The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3
signaling, resulting insuppression of human myeloma cell growth
and survival.

J 2011

The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting insuppression of human myeloma cell growth and survival.

SCUTO, A., Pavel KREJČÍ, L. POPPLEWELL, J. WU, Y. WANG et. al.

Basic information

Original name

The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting insuppression of human myeloma cell growth and survival.

Name in Czech

he novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting insuppression of human myeloma cell growth and survival.

Authors

SCUTO, A. (840 United States of America), Pavel KREJČÍ (203 Czech Republic, guarantor, belonging to the institution), L. POPPLEWELL (840 United States of America), J. WU (840 United States of America), Y. WANG (840 United States of America), M. KUJAWSKI (840 United States of America), C. KOWOLIK (840 United States of America), H. XIN (840 United States of America), L. CHEN (840 United States of America), Y. WANG (840 United States of America), L. KRETZNER (840 United States of America), H. YU (840 United States of America), W.R. WILCOX (840 United States of America), Y. YEN (840 United States of America), S. FORMAN (840 United States of America) and R. JOVE (840 United States of America)

Edition

Leukemia, London : England, Nature Publishing Group, Specialist Jour, 2011, 0887-6924

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30105 Physiology

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

Impact factor

Impact factor: 9.561

RIV identification code

RIV/00216224:14310/11:00050507

Organization unit

Faculty of Science

DOI

http://dx.doi.org/10.1038/leu.2010.289

UT WoS

000288159500017

Keywords in English

myeloma; JAK2; STAT3; FGFR3

Abstract

V originále

IL-6 and downstream JAK-dependent signaling pathways have critical roles in the pathophysiology of multiple myeloma (MM). We investigated the effects of a novel small-molecule JAK inhibitor (AZD1480) on IL-6/JAK signal transduction and its biological consequences on the human myeloma-derived cell lines U266 and Kms. 11. At low micromolar concentrations, AZD1480 blocks cell proliferation and induces apoptosis of myeloma cell lines. These biological responses to AZD1480 are associated with concomitant inhibition of phosphorylation of JAK2, STAT3 and MAPK signaling proteins. In addition, there is inhibition of expression of STAT3 target genes, particularly Cyclin D2. Examination of a wider variety of myeloma cells (RPMI 8226, OPM-2, NCI-H929, Kms. 18, MM1. S and IM-9), as well as primary myeloma cells, showed that AZD1480 has broad efficacy. In contrast, viability of normal peripheral blood (PB) mononuclear cells and CD138(+) cells derived from healthy controls was not significantly inhibited. Importantly, AZD1480 induces cell death of Kms. 11 cells grown in the presence of HS-5 bone marrow (BM)-derived stromal cells and inhibits tumor growth in a Kms. 11 xenograft mouse model, accompanied with inhibition of phospho-FGFR3, phospho-JAK2, phospho- STAT3 and Cyclin D2 levels. In sum, AZD1480 blocks proliferation, survival, FGFR3 and JAK/STAT3 signaling in myeloma cells cultured alone or cocultured with BM stromal cells, and in vivo. Thus, AZD1480 represents a potential new therapeutic agent for patients with MM.

Links

GA301/09/0587, research and development project

Name: Nové dráhy FGFR3 signalingu v achondroplázii

Investor: Czech Science Foundation, Novel pathway of FGFR3 signaling in achondroplasia

MSM0021622430, plan (intention)

Name: Funkční a molekulární charakteristiky nádorových a normálních kmenových buněk - identifikace cílů pro nová terapeutika a terapeutické strategie

Investor: Ministry of Education, Youth and Sports of the CR, Functional and molecular characteristics of cancer and normal stem cells - identification of targets for novel therapeutics and therapeutic strategies

Citovat

SCUTO, A., Pavel KREJČÍ, L. POPPLEWELL, J. WU, Y. WANG, M. KUJAWSKI, C. KOWOLIK, H. XIN, L. CHEN, Y. WANG, L. KRETZNER, H. YU, W.R. WILCOX, Y. YEN, S. FORMAN and R. JOVE. The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting insuppression of human myeloma cell growth and survival. Leukemia. London : England: Nature Publishing Group, Specialist Jour, 2011, vol. 25, No 3, p. 538-550. ISSN 0887-6924. Available from: https://dx.doi.org/10.1038/leu.2010.289.

