Inhibition of the IL-6 signaling pathway: A strategy to combat chronic inflammatory diseases and cancer

Ataie-Kachoie, Parvin; Pourgholami, Mohammad H.; Morris, David L.

doi:10.1016/j.cytogfr.2012.09.001

Cited by 102 publications

(85 citation statements)

References 130 publications

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“…The cancer-bearing animals have shown that an increased value of IL-1β and IL-6 has been found to play an important role in various tumor behaviors, including proliferation and differentiation of tumor cells and apoptosis [58], invasion and growth of malignancies [51], and cell migration and attachment leading to metastasis [55]. IL-6 has been proved to be implicated in the etiology of these major complications in breast cancer patients [25]. IL-8 mainly plays a vital role in angiogenesis, tumor progression, and cell invasion [11], thereby stimulating cancer cell growth and contributing to metastasis and recurrence [3].…”

Section: Discussionmentioning

confidence: 99%

d-pinitol mitigates tumor growth by modulating interleukins and hormones and induces apoptosis in rat breast carcinogenesis through inhibition of NF-κB

Rengarajan

Nandakumar

Rajendran³

et al. 2015

J Physiol Biochem

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Breast cancer is the most prevalent malignant neoplasm in the world, and chemoprevention through dietary intervention strategy is an emerging option to reduce the incidence. D-pinitol (DP), a major component of soya bean, possesses attractive biological actions. We have investigated whether D-pinitol have an effect on tumor growth in vivo against 7,12-dimethylbenz(a)anthracene (DMBA)-initiated rat mammary carcinogenesis and investigated its mechanism of action. Tumors were induced in Sprague-Dawley (SD) rats by a gastric dose of 20 mg/kg DMBA, and after 13 weeks of induction period, the rats were orally administered with D-pinitol for 45 days. At the end of the assay, animals in carcinogen control group prompted a tumor incidence of 100 % and developed a tumor volume of 8.35 ± 0.56, which was significantly reduced to 5.74 ± 0.32 for the animals treated with D-pinitol. The D-pinitol treatment not only decreased the tumor volume but also further examination revealed that tumors from animals that received D-pinitol reduced nuclear factor kappa B (NF-κB) activation which in turn results in modulation of its downstreaming p53 and proteins of caspase-3 family. Bcl-2 expression and caspase-3 activation were also decreased after D-pinitol supplementation leading to induction of apoptosis and finally cell death. Furthermore, the status of the inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-2, IL-6, and tumor markers, lipid profile, and hormones was also significantly declined up on D-pinitol administration. Thus, it reveals the collective involvement of the above-mentioned parameters along with NF-κB signaling through which D-pinitol induces apoptosis and subsequently suppresses breast cancer during DMBA-induced rat breast carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

d-pinitol mitigates tumor growth by modulating interleukins and hormones and induces apoptosis in rat breast carcinogenesis through inhibition of NF-κB

Rengarajan

Nandakumar

Rajendran³

et al. 2015

J Physiol Biochem

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“…Effects such as tumor initiation, growth, and progression are mediated by proinflammatory cytokines such as TNF-a and IL-6, and an increased expression of IL-6 is associated with an unfavorable prognosis in patients with various types of cancer (Suganuma et al, 2002;Moore et al, 2010;Culig and Puhr, 2012;Ataie-Kachoie et al, 2013;Waldner and Neurath, 2014).…”

Section: Phenoconversion Of Dmes In Cancermentioning

confidence: 99%

Inflammation-Induced Phenoconversion of Polymorphic Drug Metabolizing Enzymes: Hypothesis with Implications for Personalized Medicine

