Interleukin-6 as a therapy target in oral squamous carcinoma

Čulig, Zoran

doi:10.1517/14728222.2013.733368

Cited by 16 publications

(25 citation statements)

References 31 publications

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“…26,27,31,32,36,[54][55][56][57][58][59][60] Elevated concentrations of IL-6 were found in the saliva of patients with premalignant HNSCC lesions. 26 Higher pretreatment serum IL-6 levels were associated with lower HNSCC overall survival, higher tumor recurrence, and increased development of second primary tumors. 26,31,36,59 In patient HNSCC tumor tissue specimens, IL-6 levels correlated with the HNSCC tumor grade and were reduced after effective radio-or chemotherapies.…”

Section: Discussionmentioning

confidence: 99%

“…10,25 Elevated concentrations of growth factors and cytokines that activate the STAT3 pathway have been detected in the serum and/or tumor microenvironments of patients with HNSCC. 1,5,7,8,26,27 For example, transforming growth factor alpha (TGFa)/EGFR autocrine or paracrine signaling in squamous cell carcinoma cells may support the inappropriate or sustained activation of the STAT3 pathway that in turn promotes HNSCC tumor development and/or survival. 4,5,8 Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates hematopoiesis, inflammation, immune responses, and the production of acute-phase proteins by the liver.…”

Section: Introductionmentioning

confidence: 99%

“…IL-6 is produced and secreted by many cancer cells and stromal cell constituents of the tumor microenvironment: tumor infiltrating immune cells (T cells, B cells, neutrophils, and macrophages), adipocytes, fibroblasts, and other endothelial or epithelial cell populations. 21,22,26,27 IL-6 stimulates the growth of many cancer cell types, and elevated serum IL-6 concentrations have been associated with higher cancer stage, faster tumor progression, inhibition of apoptosis, stimulation of angiogenesis, drug resistance, and an adverse prognosis in patients with many types of cancers, including HNSCC, multiple myeloma, lymphoma, ovarian cancer, prostate cancer, lung cancer, breast cancer, metastatic, and renal carcinoma. 26,[28][29][30][31][32][33][34][35] IL-6 was identified as a valuable biomarker for predicting recurrence and overall HNSCC patient survival.…”

Section: Introductionmentioning

confidence: 99%

“…21,22,26,27 IL-6 stimulates the growth of many cancer cell types, and elevated serum IL-6 concentrations have been associated with higher cancer stage, faster tumor progression, inhibition of apoptosis, stimulation of angiogenesis, drug resistance, and an adverse prognosis in patients with many types of cancers, including HNSCC, multiple myeloma, lymphoma, ovarian cancer, prostate cancer, lung cancer, breast cancer, metastatic, and renal carcinoma. 26,[28][29][30][31][32][33][34][35] IL-6 was identified as a valuable biomarker for predicting recurrence and overall HNSCC patient survival. 26,31,36 Tocilizumab, a humanized anti-IL-6Ra mAb that blocks IL-6 binding and neutralizes IL-6-induced activities, 37,38 was approved by the FDA for the treatment of inflammatory diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, Castleman's disease, and Crohn's disease.…”

Section: Introductionmentioning

confidence: 99%

“…26,[28][29][30][31][32][33][34][35] IL-6 was identified as a valuable biomarker for predicting recurrence and overall HNSCC patient survival. 26,31,36 Tocilizumab, a humanized anti-IL-6Ra mAb that blocks IL-6 binding and neutralizes IL-6-induced activities, 37,38 was approved by the FDA for the treatment of inflammatory diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, Castleman's disease, and Crohn's disease. Tocilizumab and siltuximab, an IL-6 neutralizing antibody, are in clinical trials for multiple myeloma, prostate cancer, and metastatic kidney cancer.…”

Section: Introductionmentioning

confidence: 99%

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HCS Campaign to Identify Selective Inhibitors of IL-6-Induced STAT3 Pathway Activation in Head and Neck Cancer Cell Lines

