The Role of JNK Signalling in Responses to Oxidative DNA Damage

Shaukat, Zeeshan; Liu, Dawei; Hussain, Rashid; Khan, Mubbsher Munawar; Gregory, Stephen L.

doi:10.2174/1389450116666150126111055

Cited by 26 publications

(22 citation statements)

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“…It is noteworthy that these pro-survival signaling pathways (e.g., NF- κ B and Nrf2), as well as the stress-related ROS-JNK pathway, are determinants for tumor cell survival versus death in a variety of cancers. 39, 40, 41, 42, 43, 44, 45 Thus, inactivation of NF-κB and Nrf2 signals and/or activation of the ROS-JNK signaling cascade might represent common mechanisms of action underlying the antitumor activity of DS/Cu in diverse cancers, including hematologic malignancies (e.g., myeloid and lymphoid leukemias) as we observed earlier. 19, 46 …”

Section: Discussionsupporting

confidence: 52%

Disulfiram/copper selectively eradicates AML leukemia stem cells in vitro and in vivo by simultaneous induction of ROS-JNK and inhibition of NF-κB and Nrf2

Wang

et al. 2017

Cell Death Dis

117

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Acute myeloid leukemia (AML) is a heterogeneous malignancy. Despite the advances in past decades, the clinical outcomes of AML patients remain poor. Leukemia stem cells (LSCs) is the major cause of the recurrence of AML even after aggressive treatment making, promoting development of LSC-targeted agents is an urgent clinical need. Although the antitumor activity of disulfiram (DS), an approved anti-alcoholism drug, has been demonstrated in multiple types of tumors including hematological malignancies such as AML, it remains unknown whether this agent would also be able to target cancer stem cells like LSCs. Here, we report the in vitro and in vivo activity of DS in combination with copper (Cu) against CD34+/CD38+ leukemia stem-like cells sorted from KG1α and Kasumi-1 AML cell lines, as well as primary CD34+ AML samples. DS plus Cu (DS/Cu) displayed marked inhibition of proliferation, induction of apoptosis, and suppression of colony formation in cultured AML cells while sparing the normal counterparts. DS/Cu also significantly inhibited the growth of human CD34+/CD38+ leukemic cell-derived xenografts in NOD/SCID mice. Mechanistically, DS/Cu-induced cytotoxicity was closely associated with activation of the stress-related ROS-JNK pathway as well as simultaneous inactivation of the pro-survival Nrf2 and nuclear factor-κB pathways. In summary, our findings indicate that DS/Cu selectively targets leukemia stem-like cells both in vitro and in vivo, thus suggesting a promising LSC-targeted activity of this repurposed agent for treatment of relapsed and refractory AML.

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Section: Discussionsupporting

confidence: 52%

Disulfiram/copper selectively eradicates AML leukemia stem cells in vitro and in vivo by simultaneous induction of ROS-JNK and inhibition of NF-κB and Nrf2

Wang

et al. 2017

Cell Death Dis

117

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“…The oxidative damage to DNA is particularly significant (Shaukat et al, 2015). The formation of the major oxidative DNA damage product 8-hydroxydeoxyguanosine (8-OH-dG) is often used as an indicator of oxidative DNA damage (Ihsan et al, 2011).…”

Section: Damage To Dnamentioning

confidence: 99%

The critical role of oxidative stress in the toxicity and metabolism of quinoxaline 1,4-di-N-oxides in vitro and in vivo

Wang

Martínez

Cheng

et al. 2016

Drug Metabolism Reviews

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Quinoxaline 1,4-dioxide derivatives (QdNOs) have been widely used as growth promoters and antibacterial agents. Carbadox (CBX), olaquindox (OLA), quinocetone (QCT), cyadox (CYA) and mequindox (MEQ) are the classical members of QdNOs. Some members of QdNOs are known to cause a variety of toxic effects. To date, however, almost no review has addressed the toxicity and metabolism of QdNOs in relation to oxidative stress. This review focused on the research progress associated with oxidative stress as a plausible mechanism for QdNO-induced toxicity and metabolism. The present review documented that the studies were performed over the past 10 years to interpret the generation of reactive oxygen species (ROS) and oxidative stress as the results of QdNO treatment and have correlated them with various types of QdNO toxicity, suggesting that oxidative stress plays critical roles in their toxicities. The major metabolic pathways of QdNOs are N→O group reduction and hydroxylation. Xanthine oxidoreductase (XOR), aldehyde oxidase (SsAOX1), carbonyl reductase (CBR1) and cytochrome P450 (CYP) enzymes were involved in the QdNOs metabolism. Further understanding the role of oxidative stress in QdNOs-induced toxicity will throw new light onto the use of antioxidants and scavengers of ROS as well as onto the blind spots of metabolism and the metabolizing enzymes of QdNOs. The present review might contribute to revealing the QdNOs toxicity, protecting against oxidative damage and helping to improve the rational use of concurrent drugs, while developing novel QdNO compounds with more efficient potentials and less toxic effects.

