Characterization of the enhanced apoptotic response to azidothymidine by pharmacological inhibition of NF-kB

Matteucci, Claudia; Minutolo, Antonella; Marino-Merlo, Francesca; Grelli, Sandro; Frezza, Caterina; Mastino, Antonio; Macchi, Beatrice

doi:10.1016/j.lfs.2015.01.038

Cited by 16 publications

(17 citation statements)

References 39 publications

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“…There is also extensive evidence showing that NF-κB activation suppresses apoptosis, most likely because NF-κB promotes the synthesis of proteins that can protect cells from apoptosis [56][57][58][59]. Our findings suggest that the tendency of p38 MAPK and JNK to promote apoptosis could be at least partly due to the inhibition of NF-κB activation by p38 and JNK.…”

Section: Melatonin Enhances the Effectiveness Of Cisplatin By Suppresmentioning

confidence: 51%

Melatonin Induces Cell Apoptosis in AGS Cells Through the Activation of JNK and P38 MAPK and the Suppression of Nuclear Factor-Kappa B: a Novel Therapeutic Implication for Gastric Cancer

Liu

Fan

Chen

et al. 2015

Cell Physiol Biochem

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Background/Aims: Melatonin, synthesized by the pineal gland and released into the blood, appears to have antitumour properties; however, the mechanisms of its anti-cancer effects are largely unknown, especially in stomach cancer. Here, we explore the antitumour activity of melatonin in a gastric cancer cell line (AGS) and analyse its molecular mechanisms. Methods: AGS cells were treated with melatonin, and cell viability was assessed using a CCK-8 assay. Flow cytometry was performed to evaluate apoptosis, and protein expression was examined by Western blotting. Results: Melatonin significantly inhibited cell viability, clone formation, and cell migration and invasion and induced apoptosis in AGS cells. Moreover, MAPK pathways (p38, JNK and ERK) were activated by melatonin treatment, which also significantly increased caspase-3 cleavage and Bax protein expression and decreased Bcl-2 protein expression in a time-dependent manner. Our results demonstrate that p38 and JNK inhibitors (SB203580 and SP600125, respectively) prevented melatonin-induced apoptosis; thus, the propensity of p38 MAPK and JNK to promote apoptosis could be at least partly due to the inhibition of NF-κB p65 activation by p38 and JNK. Finally, melatonin was able to strengthen cisplatin-mediated antitumour effects in human gastric carcinoma cells by up-regulating the expression of Bax, down-regulating the expression of Bcl-2 and activating the caspase-dependent apoptotic pathway. Conclusion: Melatonin induced apoptosis in AGS cells by activating the caspase-dependent apoptotic pathway and by inhibiting the nuclear translocation of NF-κB p65, two processes that are regulated by p38 and JNK. Furthermore, melatonin significantly enhanced the anti-tumour effects of cisplatin, with low systemic toxicity. These new findings suggest that melatonin may act as a potent anti-tumour agent and may have great potential as an adjuvant therapy in the future.

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Section: Melatonin Enhances the Effectiveness Of Cisplatin By Suppresmentioning

confidence: 51%

Melatonin Induces Cell Apoptosis in AGS Cells Through the Activation of JNK and P38 MAPK and the Suppression of Nuclear Factor-Kappa B: a Novel Therapeutic Implication for Gastric Cancer

Liu

Fan

Chen

et al. 2015

Cell Physiol Biochem

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“…Considering that NF-κB was able to directly bind to the CXCL10 promoter and initiate CXCL10 expression, it was thus examined whether NF-κB was involved in COMMD7-induced CXCL10 expression. To this end, two different NF-κB inhibitors, celastrol and Bay 11-7085, were used (7,8). In line with previous data, the overexpression of COMMD7 induced a significant upregulation of CXCL10 expression in Huh7 cells.…”

Section: Disruption Of the Cxcl10 /Cxcr3 A Xis Reduces Commd7-mediatementioning

confidence: 64%

COMMD7 activates CXCL10 production by regulating NF-κB and the production of reactive oxygen species

