Dasatinib synergizes with JSI-124 to inhibit growth and migration and induce apoptosis of malignant human glioma cells.
BACKGROUND
Src family kinases (SFK) collectively regulate a variety of cellular functions in many cancer types, including proliferation, invasion, motility, survival, differentiation, and angiogenesis. Although Dasatinib (BMS-354825), an ATP-competitive, small molecule tyrosine kinase inhibitor, suppresses the activity of SFKs at nanomolar concentrations, IC50 values for antiproliferative effects in glioma cell lines were well above the clinically achievable range, suggesting the need to interfere with other components of receptor-induced downstream signaling in order to achieve an optimal therapeutic effect.


METHODS
The cytotoxic effects of combining Src and STAT3 inhibition on glioma cell lines were evaluated using assays to measure cell proliferation, apoptosis and migration. Western blotting and immunocytochemistry was used to monitor its effects on cell signaling and morphology.


RESULTS
Silencing Src and STAT3 expression each partially inhibited cell proliferation and migration. In addition, JSI-124 significantly enhanced the efficacy of dasatinib in vitro. Combination of dasatinib and JSI-124 achieved significant inhibition of migration in all cell lines, which correlated with the inhibition of Src and downstream mediators of adhesion (e.g. focal adhesion kinase). Cells exposed to dasatinib and JSI-124 exhibited morphological changes that were consistent with an upstream role for Src in regulating focal adhesion complexes.


CONCLUSIONS
Targeting the Src and STAT pathways may contribute to the treatment of cancers that demonstrate increased levels of these signaling mediators, including malignant human glioma. Clinical studies in these tumor types are warranted.
Premkumar
Daniel R
DR
Department of Neurosurgery, University of Pittsburgh Medical Center.
Jane
Esther P
EP
Agostino
Naomi R
NR
Scialabba
Joseph L
JL
Pollack
Ian F
IF
J Immunol. 2008 Feb 15;180(4):2089-98
18250414
J Immunol. 2005 Oct 1;175(7):4338-46
16177074
Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4227-32
10760290
Nat Biotechnol. 2009 Jan;27(1):77-83
19098899
Pediatr Blood Cancer. 2008 Jun;50(6):1198-206
17914733
Cancer Res. 2007 Mar 1;67(5):2226-38
17332353
Nat Rev Cancer. 2004 Jun;4(6):470-80
15170449
Oncogene. 2001 May 3;20(20):2499-513
11420660
Cancer Res. 2002 Nov 15;62(22):6659-66
12438264
Br J Cancer. 2009 Jul 7;101(1):38-47
19513066
Mol Cell Biol. 1996 Apr;16(4):1595-603
8657134
Clin Cancer Res. 2006 Mar 1;12(5):1398-401
16533761
Science. 1994 Apr 1;264(5155):95-8
8140422
Cancer Res. 2005 May 15;65(10):4153-61
15899806
Cancer Res. 2005 Oct 15;65(20):9185-9
16230377
Biochem Biophys Res Commun. 1995 May 5;210(1):74-81
7741752
Clin Cancer Res. 2005 Oct 1;11(19 Pt 1):6924-32
16203784
J Cell Biol. 2002 Dec 23;159(6):923-9
12486111
Oncogene. 2002 Dec 5;21(55):8404-13
12466961
Oncogene. 2000 May 15;19(21):2474-88
10851046
Cancer Res. 2007 Mar 15;67(6):2800-8
17363602
J Thorac Oncol. 2006 Jun;1(5):403-5
17409890
Cancer Lett. 2007 Sep 18;255(1):135-44
17543444
Curr Opin Oncol. 1997 May;9(3):215-22
9229142
Oncogene. 2002 Nov 21;21(53):8075-88
12444544
Science. 1995 Jul 7;269(5220):81-3
7541555
Cancer Res. 2006 Jun 1;66(11):5542-8
16740687
Cancer Lett. 2007 Nov 8;257(1):36-46
17900801
Blood. 2006 Oct 1;108(7):2332-8
16772610
Cancer Res. 2005 Oct 15;65(20):9525-35
16230418
Clin Cancer Res. 2009 May 15;15(10):3416-22
19447875
Adv Enzyme Regul. 1984;22:27-55
6382953
Nature. 2001 Mar 29;410(6828):549-54
11279485
Nat Rev Cancer. 2006 Mar;6(3):184-92
16453012
BMC Cancer. 2003 Sep 17;3:23
13678425
Mol Cancer Ther. 2006 Dec;5(12):3014-22
17148760
Cancer Res. 2009 Mar 1;69(5):1958-65
19223541
FASEB J. 2000 Apr;14(5):729-39
10744629
Blood. 2007 Jun 15;109(12):5143-50
17317857
J Pharmacol Exp Ther. 2006 Dec;319(3):1070-80
16959960
Br J Haematol. 2006 Oct;135(1):26-32
16939498
Nature. 1999 Feb 4;397(6718):441-6
9989411
Cancer Control. 1999 Oct;6(5):427-435
10758575
Cancer Res. 2003 Mar 15;63(6):1270-9
12649187
J Biol Chem. 2002 Nov 22;277(47):45680-7
12244095
Cancer Res. 2009 Sep 1;69(17):6889-98
19690143
Mol Carcinog. 2006 Jan;45(1):47-59
16267832
Oncogene. 2000 Dec 27;19(56):6613-26
11426647
Oncogene. 2007 Apr 12;26(17):2435-44
17043651
J Biol Chem. 2003 Jan 17;278(3):1671-9
12429742
Genes Dev. 2001 Jun 1;15(11):1311-33
11390353
Curr Opin Oncol. 1999 Nov;11(6):490-6
10550013
Mol Carcinog. 2006 May;45(5):288-301
16550610
Cell. 1994 Apr 8;77(1):63-71
7512451
J Med Chem. 2004 Dec 30;47(27):6658-61
15615512
Cancer Lett. 2009 Oct 8;283(2):143-51
19398150
Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7319-24
11404481
Breast Cancer Res Treat. 2007 Nov;105(3):319-26
17268817
Oncogene. 2002 Jan 3;21(1):65-77
11791177