Transforming growth factor beta receptor I kinase inhibitor down-regulates cytokine secretion and multiple myeloma cell growth in the bone marrow microenvironment.
OBJECTIVE
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-beta1 than BMSCs from healthy donors, which in turn induces interleukin (IL)-6 secretion. We show here that the TGF-beta 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.


METHODS
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.
Hayashi
Toshiaki
T
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Hideshima
Teru
T
Nguyen
Aaron N
AN
Munoz
Olivier
O
Podar
Klaus
K
Hamasaki
Makoto
M
Ishitsuka
Kenji
K
Yasui
Hiroshi
H
Richardson
Paul
P
Chakravarty
Sarvajit
S
Murphy
Alison
A
Chauhan
Dharminder
D
Higgins
Linda S
LS
Anderson
Kenneth C
KC
D000970:Antineoplastic Agents / Q000494:pharmacology; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015151:Immunoblotting; D015850:Interleukin-6 / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology; D008856:Microscopy, Fluorescence; D009101:Multiple Myeloma / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
D000970:Antineoplastic Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015850:Interleukin-6; D018125:Receptors, Transforming Growth Factor beta; D014157:Transcription Factors