title: A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo.
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. IC(50) values for WP1066 were 5.6 muM in U87-MG cells and 3.7 muM 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-X(L) 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.
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: A
authors.initials: A
authors.lastname: Iwamaru
authors.forename: S
authors.initials: S
authors.lastname: Szymanski
authors.forename: E
authors.initials: E
authors.lastname: Iwado
authors.forename: H
authors.initials: H
authors.lastname: Aoki
authors.forename: T
authors.initials: T
authors.lastname: Yokoyama
authors.forename: I
authors.initials: I
authors.lastname: Fokt
authors.forename: K
authors.initials: K
authors.lastname: Hess
authors.forename: C
authors.initials: C
authors.lastname: Conrad
authors.forename: T
authors.initials: T
authors.lastname: Madden
authors.forename: R
authors.initials: R
authors.lastname: Sawaya
authors.forename: S
authors.initials: S
authors.lastname: Kondo
authors.forename: W
authors.initials: W
authors.lastname: Priebe
authors.forename: Y
authors.initials: Y
authors.lastname: Kondo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D020032:Tyrphostins / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011725:Pyridines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D020032:Tyrphostins; C519885:WP1066; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide