Cited by 110Multiple Myeloma Research and TreatmentsTGF-β signaling in diseasesBone health and treatments

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Transforming Growth Factor β Receptor I Kinase Inhibitor Down-Regulates Cytokine Secretion and Multiple Myeloma Cell Growth in the Bone Marrow Microenvironment

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Hayashi, Toshiaki, Hideshima, Teru, Nguyen, Aaron N., Munoz, Olivier, Podar, Klaus, Hamasaki, Makoto, Ishitsuka, Kenji, Yasui, Hiroshi, Richardson, Paul, Chakravarty, Sarvajit, Murphy, Alison, Chauhan, Dharminder, Higgins, Linda S., Anderson, Kenneth C.·2004·Clinical Cancer Research

DOI 10.1158/1078-0432.ccr-04-0632

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Abstract

Purpose: Transforming growth factors (TGFs) have pleiotropic biological effects on tumor cells and their environment. In multiple myeloma (MM), we have reported that bone marrow stromal cells (BMSCs) from MM patients produce more TGF-β1 than BMSCs from healthy donors, which in turn induces interleukin (IL)-6 secretion. We show here that the TGF-β receptor I kinase inhibitor SD-208 significantly decreases secretion of both IL-6 and vascular endothelial growth factor (VEGF) from BMSCs, as well as tumor cell growth triggered by MM cell adhesion to BMSCs. Experimental Design: Cytokine production and MM cell proliferation triggered by TGF-β1 or adhesion to BMSCs were examined in the presence or absence of SD-208. Effects of SD-208 on TGF-β1–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-β1 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-β1–triggered nuclear accumulation of Smad2/3 and hypoxia-inducible factor 1α, 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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In Vitro Hypoxic Preconditioning of Bone Marrow Stromal Cells Triggers ERK-Mediated Signaling and Growth of L363 Myeloma Cells Celulele stromale ale mduvei hematopoietice precondiionate la hipoxie in vitro induc proliferarea celulelor mielomatoase L363 i semnalizarea intracelularERK-mediat
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Authors: Hayashi, T., Hideshima, T., Nguyen, A. N., Munoz, O., Podar, K., Hamasaki, M., Ishitsuka, K., Yasui, H., Richardson, P., Chakravarty, S., Murphy, A., Chauhan, D., Higgins, L. S., & Anderson, K. C.
Affiliations: Harvard University (US)
2SCIOS Inc., Sunnyvale, California
ORCID: Hayashi, Toshiaki
Hideshima, Teru
Podar, Klaus
Ishitsuka, Kenji
Yasui, Hiroshi
Richardson, Paul
Chakravarty, Sarvajit
Chauhan, Dharminder
Anderson, Kenneth C.
Venue: Clinical Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2004-11-15
Volume: 10
Issue: 22
Pages: 7540-7546
ISSN: 1078-0432 (ISSN-L)
1557-3265
DOI: 10.1158/1078-0432.ccr-04-0632
OpenAlex: W2148046607
Cited by: 110
References: 31
Citations by year: 2025: 3 · 2024: 2 · 2023: 3 · 2022: 7 · 2021: 4 · 2020: 4 · 2019: 1 · 2018: 4 · 2017: 5 · 2016: 4 · 2014: 2 · 2013: 4 · 2012: 11
FWCI: 5.30
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Clinical Cancer Research (publishedVersion)
PubMed (publishedVersion)
Funders: U.S. Public Health Service (P0178378)
Topics: Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Health Sciences › Medicine › Oncology › Bone health and treatments
Keywords: multiple myeloma, TGF-beta receptor I kinase inhibitor, SD-208, TGF-β1, mesenchymal stem cells, interleukin-6, vascular endothelial growth factor, cytokine production, tumor cell adhesion, Smad2/3, hypoxia-inducible factor-1α, tumor microenvironment, tumor cell proliferation
MeSH terms: Antineoplastic Agents, Bone Marrow, Bone Marrow Cells, Cell Adhesion, Enzyme Inhibitors, Humans, Lymphocytes, Microscopy, Fluorescence, Multiple Myeloma, Transcription Factors, Immunoblotting, Signal Transduction, Down-Regulation, Interleukin-6, Cytokines, Receptors, Transforming Growth Factor beta, Reverse Transcriptase Polymerase Chain Reaction, Cell Line, Tumor, Cell Proliferation, Hypoxia-Inducible Factor 1, alpha Subunit

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Transforming Growth Factor β Receptor I Kinase Inhibitor Down-Regulates Cytokine Secretion and Multiple Myeloma Cell Growth in the Bone Marrow Microenvironment

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