STAT3 as a potential therapeutic target in triple negative breast cancer: a systematic review

Qin, Jiang-Jiang; Yan, Li; Zhang, Jia; Zhang, Wei-Dong

doi:10.1186/s13046-019-1206-z

Journal of Experimental & Clinical Cancer Research

Table 1 Summary of STAT3 inhibitors and their mechanisms of action for TNBC therapy

From: STAT3 as a potential therapeutic target in triple negative breast cancer: a systematic review

Inhibitors	Mechanisms of action	In vitro activity	In vivo activity	Reference
Strategy 1: Target upstream regulators of STAT3
Carfilzomib	Inhibits IL-6/STAT3 signaling pathway	Inhibits mitosis and proliferation and induces apoptosis	Reduces serum IL-6 levels in tumor-bearing mice	[87]
Manuka honey	Inhibits IL-6/STAT3 signaling pathway	Inhibits cell viability and colony formation, induces apoptosis, impairs cell migration and invasion, and inhibits angiogenesis	NR	[88]
Bazedoxifene	Inhibits IL6/gp130/STAT3 signaling pathway	Inhibits cell viability, colony formation and cell migration and synergistically enhances the activity of paclitaxel	Suppresses tumor growth	[89, 90]
Ganoderma lucidum extract	Inhibits IL-6/JAK/STAT3 signaling pathway	Inhibits cell viability and induces apoptosis	Suppresses tumor growth	[91]
Arsenic trioxide	Inhibits EZH2/NF-κB/IL-6/STAT3/VEGF signaling pathway	Inhibits angiogenesis	NR	[96]
Deguelin	Inhibits EGFR/STAT3 signaling pathway	Inhibits cell viability	Suppresses tumor growth	[92]
Picrasidine G	Inhibits EGFR/STAT3 signaling pathway	Inhibits cell viability and induces apoptosis	NR	[93]
Cantharidin	Inhibits EGFR/STAT3 signaling pathway	Inhibits cell viability and induces apoptosis	NR	[94]
Silibinin	Inhibits JAK2/STAT3/MMP2 signaling pathway	Inhibits cell viability, migration and invasion	NR	[97]
Silibinin	Inhibits EGFR/STAT3/Fibronectin signaling pathway	NR	NR	[95]
Ganoderic acid A	Inhibits JAK2/STAT3 signaling pathway	Inhibits cell viability and invasive capacity and induces apoptosis	NR	[98]
Nintedanib	Modulates SHP-1/p-STAT3 signaling pathway	Inhibits cell viability and induces apoptosis	Suppresses tumor growth	[99]
SC-78	Modulates SHP-1/p-STAT3/VEGF-A signaling pathway	Inhibits cell migration and tube formation	Suppresses tumor growth and metastasis	[100]
1,2,3,4,6-penta-O-galloyl-beta-D-glucose	Modulates SHP-1/p-STAT3 signaling pathway	NR	Suppresses tumor growth and metastasis	[101]
SC-2001	Modulates RFX-1/SHP-1/p-STAT3 signaling pathway	Inhibits cell growth and induces apoptosis	Suppresses tumor growth	[95, 102]
Isolinderalactone	Enhances SOCS3-mediated STAT3 dephosphorylation	Inhibits cell viability and colony formation and induces apoptosis	Suppresses tumor growth	[103]
Compound 57	Binds to HSP90 and inhibits the expression and phosphorylation of STAT3	Inhibits cell viability	NR	[104]
L80	Binds to HSP90 and inhibits the expression and phosphorylation of STAT3	Inhibits cell viability induces apoptosis, and suppresses BCSC-like properties	Suppresses the growth of BCSC-enriched TNBC tumors and distant metastasis	[105]
Nor-wogonin	Inhibits TAK1-mediated STAT3 activation	Inhibits cell viability and proliferation and induces G1 and G2/M phases arrest and apoptosis	NR	[106]
Thioridazine	Inhibits DRD2-mediated STAT3 activation	Inhibits cell self-renewal, proliferation, and viability and induces G1 arrest	NR	[107]
Strategy 2: Directly bind to STAT3 and inhibit its activation