@article{971588,
   author = {Scuto, A. and Krejčí, Pavel and Popplewell, L. and Wu, J. and Wang, Y. and Kujawski, M. and Kowolik, C. and Xin, H. and Chen, L. and Wang, Y. and Kretzner, L. and Yu, H. and Wilcox, W.R. and Yen, Y. and Forman, S. and Jove, R.},
   article_location = {London : England},
   article_number = {3},
   doi = {http://dx.doi.org/10.1038/leu.2010.289},
   keywords = {myeloma; JAK2; STAT3; FGFR3},
   language = {eng},
   issn = {0887-6924},
   journal = {Leukemia},
   title = {The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting insuppression of human myeloma cell growth and survival.},
   volume = {25},
   year = {2011}
}

TY  - JOUR
ID  - 971588
AU  - Scuto, A. - Krejčí, Pavel - Popplewell, L. - Wu, J. - Wang, Y. - Kujawski, M. - Kowolik, C. - Xin, H. - Chen, L. - Wang, Y. - Kretzner, L. - Yu, H. - Wilcox, W.R. - Yen, Y. - Forman, S. - Jove, R.
PY  - 2011
TI  - The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting insuppression of human myeloma cell growth and survival.
JF  - Leukemia
VL  - 25
IS  - 3
SP  - 538-550
EP  - 538-550
PB  - Nature Publishing Group, Specialist Jour
SN  - 08876924
KW  - myeloma
KW  - JAK2
KW  - STAT3
KW  - FGFR3
N2  - IL-6 and downstream JAK-dependent signaling pathways have critical roles in the pathophysiology of multiple myeloma (MM). We investigated the effects of a novel small-molecule JAK inhibitor (AZD1480) on IL-6/JAK signal transduction and its biological consequences on the human myeloma-derived cell lines U266 and Kms. 11. At low micromolar concentrations, AZD1480 blocks cell proliferation and induces apoptosis of myeloma cell lines. These biological responses to AZD1480 are associated with concomitant inhibition of phosphorylation of JAK2, STAT3 and MAPK signaling proteins. In addition, there is inhibition of expression of STAT3 target genes, particularly Cyclin D2. Examination of a wider variety of myeloma cells (RPMI 8226, OPM-2, NCI-H929, Kms. 18, MM1. S and IM-9), as well as primary myeloma cells, showed that AZD1480 has broad efficacy. In contrast, viability of normal peripheral blood (PB) mononuclear cells and CD138(+) cells derived from healthy controls was not significantly inhibited. Importantly, AZD1480 induces cell death of Kms. 11 cells grown in the presence of HS-5 bone marrow (BM)-derived stromal cells and inhibits tumor growth in a Kms. 11 xenograft mouse model, accompanied with inhibition of phospho-FGFR3, phospho-JAK2, phospho- STAT3 and Cyclin D2 levels. In sum, AZD1480 blocks proliferation, survival, FGFR3 and JAK/STAT3 signaling in myeloma cells cultured alone or cocultured with BM stromal cells, and in vivo. Thus, AZD1480 represents a potential new therapeutic agent for patients with MM.
ER  -

SCUTO, A., Pavel KREJČÍ, L. POPPLEWELL, J. WU, Y. WANG, M. KUJAWSKI, C. KOWOLIK, H. XIN, L. CHEN, Y. WANG, L. KRETZNER, H. YU, W.R. WILCOX, Y. YEN, S. FORMAN and R. JOVE. The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting insuppression of human myeloma cell growth and survival. \textit{Leukemia}. London : England: Nature Publishing Group, Specialist Jour, 2011, vol.~25, No~3, p.~538-550. ISSN~0887-6924. Available from: https://dx.doi.org/10.1038/leu.2010.289.

Detailed Information on Publication Record