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“…Although current studies consistently indicate that JNK1 is a promising drug target for the treatment of obesity-driven insulin resistance, the long-term efficacy of JNK1 ablation for the treatment of obesity-related diseases is unknown, and there are safety concerns. Obesity and diabetes are conditions associated with oxidative stress (18,19), and JNK1 is a central mediator of the physiologic response to oxidative stress, with outcomes ranging from increased survival to cell death, depending on intensity, length, and context of its activation (20)(21)(22). JNK was shown to promote tolerance to oxidative stress and increase life span in Drosophila and in Caenorhabditis elegans, by a mechanism involving increased Forkhead box O (FoxO)-dependent antioxidant defense (23)(24)(25)(26).…”

mentioning

confidence: 99%

“…JNK was shown to promote tolerance to oxidative stress and increase life span in Drosophila and in Caenorhabditis elegans, by a mechanism involving increased Forkhead box O (FoxO)-dependent antioxidant defense (23)(24)(25)(26). JNK is a major signal transducer mediating FoxO activation in response to oxidative stress (20,27), and controls the expression of the antioxidant proteins sestrin-2 (Sesn2) and heme oxygenase (HO)-1 via the transcription factor AP-1 (28)(29)(30)(31). Mouse embryonic fibroblasts lacking JNK1 and -2 display increased sensitivity to hydrogen peroxide, indicating that JNK activity sustains oxidative stress tolerance in vertebrate cells (32).…”

mentioning

confidence: 99%

“…Mouse embryonic fibroblasts lacking JNK1 and -2 display increased sensitivity to hydrogen peroxide, indicating that JNK activity sustains oxidative stress tolerance in vertebrate cells (32). Finally, the well-documented action of sustained JNK activation in promoting apoptosis in response to oxidative stress may also play an important role in tissue homeostasis by eliminating irreversibly damaged cells, hence preventing the excessive inflammation that would result from a necrotic cell (20)(21)(22). However, the physiologic and pathophysiological relevance of JNK1-induced oxidative stress tolerance in vertebrates, in particular in mouse models of obesity and insulin resistance, is unknown.…”

mentioning

confidence: 99%

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JNK1 ablation in mice confers long‐term metabolic protection from diet‐induced obesity at the cost of moderate skin oxidative damage

et al. 2016

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Obesity and insulin resistance are associated with oxidative stress, which may be implicated in the progression of obesity-related diseases. The kinase JNK1 has emerged as a promising drug target for the treatment of obesity and type 2 diabetes. JNK1 is also a key mediator of the oxidative stress response, which can promote cell death or survival, depending on the magnitude and context of its activation. In this article, we describe a study in which the long-term effects of JNK1 inactivation on glucose homeostasis and oxidative stress in obese mice were investigated for the first time. Mice lacking JNK1 (JNK1(-/-)) were fed an obesogenic high-fat diet (HFD) for a long period. JNK1(-/-) mice fed an HFD for the long term had reduced expression of antioxidant genes in their skin, more skin oxidative damage, and increased epidermal thickness and inflammation compared with the effects in control wild-type mice. However, we also observed that the protection from obesity, adipose tissue inflammation, steatosis, and insulin resistance, conferred by JNK1 ablation, was sustained over a long period and was paralleled by decreased oxidative damage in fat and liver. We conclude that compounds targeting JNK1 activity in brain and adipose tissue, which do not accumulate in the skin, may be safer and most effective.-Becattini, B., Zani, F., Breasson, L., Sardi, C., D'Agostino, V. G., Choo, M.-K., Provenzani, A., Park, J. M., Solinas, G. JNK1 ablation in mice confers long-term metabolic protection from diet-induced obesity at the cost of moderate skin oxidative damage.

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The Role of JNK Signalling in Responses to Oxidative DNA Damage

Cited by 26 publications

References 0 publications

Disulfiram/copper selectively eradicates AML leukemia stem cells in vitro and in vivo by simultaneous induction of ROS-JNK and inhibition of NF-κB and Nrf2

Disulfiram/copper selectively eradicates AML leukemia stem cells in vitro and in vivo by simultaneous induction of ROS-JNK and inhibition of NF-κB and Nrf2

The critical role of oxidative stress in the toxicity and metabolism of quinoxaline 1,4-di-N-oxides in vitro and in vivo

JNK1 ablation in mice confers long‐term metabolic protection from diet‐induced obesity at the cost of moderate skin oxidative damage

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