Trimebutine attenuates high mobility group box 1–receptor for advanced glycation end-products inflammatory signaling pathways

Nakajima, Shingo; Ogawa, Naomi; Yokoue, Natsuki; Tachibana, Haruki; Tamada, Kenya; Okazawa, Miwa; Sato, Akira; Oyama, Takahiro; Abe, Hideaki; Kamiya, Tomoyasu; Yoshimori, Atsushi; Yoshizawa, Kazumi; Inoue, Shigeaki; Yokomizo, Takehiko; Uchiumi, Fumiaki; Abe, Takehiko; Tanuma, Sei Ichi

doi:10.1016/j.bbrc.2020.09.126

Cited by 11 publications

(16 citation statements)

References 27 publications

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“…In this study, we identified compound 3 as a dual anti-cancer and anti-inflammatory molecule from 6M3SC derivatives. Although small molecular candidates for the suppression of the RAGE-mediated signaling pathway have been reported, none have been approved for clinical use to date [27,28,63]. The use of these candidates in clinical applications for cancer chemotherapy requires knowledge of the mechanism of action in signaling pathways and the gene regulation of both inflammation and carcinogenesis (Figure 7).…”

Section: Discussionmentioning

confidence: 99%

“…ELISA Assay for IL-6 RAW264.7 cells (6 × 10 4 cells/dish) were seeded in a 96-well plate and incubated for 22 h. After changing the medium to Opti-MEM ® , the RAW264.7 cells were pretreated with various concentrations of compounds for 2 h and stimulated with HMGB1. After 18 h of incubation, the concentrations of IL-6 in the culture supernatants were quantified using Mouse IL-6 Uncoated ELISA Kit, in accordance with the manufacturer's instructions [27,28].…”

Section: Cells and Cell Culturementioning

confidence: 99%

“…After the incubation, the absorbance of the samples was detected at 450 nm using a Synergy™ HTX Multi-Mode Microplate Reader (BioTek Instruments, Inc.; Winooski, VT, USA). Cell viability was expressed as a percentage of the control cells treated with the vehicle alone RAW264.7 cells [27,28]. The same assay system was used to assess the viability of human glioblastoma T98G cells [29].…”

Section: Assay For Cell Viabilitymentioning

confidence: 99%

“…Recently, it was discovered that papaverine (a non-narcotic, opium alkaloid medicine) and trimebutine (a spasmolytic drug) suppress the HMGB1-RAGE inflammatory signaling pathway and thereby attenuate sepsis [27,28]. Furthermore, it was demonstrated that papaverine can cancel the HMGB1-elicited proliferation of human glioblastoma cell lines, both temozolomide (TMZ)-sensitive U87MG and TMZ-resistant T98G cells [29].…”

Section: Introductionmentioning

confidence: 99%

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A Unique Anti-Cancer 3-Styrylchromone Suppresses Inflammatory Response via HMGB1-RAGE Signaling

et al. 2021

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High mobility group box 1 (HMGB1)-receptor for advanced glycation endo-products (RAGE) axis serves as a key player in linking inflammation and carcinogenesis. Recently, papaverine was revealed to suppress the HMGB1-RAGE inflammatory signaling pathway and cancer cell proliferation. Therefore, a dual suppressor targeting this axis is expected to become a new type of therapeutic agent to treat cancer. Methods: Papaverine 3D pharmacophore mimetic compounds were selected by the LigandScout software from our in-house, anti-cancer chemical library and assessed for their anti-inflammatory activities by a HMGB1-RAGE-mediated interleukin-6 production assay using macrophage-like RAW264.7 cells. Molecular-biological analyses, such as Western blotting, were performed to clarify the mechanism of action. Results: A unique 6-methoxy-3-hydroxy-styrylchromone was found to possess potent anti-inflammatory and anti-cancer activities via the suppression of the HMGB1-RAGE-extracellular signal-regulated kinase 1/2 signaling pathway. Furthermore, the 3D pharmacophore-activity relationship analyses revealed that the hydroxyl group at the C4′ position of the benzene ring in a 3-styryl moiety was significant in its dual suppressive effects. Conclusions: These findings indicated that this compound may provide a valuable scaffold for the development of a new type of anti-cancer drug possessing anti-inflammatory activity and as a tool for understanding the link between inflammation and carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Cells and Cell Culturementioning

confidence: 99%

Section: Assay For Cell Viabilitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Unique Anti-Cancer 3-Styrylchromone Suppresses Inflammatory Response via HMGB1-RAGE Signaling

et al. 2021

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“…Finally, pentoxifylline and thalidomide, inhibitors of tumor necrosis factor (TNF)-α synthesis, enhanced the anti-tumor action of anti-cancer drugs [ 52 , 53 ]. Additionally, papaverine, which is an opium alkaloid antispasmodic drug used primarily for treating visceral spasm and vasospasm [ 54 ], had both anti-inflammatory and anti-cancer activities via inhibition of RAGE function [ 54 , 55 , 56 , 57 ]. Indeed, papaverine suppressed the HMGB1-RAGE inflammatory signaling pathway and thereby attenuated mortality in a cecal ligation and puncture-induced sepsis mouse model [ 54 ].…”