Johnston

Sen

Hua

et al. 2015

ASSAY and Drug Development Technologies

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Signal transducer and activator of transcription factor 3 (STAT3) is hyperactivated in head and neck squamous cell carcinomas (HNSCC). Cumulative evidence indicates that IL-6 production by HNSCC cells and/or stromal cells in the tumor microenvironment activates STAT3 and contributes to tumor progression and drug resistance. A library of 94,491 compounds from the Molecular Library Screening Center Network (MLSCN) was screened for the ability to inhibit interleukin-6 (IL-6)-induced pSTAT3 activation. For contractual reasons, the primary high-content screening (HCS) campaign was conducted over several months in 3 distinct phases; 1,068 (1.1%) primary HCS actives remained after cytotoxic or fluorescent outliers were eliminated. One thousand one hundred eighty-seven compounds were cherry-picked for confirmation; actives identified in the primary HCS and compounds selected by a structural similarity search of the remaining MLSCN library using hits identified in phases I and II of the screen. Actives were confirmed in pSTAT3 IC 50 assays, and an IFNc-induced pSTAT1 activation assay was used to prioritize selective inhibitors of STAT3 activation that would not inhibit STAT1 tumor suppressor functions. Two hundred three concentration-dependent inhibitors of IL-6-induced pSTAT3 activation were identified and 89 of these also produced IC 50 s against IFN-c-induced pSTAT1 activation. Forty-nine compounds met our hit criteria: they reproducibly inhibited IL-6-induced pSTAT3 activation by ‡70% at 20 lM; their pSTAT3 activation IC 50 s were £25 lM; they were ‡2-fold selective for pSTAT3 inhibition over pSTAT1 inhibition; a cross target query of PubChem indicated that they were not biologically promiscuous; and they were ‡90% pure. Twenty-six chemically tractable hits that passed filters for nuisance compounds and had acceptable drug-like and ADME-Tox properties by computational evaluation were purchased for characterization. The hit structures were distributed among 5 clusters and 8 singletons. Twenty-four compounds inhibited IL-6-induced pSTAT3 activation with IC 50 s £20 lM and 13 were ‡3-fold selective versus inhibition of pSTAT1 activation. Eighteen hits inhibited the growth of HNSCC cell lines with average IC 50 s £ 20 lM. Four chemical series were progressed into lead optimization: the guanidinoquinazolines, the triazolothiadiazines, the amino alcohols, and an oxazole-piperazine singleton.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HCS Campaign to Identify Selective Inhibitors of IL-6-Induced STAT3 Pathway Activation in Head and Neck Cancer Cell Lines

Johnston

Sen

Hua

et al. 2015

ASSAY and Drug Development Technologies

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MicroRNAs as effective surrogate biomarkers for early diagnosis of oral cancer

et al. 2018

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Clinical Roles of Interleukin-6 and STAT3 in Oral Squamous Cell Carcinoma

Shinagawa

Yanamoto

Naruse

et al. 2016

Pathol. Oncol. Res.

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The effect inflammation has on cancer prognosis is marked by the presence of cytokines and chemokines. Interleukin-6 (IL-6) is one a multifunctional cytokine that regulates inflammatory responses. We investigated the roles of IL-6 and STAT3 and examined the relationship between IL-6 signaling and clinicopathological factors in patients with oral squamous cell carcinoma (OSCC). We retrospectively examined 116 patients who underwent radical surgery for OSCC. IL-6 and STAT3 expression were detected by immunohistochemistry. IL-6 and STAT3 positivity were detected by IHC, at 78.4 and 80.2 %, respectively. IL-6 expression was significantly associated with pattern of invasion (P = 0.004), vascular invasion (P = 0.003), and pathological nodal status (P = 0.019). Multivariate logistic regression analysis revealed that IL-6 expression was significantly associated with vascular invasion (P = 0.044). Meanwhile, there was no significant association between STAT3 expression and clinicopathological factors and no significant relationship between IL-6 and STAT3 expression. IL-6 expression was significantly associated with 5-year disease-free survival. These results suggest that IL-6 is involved in lymphangiogenesis and recurrence in OSCC.

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Interleukin-6 as a therapy target in oral squamous carcinoma

Cited by 16 publications

References 31 publications

HCS Campaign to Identify Selective Inhibitors of IL-6-Induced STAT3 Pathway Activation in Head and Neck Cancer Cell Lines

HCS Campaign to Identify Selective Inhibitors of IL-6-Induced STAT3 Pathway Activation in Head and Neck Cancer Cell Lines

MicroRNAs as effective surrogate biomarkers for early diagnosis of oral cancer

Clinical Roles of Interleukin-6 and STAT3 in Oral Squamous Cell Carcinoma

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