Abstract | PURPOSE: EXPERIMENTAL DESIGN:
Cytokine production and MM cell proliferation triggered by TGF-beta1 or adhesion to BMSCs were examined in the presence or absence of SD-208. Effects of SD-208 on TGF-beta1-induced signaling pathways triggering IL-6 and VEGF transcription in BMSCs were also delineated. RESULTS:
SD-208 significantly inhibits not only transcription but also secretion of both IL-6 and VEGF from BMSCs triggered by either TGF-beta1 or adhesion of MM cells to BMSCs. Moreover, SD-208 decreased tumor cell growth triggered by MM cell adhesion to BMSCs. SD-208 works, at least in part, by blocking TGF-beta1-triggered nuclear accumulation of Smad2/3 and hypoxia-inducible factor 1alpha, as well as related production of IL-6 and VEGF, respectively. CONCLUSIONS: These studies indicate that SD-208 inhibits production of cytokines mediating MM cell growth, survival, drug resistance, and migration in the BM milieu, thereby providing the preclinical rationale for clinical evaluation of SD-208 to improve patient outcome in MM.
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Authors | Toshiaki Hayashi, Teru Hideshima, Aaron N Nguyen, Olivier Munoz, Klaus Podar, Makoto Hamasaki, Kenji Ishitsuka, Hiroshi Yasui, Paul Richardson, Sarvajit Chakravarty, Alison Murphy, Dharminder Chauhan, Linda S Higgins, Kenneth C Anderson |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 10
Issue 22
Pg. 7540-6
(Nov 15 2004)
ISSN: 1078-0432 [Print] United States |
PMID | 15569984
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Antineoplastic Agents
- Cytokines
- Enzyme Inhibitors
- HIF1A protein, human
- Hypoxia-Inducible Factor 1, alpha Subunit
- Interleukin-6
- Receptors, Transforming Growth Factor beta
- Transcription Factors
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Topics |
- Antineoplastic Agents
(pharmacology)
- Bone Marrow
(metabolism)
- Bone Marrow Cells
(cytology, metabolism)
- Cell Adhesion
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Cytokines
(biosynthesis, metabolism)
- Down-Regulation
- Enzyme Inhibitors
(pharmacology)
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit
- Immunoblotting
- Interleukin-6
(metabolism)
- Lymphocytes
(cytology)
- Microscopy, Fluorescence
- Multiple Myeloma
(metabolism)
- Receptors, Transforming Growth Factor beta
(antagonists & inhibitors)
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction
- Transcription Factors
(metabolism)
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