The potential value of amlexanox in the treatment of cancer: Molecular targets and therapeutic perspectives

Bailly, Christian

doi:10.1016/j.bcp.2021.114895

Cited by 12 publications

(7 citation statements)

References 107 publications

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“…However, no significant damage was observed in our experiments using different cell types. This finding is consistent with the fact that TBK1 inhibitors have been applied to clinical trials in humans as drugs to treat amyotrophic lateral sclerosis, diabetes, and cancer (Bailly, 2022; García‐García et al, 2021; Oakes et al, 2017; Runde et al, 2022). The use of TBK1 inhibitors to enhance transfection efficiency is simple yet effective.…”

Section: Resultssupporting

confidence: 81%

“…This result suggests that BX795 and MRT67307 bind to the same binding site as TBK1, whereas amlexanox binds to a different binding site than BX795 and MRT67307. Alternatively, BX795 and MRT67307 may directly inhibit the activity of TBK1, while amlexanox indirectly inactivates TBK1 by inhibiting another kinase that promotes TBK1 kinase (Bailly, 2022). Notably, cell viability based on the RealTime-Glo™ MT Cell Viability Assay was maintained at approximately 90% even after 30 h of treatment in the presence of transfection reagents and inhibitors.…”

Section: Combination Of Two Tbk1 Inhibitors Synergistically Enhances ...mentioning

confidence: 99%

“…TBK1 is a serine/threonine kinase that regulates a variety of cellular events, including autophagy, innate immunity, inflammatory cytokine production, mitochondrial metabolism, cell proliferation, and cancer formation (Matsumoto et al, 2015;Pilli et al, 2012;Runde et al, 2022;Sarraf et al, 2019). Several small molecules specifically inhibiting TBK1 kinase activity are widely used in basic research and medicine (Bailly, 2022;Clark et al, 2009Clark et al, , 2011Möller et al, 2020;Runde et al, 2022). However, its effects on DNA transfection remain unknown.…”

Section: Introductionmentioning

confidence: 99%

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TBK1 inhibitors enhance transfection efficiency by suppressing p62/SQSTM1 phosphorylation

et al. 2022

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DNA transfection is an essential technique in the life sciences. Non-viral transfection reagents are widely used for transfection in basic science. However, low transfection efficiency is a problem in some cell types. This low efficiency can be primarily attributed to the intracellular degradation of transfected DNA by p62-dependent selective autophagy, specifically by p62 phosphorylated at the S403 residue (p62-S403-P). To achieve efficient DNA transfection, we focused on a phosphorylation process that generates p62-S403-P and investigated whether inhibition of this process affects transfection efficiency. One of the kinases that phosphorylate p62 is TBK1. The TBK1 gene depletion in murine embryonic fibroblast cells by genome editing caused a significant reduction or loss of p62-S405-P (equivalent to human S403-P) and enhanced transfection efficiency, suggesting that TBK1 is a major kinase that phosphorylates p62 at S403. Therefore, TBK1 is a viable target for drug treatment to increase transfection efficiency. Transfection efficiency was enhanced when cells were treated with one of the following TBK1 inhibitors BX795, MRT67307, or amlexanox. This effect was synergistically improved when the two inhibitors were used in combination. Our results indicate that TBK1 inhibitors enhanced transfection efficiency by suppressing p62 phosphorylation.

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Section: Resultssupporting

confidence: 81%

Section: Combination Of Two Tbk1 Inhibitors Synergistically Enhances ...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TBK1 inhibitors enhance transfection efficiency by suppressing p62/SQSTM1 phosphorylation

et al. 2022

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“…Some patients in both trials displayed rashes diagnosed as perivascular inflammation, a pathology similar to the inflammatory skin lesions seen in Tbk1 ∆/∆ mice, suggesting an on-target side effect of TBK1 inhibition [ 187 , 279 ]. While these studies demonstrated that oral AMX is safe, well-tolerated, and effective in ameliorating metabolic abnormalities, the efficacy of AMX as an antineoplastic agent is unknown but warrants clinical investigation [ 247 , 280 ].…”

