Effect of iguratimod and other anti-rheumatic drugs on adenocarcinoma colon 26-induced cachexia in mice

Tanaka, Keiichi; Urata, Noriko; Mikami, Masayoshi; Ogasawara, M.; Matsunaga, Takayuki; Terashima, Nobuo; Suzuki, Hideaki

doi:10.1007/s00011-007-6022-9

Cited by 19 publications

(4 citation statements)

References 18 publications

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“…Anecdotally, the use of α-3 omega fatty acids (eicosapentaenoic acid) [52] and thalidomide (potent anti-TNF activity) have been reported [48]. Experimentally, glucocorticoids, aspirin [63], indomethacin [35,79], methotrexate [60], and celecoxib [23], all have been shown to have some efficacy, which are believed to be effective, in part, due to their ability to inhibit NF-ĸB activity [10,32,73,78]. However, these agents are neither potent nor selective for the NF-ĸB pathway.…”

Section: Discussionmentioning

confidence: 99%

Selective Inhibition of NF-kappa-B with NBD Peptide Reduces Tumor- Induced Wasting in a Murine Model of Cancer Cachexia In vivo

Wysong¹,

Asher

Yin

et al. 2011

JCST

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Cancer cachexia is a severe wasting syndrome characterized by the progressive loss of lean body mass and systemic inflammation, which is seen in as many as 80% of patients with advanced malignancy. It accounts for an estimated 20-30% of all cancer-related deaths. The mechanism by which cancer induces skeletal muscle atrophy in cachexia involves tumor-derived cytokines, including TNFα, IL-1, and IL-6. Upon interaction with their unique receptors on skeletal muscle, these cytokines activate NF-kappaB, a transcription factor crucial for atrophy related sarcomere proteolysis to occur. The significance of NF-κB is highlighted in studies demonstrating that genetic inhibition of NF-κB ameliorates cancer-induced muscle loss in vivo. In the present study, we evaluate a selective NF-kappaB inhibitor (NBD peptide) which targets the IkappaB complex to prevent cancer-induced skeletal muscle atrophy in an established mouse model (C26 adenocarcinoma). We identified for the first time that NBD peptide can directly inhibit tumor-induced NFkappaB activation in skeletal muscle, resulting in a decrease loss of lean muscle. We also identified that NBD peptide reduces the expression of the tumor induced ubiquitin ligases MuRF-1 and MAFbx/Atrogin-1 necessary for atrophy. These findings highlight that NBD peptide may be a potential selective therapeutic agent for the treatment of cancer cachexia.

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Section: Discussionmentioning

confidence: 99%

Selective Inhibition of NF-kappa-B with NBD Peptide Reduces Tumor- Induced Wasting in a Murine Model of Cancer Cachexia In vivo

Wysong¹,

Asher

Yin

et al. 2011

JCST

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“…Also known as iguratimod, T-614 is currently clinically available in Japan and China as a daily oral formulation administered at 25-50 mg daily, which has shown safety and efficacy in improving symptoms and disease progression in rheumatoid arthritis both as a monotherapy (92)(93)(94) and in combination with methotrexate (95). Several preclinical studies have suggested that the drug may also have utility in other settings, such as multiple sclerosis (62) and cachexia in the context of adenocarcinoma (96). MIF is an influential player in a large variety of disease processes, including autoimmune (10,11,97,98), neurologic (99, 100), metabolic (101), and oncologic conditions (102)(103)(104)(105).…”

Section: T-614 In Combination With Glucocorticoids Attenuates Diseamentioning

confidence: 99%

Identification of Iguratimod as an Inhibitor of Macrophage Migration Inhibitory Factor (MIF) with Steroid-sparing Potential

Bloom

Metz

Nalawade

et al. 2016

Journal of Biological Chemistry

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Edited by Dennis VoelkerMacrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been implicated in a broad range of inflammatory and oncologic diseases. MIF is unique among cytokines in terms of its release profile and inflammatory role, notably as an endogenous counter-regulator of the anti-inflammatory effects of glucocorticoids. In addition, it exhibits a catalytic tautomerase activity amenable to the design of high affinity small molecule inhibitors. Although several classes of these compounds have been identified, biologic characterization of these molecules remains a topic of active investigation. In this study, we used in vitro LPS-driven assays to characterize representative molecules from several classes of MIF inhibitors. We determined that MIF inhibitors exhibit distinct profiles of anti-inflammatory activity, especially with regard to TNF␣. We further investigated a molecule with relatively low anti-inflammatory activity, compound T-614 (also known as the anti-rheumatic drug iguratimod), and found that, in addition to exhibiting selective MIF inhibition in vitro and in vivo, iguratimod also has additive effects with glucocorticoids. Furthermore, we found that iguratimod synergizes with glucocorticoids in attenuating experimental autoimmune encephalitis, a model of multiple sclerosis. Our work identifies iguratimod as a valuable new candidate for drug repurposing to MIF-relevant diseases, including multiple sclerosis.

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“…Although most of the members of this family act as cyclooxygenase 2 (COX‐2) inhibitors, T‐614 is considered to be a novel immunomodulator based on more and more evidence. Existing studies showed that T‐614 reduced the production of some cytokines, including interleukin‐1β (IL‐1β), IL‐6, IL‐8, IL‐17, tumor necrosis factor α, and interferon‐γ in vitro (synovial cells and some cell lines) and in vivo (mouse models) (8–14). T‐614 has been shown to display a steroid‐like improvement in several autoimmune animal models such as collagen‐induced arthritis, MRL‐ lpr / lpr mice, and experimental autoimmune encephalomyelitis (9, 15).…”

Section: Introductionmentioning

confidence: 99%

Multicenter, randomized, double‐blind, controlled trial of treatment of active rheumatoid arthritis with T‐614 compared with methotrexate

Bao

Dai

et al. 2009

Arthritis & Rheumatism

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Effect of iguratimod and other anti-rheumatic drugs on adenocarcinoma colon 26-induced cachexia in mice

Abstract: Our results demonstrate that T-614 exerts an anticachectic effect in tumor-bearing mice through the inhibition of IL-6 gene expression.

Cited by 19 publications

References 18 publications

Selective Inhibition of NF-kappa-B with NBD Peptide Reduces Tumor- Induced Wasting in a Murine Model of Cancer Cachexia In vivo

Selective Inhibition of NF-kappa-B with NBD Peptide Reduces Tumor- Induced Wasting in a Murine Model of Cancer Cachexia In vivo

Identification of Iguratimod as an Inhibitor of Macrophage Migration Inhibitory Factor (MIF) with Steroid-sparing Potential

Multicenter, randomized, double‐blind, controlled trial of treatment of active rheumatoid arthritis with T‐614 compared with methotrexate

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