Bt354	Directly binds to SH2 domain of STAT3 and inhibits its phosphorylation	Inhibits cell viability, induces G2/M phase arrest and apoptosis, and impairs cell migration	Suppresses tumor growth	[108]
Osthole	Directly binds to STAT3 and inhibits its phosphorylation	Inhibits cell viability and induces G2/M phase arrest and apoptosis	Suppresses tumor growth	[109]
Arctigenin	Directly binds to SH2 domain of STAT3 and inhibits its phosphorylation and DNA binding ability	Inhibits cell viability, induces apoptosis, impairs cell migration and invasion, and sensitizes cells to chemotherapy	Suppresses tumor growth	[110]
Alantolactone	Directly binds to SH2 domain of STAT3 and inhibits its phosphorylation	Inhibits cell viability and colony formation and impairs cell migration and invasion	Suppresses tumor growth	[111]
KYZ3	Directly binds to SH2 domain of STAT3 and inhibits its phosphorylation	Inhibits cell viability, induces apoptosis, and impairs cell migration	Suppresses tumor growth	[113]
Strategy 3: Inhibit STAT3 phosphorylation or acetylation
Sesquiterpene lactones fraction of Inula helenium L.	Inhibits STAT3 phosphorylation and nuclear translocation	Inhibits cell viability and induces apoptosis	Suppresses tumor growth	[114]
Rhus coriaria	Inhibits STAT3 phosphorylation	Inhibits angiogenesis and impairs cell migration and invasion	Suppresses tumor growth and metastasis	[115]
Schisandrin B	Inhibits STAT3 phosphorylation and nuclear translocation	Inhibits cell viability and colony formation, induces cell cycle arrest and apoptosis, and impairs cell migration	Suppresses tumor growth	[116]
Eupalinolide J	Inhibits STAT3 phosphorylation and activation	Inhibits cell viability	NR	[117]
Galiellalactone analogues 16 and 17	Inhibits STAT3 phosphorylation and activation	Inhibits cell viability	NR	[118]
FZU-03,010	Inhibits STAT3 phosphorylation and activation	Inhibits cell viability and induces G1 phase arrest and apoptosis	NR	[119]
Niclosamide	Inhibits STAT3 phosphorylation and nuclear translocation	Reverses acquired radioresistance	Sensitizes tumors to irradiation	[120]
Flubendazole	Inhibits STAT3 phosphorylation	Inhibits cell viability, induces G2/M phase arrest and apoptosis, and suppresses BCSC-like phenotype	Suppresses tumor growth, angiogenesis and metastasis	[121]
Disulfiram	Inhibits STAT3 expression and phosphorylation	Inhibits cell viability, induces apoptosis, and impairs cancer stem cell-like properties	Suppresses tumor growth and BCSC-like properties	[122]
Salinomycin	Inhibits STAT3 phosphorylation and activation	Inhibits cell viability, promotes anoikis, impairs cell migration and invasion, and decreases CD44⁺/CD24⁻ stem-like population	NR	[123]
Metformin	Inhibits STAT3 phosphorylation	Inhibits cell viability	NR	[124]
SH-I-14	Inhibits STAT3 acetylation and disrupts DNMT1-STAT3 interaction	Inhibits cell viability	Suppresses tumor growth	[126]
Strategy 4: Block STAT3-DNA binding
Methylsulfonyl-methane	Inhibits the bindings of STAT3 to VEGF promoter and STAT5 to IGF-1R promoter	Inhibits cell viability and induces apoptosis	Suppresses tumor growth	[127]
Isoharringtonine	Inhibits STAT3-mediated Nanog expression	Inhibits cell viability, impairs cell migration, and decreases proportion of BCSC population	NR	[128]
Salidroside	Inhibits the bindings of STAT3 to MMP2 promoter	Inhibits cell migration, invasion and angiogenesis	NR	[129]

NR, not reported

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ISSN: 1756-9966

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