You

Huang

et al. 2018

Mol Med Report

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While >80% of the incidence occurs in sub‑Saharan Africa and East Asia, cases of hepatocellular carcinoma (HCC) have been rapidly increasing in Western countries. Despite its global importance, HCC is relatively under‑researched compared with other lethal cancer types, which is possibly due to the high complexity and heterogeneity of HCC. It has been reported previously that COMM domain‑containing protein 7 (COMMD7) is upregulated in HCC and promotes HCC cell proliferation by triggering C‑X‑C motif chemokine 10 (CXCL10) production. However, the value of targeting CXCL10 signal transduction in treating COMMD7‑positive tumors, or the molecular mechanisms underlying COMMD7‑mediated CXCL10 expression, has not been completely addressed. In the present study, it was demonstrated that disruption of the CXCL10/C‑X‑C chemokine receptor type 3 axis reduces COMMD7‑mediated HCC cell proliferation. Furthermore, COMMD7 modulates CXCL10 production by activating nuclear factor (NF)‑κB. Additionally, it was demonstrated that intracellular reactive oxygen species (ROS) are required for NF‑κB activation and CXCL10 production. In conclusion, COMMD7 activates CXCL10 production by regulating NF‑κB and the production of ROS. The present study highlighted the role of COMMD7 in the development of HCC, and provides novel options for anticancer drug design.

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“…We have previously demonstrated that knocking out of IκB rendered U937 cells prone to undergo apoptosis when treated with AZT 31 , and that a combination treatment with AZT plus a pharmacological inhibitor of NF-κB induced, in the same cells, apoptotic RCD associated with the suppression of anti-apoptotic genes expression and the upregulation of the mitochondrial apoptotic pathway 32 . Thus, the main achievement of this study was the demonstration that the pharmacological inhibition of NF-κB activation could prompt also HTLV-1 infected/transformed cells towards RCD when treated with a non-toxic dose of AZT.…”

Section: Discussionmentioning

confidence: 99%

“…We have observed that, in addition to its RT inhibitory activity, AZT has the capability to activate conflicting apoptosis-related signals. However, only when AZT was combined with pharmacological inhibition of IκBα phosphorylation, cells were actually pushed towards apoptosis [30][31][32] . The aim of the present study was to investigate whether the pharmacological inhibition of IκBα phosphorylation could potentiate a possible pro-apoptotic effect exerted by AZT towards HTLV-1 infected cells.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of IκBα phosphorylation potentiates regulated cell death induced by azidothymidine in HTLV-1 infected cells

et al. 2020

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Adult T cell leukemia/lymphoma (ATL) can be susceptible, at least transiently, to treatments with azidothymidine (AZT) plus IFNα and/or arsenic trioxide. However, the real role of AZT in this effect is still unclear. In fact, while reverse transcriptase (RT) inhibition could explain reduction of clonal expansion and of renewal of HTLV-1 infected cells during ATL progression, this effect alone seems insufficient to justify the evident and prompt decrease of the pro-viral load in treated patients. We have previously demonstrated that AZT is endowed with an intrinsic pro-apoptotic potential towards both peripheral blood mononuclear cells from healthy donors or some tumor cell lines, but this cytotoxic potential cannot be fully achieved unless IκBα phosphorylation is inhibited. Since the constitutive activation of NFkappa B (NF-κB) appears a common biological basis of HTLV-1-infected cells, a pharmacological inhibition of IκBα phosphorylation seems a potential strategy for treating and preventing HTLV-1 related pathologies. In this study, we have demonstrated that a combination treatment with the IκBα phosphorylation inhibitor Bay 11-7085 and AZT induced increased levels of regulated cell death (RCD) by apoptosis compared to the single treatments in HTLV-1 infected cells of different origin. Importantly, levels of RCD were considerably higher in infected cells in comparison with the uninfected ones. Inhibition of NF-κB activation following the combined treatment was confirmed by analysis of both gel-shift and functional activity of the NF-κB complex proteins, p65/p52. Moreover, a transcriptional analysis revealed that the addition of Bay 11-7085 to AZT treatment in HTLV-1-infected cells modified their transcriptional profile, by inducing the upregulation of some pro-apoptotic genes together with the downregulation of some antiapoptotic genes. Our data suggest that addition of adequate concentrations of IκBα phosphorylation inhibitor to therapeutic regimens including AZT could be a promising strategy in ATL.

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Characterization of the enhanced apoptotic response to azidothymidine by pharmacological inhibition of NF-kB

Cited by 16 publications

References 39 publications

Melatonin Induces Cell Apoptosis in AGS Cells Through the Activation of JNK and P38 MAPK and the Suppression of Nuclear Factor-Kappa B: a Novel Therapeutic Implication for Gastric Cancer

Melatonin Induces Cell Apoptosis in AGS Cells Through the Activation of JNK and P38 MAPK and the Suppression of Nuclear Factor-Kappa B: a Novel Therapeutic Implication for Gastric Cancer

COMMD7 activates CXCL10 production by regulating NF-κB and the production of reactive oxygen species

Inhibition of IκBα phosphorylation potentiates regulated cell death induced by azidothymidine in HTLV-1 infected cells

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