Section: Introductionmentioning

confidence: 99%

The role of TBK1 in cancer pathogenesis and anticancer immunity

Runde

Mack

et al. 2022

J Exp Clin Cancer Res

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The TANK-binding kinase 1 (TBK1) is a serine/threonine kinase belonging to the non-canonical inhibitor of nuclear factor-κB (IκB) kinase (IKK) family. TBK1 can be activated by pathogen-associated molecular patterns (PAMPs), inflammatory cytokines, and oncogenic kinases, including activated K-RAS/N-RAS mutants. TBK1 primarily mediates IRF3/7 activation and NF-κB signaling to regulate inflammatory cytokine production and the activation of innate immunity. TBK1 is also involved in the regulation of several other cellular activities, including autophagy, mitochondrial metabolism, and cellular proliferation. Although TBK1 mutations have not been reported in human cancers, aberrant TBK1 activation has been implicated in the oncogenesis of several types of cancer, including leukemia and solid tumors with KRAS-activating mutations. As such, TBK1 has been proposed to be a feasible target for pharmacological treatment of these types of cancer. Studies suggest that TBK1 inhibition suppresses cancer development not only by directly suppressing the proliferation and survival of cancer cells but also by activating antitumor T-cell immunity. Several small molecule inhibitors of TBK1 have been identified and interrogated. However, to this point, only momelotinib (MMB)/CYT387 has been evaluated as a cancer therapy in clinical trials, while amlexanox (AMX) has been evaluated clinically for treatment of type II diabetes, nonalcoholic fatty liver disease, and obesity. In this review, we summarize advances in research into TBK1 signaling pathways and regulation, as well as recent studies on TBK1 in cancer pathogenesis. We also discuss the potential molecular mechanisms of targeting TBK1 for cancer treatment. We hope that our effort can help to stimulate the development of novel strategies for targeting TBK1 signaling in future approaches to cancer therapy.

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“…The Amlexanox (azoxanthone drug) was used for curing mouth aphthous ulcers as a 5% topical oral paste and is the one approved clinically by the US FDA for aphthous ulcers treatment. It also exhibits novel applications in pharmacy [33][34][35][36]. L-Cysteine S-sulfate is an organic thiosulfate.…”

Section: Discussionmentioning

confidence: 99%

Biological Characterization of Cleome felina L.f. Extracts for Phytochemical, Antimicrobial, and Hepatoprotective Activities in Wister Albino Rats

Shaikh,

Niazi,

Bepari

et al. 2023

Antibiotics

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The present study aims to explore the phytochemical constitution and biological activities of Cleome felina L.f. (Cleomaceae). C. felina (leaves, stem, and root) extracts (acetone, methanol, and water) were qualitatively assessed for phytochemical presence. Methanolic leaves extract revealed more positive phyto-compounds among all the extracts; further, methanolic leaves extract was evaluated for FTIR, EDX, GCMS, antimicrobial assay, acute toxicity, and paracetamol-induced hepatoprotective activity in Wister albino rats. FTIR and EDX analysis unveiled important functional groups and elements in the leaves. GCMS analysis of methanolic leaves extract exposed 12 active phyto-compounds: major constituents detected were 1-Butanol, 3-methyl-, formate-48.79%; 1-Decanol, 2-ethyl-13.40%; 1,6-Anhydro-β-d-talopyranose-12.49%; Ethene, 1,2-bis(methylthio)-7.22%; Decane-4.02%; 3-Methylene-7, 11-dimethyl-1-dodecene-3.085%; Amlexanox-2.50%; 1,2,3,4-Cyclopentanetetrol, (1α,2β,3β,4α)-2.07%; L-Cysteine S-sulfate-1.84%; n-Hexadecanoic acid-1.70%; and Flucarbazone-1.55%. The antimicrobial assay showed a moderate zone of inhibition against S. aureus, B. cereus, E. coli, P. aeruginosa, C. albicans, and C. glabrata at 100 µL/mL concentration. Additionally, acute toxicity revealed no behavioral sign of the toxic effect. The significant results were obtained for methanolic leaves extract (low-50 and high-100 mg/kg b.wt. dose) for hepatoprotective activity, where it dramatically reduced serum blood biochemical markers (AST, ALT, ALP, Total bilirubin, and cholesterol) and exhibited elevated hepatic antioxidant enzymes (SOD, CAT, and GSH) concentration with lipid peroxidation retardation. To conclude, C. felina methanolic leaves extract ameliorated important phytochemical compounds and showed significant antimicrobial and hepatoprotective efficacy; therefore, utilization of C. felina leaves suggested in pharmacological applications, and in numerous cosmetics, herbicides, and food industries, would be a great scope for future hepatoprotective drug designing.

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The potential value of amlexanox in the treatment of cancer: Molecular targets and therapeutic perspectives

Cited by 12 publications

References 107 publications

TBK1 inhibitors enhance transfection efficiency by suppressing p62/SQSTM1 phosphorylation

TBK1 inhibitors enhance transfection efficiency by suppressing p62/SQSTM1 phosphorylation

The role of TBK1 in cancer pathogenesis and anticancer immunity

Biological Characterization of Cleome felina L.f. Extracts for Phytochemical, Antimicrobial, and Hepatoprotective Activities in Wister Albino Rats

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