Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 1891 - 1899 |
| Number of pages | 9 |
| Journal | Leukemia |
| Volume | 25 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 2011 |
Cite this
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The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells. / Monaghan, Katherine; Khong, Tiffany; Burns, C; Spencer, Andrew.
In: Leukemia, Vol. 25, No. 12, 2011, p. 1891 - 1899.Research output: Contribution to journal › Article › Other
TY - JOUR
T1 - The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells
AU - Monaghan, Katherine
AU - Khong, Tiffany
AU - Burns, C
AU - Spencer, Andrew
PY - 2011
Y1 - 2011
N2 - Janus kinases (JAKs) are involved in various signalling pathways exploited by malignant cells. In multiple myeloma (MM), the interleukin-6/JAK/signal transducers and activators of transcription (IL-6/JAK/STAT) pathway has been the focus of research for a number of years and IL-6 has an established role in MM drug resistance. JAKs therefore make a rational drug target for anti-MM therapy. CYT387 is a novel, orally bioavailable JAK1/2 inhibitor, which has recently been described. This preclinical evaluation of CYT387 for treatment of MM demonstrated that CYT387 was able to prevent IL-6-induced phosphorylation of STAT3 and greatly decrease IL-6-and insulin-like growth factor-1-induced phosphorylation of AKT and extracellular signal-regulated kinase in human myeloma cell lines (HMCL). CYT387 inhibited MM proliferation in a time-and dose-dependent manner in 6/8 HMCL, and this was not abrogated by the addition of exogenous IL-6 (3/3 HMCL). Cell cycling was inhibited with a G 2/M accumulation of cells, and apoptosis was induced by CYT387 in all HMCL tested (3/3). CYT387 synergised in killing HMCL when used in combination with the conventional anti-MM therapies melphalan and bortezomib. Importantly, apoptosis was also induced in primary patient MM cells (n6) with CYT387 as a single agent, and again synergy was seen when combined with conventional therapies. A? 2011 Macmillan Publishers Limited All rights reserved.
AB - Janus kinases (JAKs) are involved in various signalling pathways exploited by malignant cells. In multiple myeloma (MM), the interleukin-6/JAK/signal transducers and activators of transcription (IL-6/JAK/STAT) pathway has been the focus of research for a number of years and IL-6 has an established role in MM drug resistance. JAKs therefore make a rational drug target for anti-MM therapy. CYT387 is a novel, orally bioavailable JAK1/2 inhibitor, which has recently been described. This preclinical evaluation of CYT387 for treatment of MM demonstrated that CYT387 was able to prevent IL-6-induced phosphorylation of STAT3 and greatly decrease IL-6-and insulin-like growth factor-1-induced phosphorylation of AKT and extracellular signal-regulated kinase in human myeloma cell lines (HMCL). CYT387 inhibited MM proliferation in a time-and dose-dependent manner in 6/8 HMCL, and this was not abrogated by the addition of exogenous IL-6 (3/3 HMCL). Cell cycling was inhibited with a G 2/M accumulation of cells, and apoptosis was induced by CYT387 in all HMCL tested (3/3). CYT387 synergised in killing HMCL when used in combination with the conventional anti-MM therapies melphalan and bortezomib. Importantly, apoptosis was also induced in primary patient MM cells (n6) with CYT387 as a single agent, and again synergy was seen when combined with conventional therapies. A? 2011 Macmillan Publishers Limited All rights reserved.
UR - http://www.nature.com.ezproxy.lib.monash.edu.au/leu/journal/v25/n12/full/leu2011175a.html
U2 - 10.1038/leu.2011.175
DO - 10.1038/leu.2011.175
M3 - Article
VL - 25
SP - 1891
EP - 1899
JO - Leukemia
JF - Leukemia
SN - 0887-6924
IS - 12
ER -