Shah¹,

2014

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Phenoconversion transiently converts genotypic extensive metabolizers (EMs) into phenotypic poor metabolizers (PMs) of drugs, potentially with corresponding changes in clinical response. This phenomenon, typically resulting from coadministration of medications that inhibit certain drug metabolizing enzymes (DMEs), is especially well documented for enzymes of the cytochrome P450 family. Nonclinical evidence gathered over the last two decades also strongly implicates elevated levels of some proinflammatory cytokines, released during inflammation, in down-regulation of drug metabolism, especially by certain DMEs of the P450 family, thereby potentially causing transient phenoconversion. Clinically, phenoconversion of NAT2, CYP2C19, and CYP2D6 has been documented in inflammatory conditions associated with elevated cytokines, such as human immunodeficiency virus infection, cancer, and liver disease. The potential of other inflammatory conditions to cause phenoconversion has not been studied but experimental and anecdotal clinical evidence supports infectioninduced down-regulation of CYP1A2, CYP3A4, and CYP2C9 as well. Collectively, the evidence supports a hypothesis that certain inflammatory conditions associated with elevated proinflammatory cytokines may cause phenoconversion of certain DMEs. Since inflammatory conditions associated with elevated levels of proinflammatory cytokines are highly prevalent, phenoconversion of genotypic EM patients into transient phenotypic PMs may be more frequent than appreciated. Since drug pharmacokinetics, and therefore the clinical response, is influenced by DME phenotype rather than genotype per se, phenoconversion (whatever its cause) can have a significant impact on the analysis and interpretation of genotype-focused clinical outcome association studies. There is a risk that focusing on genotype alone may miss important associations between clinical outcomes and DME phenotypes, thus compromising future prospects of personalized medicine.

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“…Increased expression of IL-6 has been detected and associated with an unfavorable prognosis and metastasis in patients with cancer (9). Therefore, targeting IL-6-mediated pathways can offer an effective treatment modality (10). Several studies have suggested the role of IL-6 in modulating the tumor microenvironment, which is triggered by inducing epithelial-to mesenchymal transition (EMT) followed by downregulation the expression of E-cadherin and upregulation the expression levels of Vimentin, N-cadherin, Snail and Twist (11,12).…”

Section: Introductionmentioning

confidence: 99%

Expression of interleukin-6 is associated with epithelial-mesenchymal transition and survival rates in gallbladder cancer

Zhang

Gong

Zhang

et al. 2014

Molecular Medicine Reports

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Abstract. The present study aimed to investigate the expression of interleukin-6 (IL-6) in gallbladder cancer (GBC) tissues and its correlation with survival rate. The association between IL-6 and epithelial-mesenchymal transition (EMT)-associated markers was also examined. Using immunohistochemistry, reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis, the protein and mRNA expression levels of IL-6, Twist, E-cadherin and Vimentin in 20 GBC tissues were analyzed. The IL-6, Twist and Vimentin proteins were overexpressed in 40, 20 and 70% of the human GBC samples, respectively. The protein expression of E-cadherin was higher in only 5% of the GBC samples. These differences were significant (P<0.05). Western blot analysis also revealed overexpression of IL-6, Twist and Vimentin and underexpression of E-cadherin in the GBC samples with poor differentiation, local invasion and a higher tumor-node-metastasis (TNM) stage (P<0.05). Higher mRNA expression levels of IL-6, Twist and Vimentin and a reduced expression level of E-cadherin were also demonstrated in the GBC tissues (P<0.05). The degree of differentiation, local invasion, lymph node metastasis and clinical stage were significantly associated with the mRNA expression levels of IL-6, Twist and E-cadherin. The increased expression levels of IL-6 and Twist and the reduced expression of E-cadherin correlated with shorter median survival rates (P<0.05). Line regression results revealed correlation among the mRNA expression levels of IL-6, Twist, E-cadherin and Vimentin. To the best of our knowledge, the present study is the first to demonstrate that IL-6 is associated with EMT-associated markers, tumor differentiation, local invasion, TNM stage and survival rates in GBC.

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Inhibition of the IL-6 signaling pathway: A strategy to combat chronic inflammatory diseases and cancer

Cited by 102 publications

References 130 publications

d-pinitol mitigates tumor growth by modulating interleukins and hormones and induces apoptosis in rat breast carcinogenesis through inhibition of NF-κB

d-pinitol mitigates tumor growth by modulating interleukins and hormones and induces apoptosis in rat breast carcinogenesis through inhibition of NF-κB

Inflammation-Induced Phenoconversion of Polymorphic Drug Metabolizing Enzymes: Hypothesis with Implications for Personalized Medicine

Expression of interleukin-6 is associated with epithelial-mesenchymal transition and survival rates in gallbladder cancer

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