Pharmacological inhibition of the IKKε/TBK-1 axis potentiates the anti-tumour and anti-metastatic effects of Docetaxel in mouse models of breast cancer

Bishop, Ryan T.; Marino, Silvia; Ridder, Daniëlle de; Allen, Richard; Lefley, Diane V.; Sims, Andrew H.; Wang, Ning; Ottewell, Penelope D.; Idris, Aymen I.

doi:10.1016/j.canlet.2019.02.032

Cited by 22 publications

(14 citation statements)

References 43 publications

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“…Breast cancer cells acquire osteotropic characteristic compared to their parental counterpart [55,63] and our previous studies have shown that NFB inhibition at the IKK level reduces the ability of osteotropic breast cancer cells to metastasise to bone and influence bone cell activity [46,88,89]. Our present in vivo, ex vivo and in vitro studies using the osteotropic clones of human MDA-MB-231 and mouse 4T1-Luc2 complement our previous findings and show that 6877002 significantly reduced the ability of these cells to migrate, invade and support osteoclastogenesis in the presence of RANKL.…”

Section: Discussionmentioning

confidence: 99%

Combined administration of a small-molecule inhibitor of TRAF6 and Docetaxel reduces breast cancer skeletal metastasis and osteolysis

Bishop

Marino

Carrasco³

et al. 2020

Cancer Letters

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Section: Discussionmentioning

confidence: 99%

Combined administration of a small-molecule inhibitor of TRAF6 and Docetaxel reduces breast cancer skeletal metastasis and osteolysis

Bishop

Marino

Carrasco³

et al. 2020

Cancer Letters

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“…Hu et al (19) also reported that downregulated expression levels of NLRX1 were associated with liver cancer prognosis. NF-κB is a pivotal mammalian transcription factor that was discovered to exert protumorigenic effects in liver (35), lung (36), breast (37) and prostate (38) cancer, in addition to in GC (39). In normal cells, NF-κB is located in the cytosol in the form of an inactive complex bound to IκBα.…”

Section: Discussionmentioning

confidence: 99%

NOD‑like receptor X1, tumor necrosis factor receptor‑associated factor 6 and NF‑κB are associated with clinicopathological characteristics in gastric cancer

Wang

Ye-wei

2021

Exp Ther Med

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Gastric cancer (GC) is a common cancer worldwide and its precise mechanism is largely unknown. The aim of the present study was to evaluate the expression levels of NOD-like receptor X1 (NLRX1), tumor necrosis factor receptor-associated factor 6 (TRAF6) and NF-κB in GC and normal gastric tissue samples to determine the association with the clinicopathological features of GC. GC and adjacent normal gastric tissues from 60 patients with GC were analyzed using immunohistochemistry and western blotting analysis. In addition, the association between NLRX1, TRAF6 and NF-κB expression levels were investigated by Spearman's correlation analysis. The results revealed that NLRX1 protein expression levels were downregulated in the GC tissues compared with the normal gastric tissues (P<0.05). Conversely, TRAF6 and NF-κB protein expression levels were upregulated in the GC tissues compared with the normal gastric tissues (P<0.05). A significant difference was identified between GC patients with high and low expression levels of each protein in the tumor size, vascular invasion, neural invasion, lymph node metastasis, differentiation, gross stage and clinical stage. In addition, a negative correlation was observed between NLRX1 and TRAF6, and NLRX1 and NF-κB expression levels, while a positive correlation was observed between TRAF6 and NF-κB expression levels. In conclusion, NLRX1 expression levels were discovered to be downregulated in GC tissues. The expression levels of NLRX1, TRAF6 and NF-κB were also significantly associated with the clinicopathological characteristics of GC, and the aforementioned results indicated that NLRX1 may be a biomarker in assessing GC.

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“…The oral administration of the drug revealed a significantly reduced tumor growth in comparison to the vehicle-treated mice, which confirms our results from the cell culture. Amlexanox has already shown anti-cancer activity in different tumor types-e.g., breast cancer [52,53], prostate cancer [54] and glioblastoma [55]-And is now also identified as a promising therapeutic option in melanoma. Since amlexanox constitutes an approved drug with already confirmed pharmacological safety and only minor side effects, it might be promising to consider its re-purposing for the treatment of melanoma.…”

Section: Discussionmentioning

confidence: 99%

The Specific IKKε/TBK1 Inhibitor Amlexanox Suppresses Human Melanoma by the Inhibition of Autophagy, NF-κB and MAP Kinase Pathways

Möller

Wasel

Schmetzer

et al. 2020

IJMS

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Inhibitor-kappaB kinase epsilon (IKKε) and TANK-binding kinase 1 (TBK1) are non-canonical IκB kinases, both described as contributors to tumor growth and metastasis in different cancer types. Several hints indicate that they are also involved in the pathogenesis of melanoma; however, the impact of their inhibition as a potential therapeutic measure in this “difficult-to-treat” cancer type has not been investigated so far. We assessed IKKε and TBK1 expression in human malignant melanoma cells, primary tumors and the metastasis of melanoma patients. Both kinases were expressed in the primary tumor and in metastasis and showed a significant overexpression in tumor cells in comparison to melanocytes. The pharmacological inhibition of IKKε/TBK1 by the approved drug amlexanox reduced cell proliferation, migration and invasion. Amlexanox did not affect the cell cycle progression nor apoptosis induction but significantly suppressed autophagy in melanoma cells. The analysis of potential functional downstream targets revealed that NF-кB and ERK pathways might be involved in kinase-mediated effects. In an in vivo xenograft model in nude mice, amlexanox treatment significantly reduced tumor growth. In conclusion, amlexanox was able to suppress tumor progression potentially by the inhibition of autophagy as well as NF-кB and MAP kinase pathways and might therefore constitute a promising candidate for melanoma therapy.

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Pharmacological inhibition of the IKKε/TBK-1 axis potentiates the anti-tumour and anti-metastatic effects of Docetaxel in mouse models of breast cancer

Cited by 22 publications

References 43 publications

Combined administration of a small-molecule inhibitor of TRAF6 and Docetaxel reduces breast cancer skeletal metastasis and osteolysis

Combined administration of a small-molecule inhibitor of TRAF6 and Docetaxel reduces breast cancer skeletal metastasis and osteolysis

NOD‑like receptor X1, tumor necrosis factor receptor‑associated factor 6 and NF‑κB are associated with clinicopathological characteristics in gastric cancer

The Specific IKKε/TBK1 Inhibitor Amlexanox Suppresses Human Melanoma by the Inhibition of Autophagy, NF-κB and MAP Kinase Pathways

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