.

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.

• Authors: Kai-Da Wu, Young Shin Cho, Jonathan Katz, Vladimir Ponomarev, Selina Chen-Kiang, Samuel J Danishefsky, Malcolm A S Moore
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 102 Issue 30 Pg. 10640-5 (Jul 26 2005) ISSN: 0027-8424 [Print] United States
• PMID: 16030145 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 26-trifluoro-(E)-9,10-dehydro-12,13-desoxyepothilone B
• Annexin A5
• Epothilones
• JNK Mitogen-Activated Protein Kinases
• CASP8 protein, human
• CASP9 protein, human
• Casp8 protein, mouse
• Casp9 protein, mouse
• Caspase 8
• Caspase 9
• Caspases

Topics

• Animals
• Annexin A5 (metabolism)
• Apoptosis (drug effects)
• Bone Marrow Cells (drug effects)
• Caspase 8
• Caspase 9
• Caspases (metabolism)
• Cell Cycle (drug effects)
• Cell Line
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Epothilones (pharmacology)
• Immunoblotting
• Inhibitory Concentration 50
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Mice
• Multiple Myeloma (metabolism)