STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers

Wang, Xiaochun; Crowe, Philip; Goldstein, David; Yang, Jialin

doi:10.3892/ijo.2012.1568

Cited by 184 publications

(148 citation statements)

References 129 publications

(106 reference statements)

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“…Persistent activation of STAT3 contributes to tumor growth and progression, and STAT3 has been identified as an attractive anticancer target (17,(39)(40)(41). The evidence for elevated somatotroph adenoma STAT3 and STAT3 regulation of GH suggests STAT3 as a potential cellular target to treat acromegaly.…”

Section: Discussionmentioning

confidence: 99%

“…The evidence for elevated somatotroph adenoma STAT3 and STAT3 regulation of GH suggests STAT3 as a potential cellular target to treat acromegaly. Small-molecule STAT3 inhibitors have been used in preclinical and clinical studies (17,24,25,(42)(43)(44)(45), and we tested S3I-201, a cell-permeable amidosalicylic acid compound that selectively inhibits STAT3 DNA-binding activity in vitro (IC 50 = 86 ± 33 μM) (24,25). Here, we show that, using a dose of 5 mg/kg, S3I-201 inhibited rat GH3 pituitary cell growth in vitro and attenuated growth of somatotroph tumor xenografts in Wistar Furth rats.…”

Section: Discussionmentioning

confidence: 99%

“…Phosphorylated cytoplasmic STAT3 dimerizes and translocates to the nucleus, subsequently regulating target genes to modulate cell proliferation, survival and differentiation (10)(11)(12), and overexpression and/or constitutive activation of STAT3 are encountered in human cancers (11,13). STAT3 is a cancer therapeutic target, as constitutive STAT3 inhibition by small-molecule inhibitors is associated with cell growth suppression and cell death (14)(15)(16), and phase I/II oncology trials using STAT3 inhibition are ongoing (17). In the pituitary, STAT3 mediates gp130-controlled corticotroph cell proliferation and function (18,19), and STAT3 acts as a critical regulator for leukemia inhibitory factor-mediated proopiomelanocortin expression and adrenocorticotrophin secretion (19)(20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

STAT3 upregulation in pituitary somatotroph adenomas induces growth hormone hypersecretion

Zhou¹,

Jiao²,

Wang³

et al. 2015

J. Clin. Invest.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

STAT3 upregulation in pituitary somatotroph adenomas induces growth hormone hypersecretion

Zhou¹,

Jiao²,

Wang³

et al. 2015

J. Clin. Invest.

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“…Aberrantly STAT3 activation contributes to oncogenesis by preventing apoptosis, inducing cell proliferation, angiogenesis, invasion, and metastasis as well as suppressing antitumor immune responses (30,31). Phosphorylated STAT3 dimerizes and translocates into the nucleus to bind to specific DNA response elements to induce the transcription of downstream genes, such as BCL-xL, MCL1 and c-Myc (32).…”

Section: Discussionmentioning

confidence: 99%

The antipsychotic drug pimozide inhibits cell growth in prostate cancer through suppression of STAT3 activation

Zhou

Chen

et al. 2015

International Journal of Oncology

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Abstract. Currently, drug discovery and development for clinical treatment of prostate cancer has received increased attention, specifically the STAT3 inhibitor. Our previous study reported that the neuroleptic drug pimozide had antitumor activity against hepatocellular carcinoma cells or stem-like cells through suppressing the STAT3 activity. In the present study we demonstrate that pimozide inhibits cell growth and cellular STAT3 activation in prostate cancer cells. Our results showed that pimozide inhibited prostate cancer cell proliferation in a dose-and time-dependent manner by inducing G1 phase cell cycle arrest, downregulated the ability of colony formation and sphere forming, as well as suppressed cells migration in both DU145 and LNCaP cells. Surprisingly, pimozide reduced the basal expression of phosphorylation STAT3 at tyrosine 705 and reversed the expression of phosphorylation of STAT3 induced by IL-6 addition, suggesting that pimozide can suppress cellular STAT3 activation. Thus, the antipsychotic agent pimozide may be a potential and novel therapeutic for patients with advanced prostate cancer.

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“…In fact, previous attempts to target STAT3 in cancer therapy have included direct chemical inhibitors of STAT3, JAK and Src, IL-6 receptor antagonists, antisense strategies, decoy phosphopeptides, decoy duplex oligonucleotides, dominant negative proteins, RNA interference, chemopreventive agents, and G-quartet oligodeoxynucleotides (Jing and Tweardy, 2005;Sansone and Bromberg, 2012;Wang et al, 2012;Siveen et al, 2014). Recently, resistance to standard anticancer therapies has been correlated to constitutive or unabated activation of STAT3, indicating that combination therapy with STAT3 inhibitors may be important for patient treatment .…”

Section: Discussionmentioning

confidence: 99%

Novel Thiosemicarbazones Regulate the Signal Transducer and Activator of Transcription 3 (STAT3) Pathway: Inhibition of Constitutive and Interleukin 6–Induced Activation by Iron Depletion

et al. 2015

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Pharmacologic manipulation of metal pools in tumor cells is a promising strategy for cancer treatment. Here, we reveal how the iron-binding ligands desferrioxamine (DFO), di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) inhibit constitutive and interleukin 6-induced activation of signal transducer and activator of transcription 3 (STAT3) signaling, which promotes proliferation, survival, and metastasis of cancer cells. We demonstrate that DFO, Dp44mT, and DpC significantly decrease constitutive phosphorylation of the STAT3 transcription factor at Tyr705 in the pancreatic cancer cell lines PANC-1 and MIAPaCa-2 as well as the prostate cancer cell line DU145. These compounds also significantly decrease the dimerized STAT3 levels, the binding of nuclear STAT3 to its target DNA, and the expression of downstream targets of STAT3, including cyclin D1, c-myc, and Bcl-2. Examination of upstream mediators of STAT3 in response to these ligands has revealed that Dp44mT and DpC could significantly decrease activation of the nonreceptor tyrosine kinase Src and activation of cAbl in DU145 and MIAPaCa-2 cells. In contrast to the effects of Dp44mT, DpC, or DFO on inhibiting STAT3 activation, the negative control compound di-2-pyridylketone 2-methyl-3-thiosemicarbazone, or the DFO:Fe complex, which cannot bind cellular iron, had no effect. This demonstrates the role of iron-binding in the activity observed. Immunohistochemical staining of PANC-1 tumor xenografts showed a marked decrease in STAT3 in the tumors of mice treated with Dp44mT or DpC compared with the vehicle. Collectively, these studies demonstrate suppression of STAT3 activity by iron depletion in vitro and in vivo, and reveal insights into regulation of the critical oncogenic STAT3 pathway.

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STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers

Cited by 184 publications

References 129 publications

STAT3 upregulation in pituitary somatotroph adenomas induces growth hormone hypersecretion

STAT3 upregulation in pituitary somatotroph adenomas induces growth hormone hypersecretion

The antipsychotic drug pimozide inhibits cell growth in prostate cancer through suppression of STAT3 activation

Novel Thiosemicarbazones Regulate the Signal Transducer and Activator of Transcription 3 (STAT3) Pathway: Inhibition of Constitutive and Interleukin 6–Induced Activation by Iron Depletion

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