Investigation of antitumor effects of synthetic epothilone analogs in human myeloma models in vitro and in vivo Journal Article
| Authors: | Wu, K. D.; Cho, Y. S.; Katz, J.; Ponomarev, V.; Chen-Kiang, S.; Danishefsky, S. J.; Moore, M. A. S. |
| Article Title: | 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 IC 50), whereas normal human bone marrow stromal cells (HS-27A and HS-5 lines) were relatively resistant (10- to 15-fold higher IC 50). Cell-cycle analysis demonstrated that Flu caused G 2/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. © 2005 by The National Academy of Sciences of the USA. |
| Keywords: | controlled study; unclassified drug; nonhuman; cell proliferation; animal cell; mouse; animals; mice; bone marrow cells; cell cycle; cd34 antigen; apoptosis; multiple myeloma; stress activated protein kinase; cell line; animal experiment; animal model; antineoplastic activity; enzyme activation; drug effect; dose-response relationship, drug; caspases; cancer therapy; dna; enzyme phosphorylation; xenograft; immunoblotting; caspase 8; caspase 9; inhibitory concentration 50; microtubule; mitochondrial protein; enzyme assay; scid mouse; myeloma; epothilones; epothilone derivative; mouse model; jnk mitogen-activated protein kinases; fludelone; annexin a5; targeting; 12,13 desoxyepothilone b; trifluoro |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 102 |
| Issue: | 30 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2005-07-26 |
| Start Page: | 10640 |
| End Page: | 10645 |
| Language: | English |
| DOI: | 10.1073/pnas.0504512102 |
| PUBMED: | 16030145 |
| PROVIDER: | scopus |
| PMCID: | PMC1180795 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 26" - "Export Date: 24 October 2012" - "CODEN: PNASA" - "Source: Scopus" |
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