A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2006-10-16

AUTHORS

A Iwamaru, S Szymanski, E Iwado, H Aoki, T Yokoyama, I Fokt, K Hess, C Conrad, T Madden, R Sawaya, S Kondo, W Priebe, Y Kondo

ABSTRACT

Signal transducer and activator of transcription-3 (STAT3) is constitutively activated in a variety of cancer types, including malignant gliomas. STAT3 is activated by phosphorylation of a tyrosine residue, after which it dimerizes and translocates into the nucleus. There it regulates the expression of several genes responsible for proliferation and survival at the transcriptional level. A selective inhibitor of STAT3 phosphorylation, AG490, has been shown to inhibit growth and induce apoptosis in some cancer cell types. However, although AG490 routinely shows in vitro anticancer activity, it has not consistently demonstrated an in vivo anticancer effect in animal models. Here, we have tested WP1066, a novel inhibitor structurally related to AG490 but significantly more potent and active, against human malignant glioma U87-MG and U373-MG cells in vitro and in vivo. IC50 values for WP1066 were 5.6 μM in U87-MG cells and 3.7 μM in U373-MG cells, which represents 18-fold and eightfold increases in potency, respectively, over that of AG490. WP1066 activated Bax, suppressed the expression of c-myc, Bcl-XL and Mcl-1, and induced apoptosis. Systemic intraperitoneal administration of WP1066 in mice significantly (P<0.001) inhibited the growth of subcutaneous malignant glioma xenografts during the 30-day follow-up period. Immunohistochemical analysis of the excised tumors revealed that phosphorylated STAT3 levels in the WP1066 treatment group remained inhibited at 3 weeks after the final WP1066 injection, whereas tumors from the control group expressed high levels of phosphorylated STAT3. We conclude that WP1066 holds promise as a therapeutic agent against malignant gliomas. More... »

PAGES

2435-2444

References to SciGraph publications

Journal

TITLE

Oncogene

ISSUE

17

VOLUME

26

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.onc.1210031

DOI

http://dx.doi.org/10.1038/sj.onc.1210031

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1031711164

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/17043651


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29 schema:description Signal transducer and activator of transcription-3 (STAT3) is constitutively activated in a variety of cancer types, including malignant gliomas. STAT3 is activated by phosphorylation of a tyrosine residue, after which it dimerizes and translocates into the nucleus. There it regulates the expression of several genes responsible for proliferation and survival at the transcriptional level. A selective inhibitor of STAT3 phosphorylation, AG490, has been shown to inhibit growth and induce apoptosis in some cancer cell types. However, although AG490 routinely shows in vitro anticancer activity, it has not consistently demonstrated an in vivo anticancer effect in animal models. Here, we have tested WP1066, a novel inhibitor structurally related to AG490 but significantly more potent and active, against human malignant glioma U87-MG and U373-MG cells in vitro and in vivo. IC50 values for WP1066 were 5.6 μM in U87-MG cells and 3.7 μM in U373-MG cells, which represents 18-fold and eightfold increases in potency, respectively, over that of AG490. WP1066 activated Bax, suppressed the expression of c-myc, Bcl-XL and Mcl-1, and induced apoptosis. Systemic intraperitoneal administration of WP1066 in mice significantly (P<0.001) inhibited the growth of subcutaneous malignant glioma xenografts during the 30-day follow-up period. Immunohistochemical analysis of the excised tumors revealed that phosphorylated STAT3 levels in the WP1066 treatment group remained inhibited at 3 weeks after the final WP1066 injection, whereas tumors from the control group expressed high levels of phosphorylated STAT3. We conclude that WP1066 holds promise as a therapeutic agent against malignant gliomas.
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36 Bax
37 Bcl-xL
38 Mcl-1
39 STAT3
40 STAT3 levels
41 STAT3 pathway
42 STAT3 phosphorylation
43 U373 MG cells
44 U87-MG
45 U87-MG cells
46 WP1066
47 activator
48 activity
49 administration
50 agents
51 analysis
52 animal models
53 anticancer activity
54 anticancer effects
55 apoptosis
56 c-Myc
57 cancer cell types
58 cancer types
59 cell types
60 cells
61 control group
62 effect
63 eightfold increase
64 excised tumor
65 expression
66 follow
67 genes
68 glioma cells
69 glioma xenografts
70 gliomas
71 group
72 growth
73 high levels
74 immunohistochemical analysis
75 increase
76 inhibitors
77 injection
78 intraperitoneal administration
79 levels
80 malignant glioma cells
81 malignant glioma xenografts
82 malignant gliomas
83 mice
84 model
85 novel inhibitors
86 nucleus
87 pathway
88 period
89 phosphorylated STAT3
90 phosphorylation
91 potency
92 proliferation
93 promise
94 residues
95 selective inhibitor
96 signal transducer
97 survival
98 systemic intraperitoneal administration
99 therapeutic agents
100 transcription 3
101 transcriptional level
102 transducer
103 treatment groups
104 tumors
105 types
106 tyrosine residues
107 values
108 variety
109 vitro
110 vivo
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112 weeks
113 xenografts
114 μM
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