Section: Introductionmentioning

confidence: 99%

A Dual Anti-Inflammatory and Anti-Proliferative 3-Styrylchromone Derivative Synergistically Enhances the Anti-Cancer Effects of DNA-Damaging Agents on Colon Cancer Cells by Targeting HMGB1-RAGE-ERK1/2 Signaling

Tanuma

Oyama

Okazawa

et al. 2022

IJMS

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The current anti-cancer treatments are not enough to eradicate tumors, and therefore, new modalities and strategies are still needed. Most tumors generate an inflammatory tumor microenvironment (TME) and maintain the niche for their development. Because of the critical role of inflammation via high-mobility group box 1 (HMGB1)–receptor for advanced glycation end-products (RAGE) signaling pathway in the TME, a novel compound possessing both anti-cancer and anti-inflammatory activities by suppressing the HMGB1-RAGE axis provides an effective strategy for cancer treatment. A recent work of our group found that some anti-cancer 3-styrylchromones have weak anti-inflammatory activities via the suppression of this axis. In this direction, we searched such anti-cancer molecules possessing potent anti-inflammatory activities and discovered 7-methoxy-3-hydroxy-styrylchromone (C6) having dual suppressive activities. Mechanism-of-action studies revealed that C6 inhibited the increased phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) under the stimulation of HMGB1-RAGE signaling and thereby suppressed cytokine production in macrophage-like RAW264.7 cells. On the other hand, in colorectal cancer HCT116 cells, C6 inhibited the activation of ERK1/2, cyclin-dependent kinase 1, and AKT, down-regulated the protein level of XIAP, and up-regulated pro-apoptotic Bax and caspase-3/7 expression. These alterations are suggested to be involved in the C6-induced suppression of cell cycle/proliferation and initiation of apoptosis in the cancer cells. More importantly, in cancer cells, the treatment of C6 potentiates the anti-cancer effects of DNA-damaging agents. Thus, C6 may be a promising lead for the generation of a novel class of cancer therapeutics.

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Simultaneous Determination of Ruscogenin, Neoruscogenin, Trimebutin, and Parabens in Cream Formulation by Reverse Phase High Performance Liquid Chromatography

Özen,

Nemutlu

2023

Chromatographia

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A simple and rapid reverse phase high performance liquid chromatography (RP-HPLC) method for analysis of ruscogenin (RUS), neoruscogenin (NRUS), trimebutine (TB), methylparaben (MP) propylparaben (PP) in pharmaceutical preparations has been developed and validated. In this study, a RP-HPLC method was developed for the determination of RUS, NRUS, TB, MP and PP and applied for analysis of pharmaceutical cream formulations. ACE C18 Column 121-2546 (250x4.6 mm) was used at 25 °C and gradient elution was performed with mobile phase consisting of a mixture of ACN:Buffer (pH:3.9). RUS, NRUS, TB, MP and PP eluted within 17 minutes. Peak homogeneity data of RUS, NRUS, TB, MP and PP in the pharmaceutical cream samples peaks obtained using photodiode array detector, in the cream sample chromatograms, demonstrated the speci city of the method. The developed method was validated according to the ICH guidelines. Linear ranges were 1.00, 5.00, 10.0, 25.0, 50.0, 100, 150 μg/mL for MP, RUS and 5.00 -10.0, 25.0, 50.0, 100, 150, 200 μg/mL for NRUS, PP and 10.0-25.0, 50.0, 100, 150, 200 μg/mL for TB. Validation parameters, such as stability, linearity, sensitivity, accuracy, precision, recovery, robustness and ruggedness were evaluated according to ICH guidelines and the method was simple, rapid, selective, sensitive, accurate, precise, robust and rugged. We developed a fast, low-cost RP-HPLC method with time of 17 minutes for simultaneous analysis of RUS, NRUS, TB and preservatives (MP and PP) in pharmaceutical preparations with semi-solid dosage form. The developed method was successfully applied for the quanti cation of RUS, NRUS, TB and preservatives (MP and PP) in pharmaceutical preparations with semi-solid dosage form. The detection limit of the method was 0.07, 0.28, 0.07, 0.45, 0.02 µg mL -1 respectively for MP, TB, PP, NRUS and RUS. HighlightsThis study is the rst method for the simultaneous analysis of ruscogenin, neoruscogenin, trimebutine, propylparaben, and methylparaben.The developed RP-HPLC method is a reliable and stability-indicating for active pharmaceutical ingredients and preservatives.Validation studies were performed according to ICH guide.The developed method is simple, selective, and sensitive.

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Trimebutine attenuates high mobility group box 1–receptor for advanced glycation end-products inflammatory signaling pathways

Cited by 11 publications

References 27 publications

A Unique Anti-Cancer 3-Styrylchromone Suppresses Inflammatory Response via HMGB1-RAGE Signaling

A Unique Anti-Cancer 3-Styrylchromone Suppresses Inflammatory Response via HMGB1-RAGE Signaling

A Dual Anti-Inflammatory and Anti-Proliferative 3-Styrylchromone Derivative Synergistically Enhances the Anti-Cancer Effects of DNA-Damaging Agents on Colon Cancer Cells by Targeting HMGB1-RAGE-ERK1/2 Signaling

Simultaneous Determination of Ruscogenin, Neoruscogenin, Trimebutin, and Parabens in Cream Formulation by Reverse Phase High Performance Liquid Chromatography

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