Crucial role of reactive oxygen species (ROS) for the proapoptotic effects of indirubin derivative DKP‐073 in melanoma cells

Zhivkova, Veselina; Kiecker, Felix; Langer, Peter; Eberle, Jürgen

doi:10.1002/mc.22924

Cited by 14 publications

(26 citation statements)

References 51 publications

(115 reference statements)

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“…Thus, antioxidants prevented Thr-167 phosphorylation and partially rescued melanoma cells from wortmannin/TRAIL-induced apoptosis [59]. The significance of ROS for apoptosis regulation in melanoma cells was reported [100,101,102], and ROS was also involved in sensitization of melanoma cells for TRAIL by cell cycle inhibition [84]. Together, these data suggest that an early Bax activation is the critical step in sensitization of melanoma cells for TRAIL, which then allows release of Smac.…”

Section: Critical Contribution Of Mitochondrial Pathways and Bcl-2mentioning

confidence: 99%

Countering TRAIL Resistance in Melanoma

Eberle

2019

Cancers

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Melanoma of the skin has become a prime example for demonstrating the success of targeted cancer therapy. Nevertheless, high mortality has remained, mainly related to tumor heterogeneity and inducible therapy resistance. But the development of new therapeutic strategies and combinations has raised hope of finally defeating this deadly disease. TNF-related apoptosis-inducing ligand (TRAIL) represents a promising antitumor strategy. The principal sensitivity of melanoma cells for TRAIL was demonstrated in previous studies; however, inducible resistance appeared as a major problem. To address this issue, combination strategies were tested, and survival pathway inhibitors were shown to sensitize melanoma cells for TRAIL-induced apoptosis. Finally, cell cycle inhibition was identified as a common principle of TRAIL sensitization in melanoma cells. Mitochondrial apoptosis pathways, pro- and antiapoptotic Bcl-2 proteins as well as the rheostat consisted of Smac (Second mitochondria-derived activator of caspase) and XIAP (X-linked inhibitor of apoptosis protein) appeared to be of particular importance. Furthermore, the role of reactive oxygen species (ROS) was recognized in this setting. Inducible TRAIL resistance in melanoma can be explained by (i) high levels of antiapoptotic Bcl-2 proteins, (ii) high levels of XIAP, and (iii) suppressed Bax activity. These hurdles have to be overcome to enable the use of TRAIL in melanoma therapy. Several strategies appear as particularly promising, including new TRAIL receptor agonists, Smac and BH3 mimetics, as well as selective kinase inhibitors.

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Section: Critical Contribution Of Mitochondrial Pathways and Bcl-2mentioning

confidence: 99%

Countering TRAIL Resistance in Melanoma

Eberle

2019

Cancers

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“…Recent studies showed that indirubin derivatives DKP-071 and DKP-073 can activate the apoptotic pathway in cutaneous T-cell lymphoma and melanoma cells by inducing the production of reactive oxygen species (ROS) (Soltan et al, 2019;Zhivkova et al, 2019). Oxidative stress and elevation of ROS induced by chemicals have pleiotropic deleterious effects including developmental toxicity.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Developmental Toxicity Induced by E804 in Zebrafish Embryos

et al. 2020

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E804, a derivative of indirubin, have multi-biological activities such as anticancer and antiinflammatory activities, but little is known about its developmental toxicity. In this study, we investigated the toxicity of E804 on the developments of zebrafish embryos. Our results showed that E804 treatment caused a significant increase of the malformation rate compared with the control groups. Pericardial edema and curved body shape were the most morphological abnormalities observed in E804-treated group. The hatching rates and body length of the zebrafish larvae was significantly decreased in E804-treated groups. E804 also affect the development of heart, liver, phagocytes and vascular formation. Further studies showed that the level of reactive oxygen species was significantly increased. The activity of total superoxide dismutase decreased and the concentration of malondialdehyde were increased. Much more apoptotic cells were detected in E804-treated group, compared with the control. In addition, geneexpression results showed that the pathways of oxidative stress and apoptosis were provoked in E804 treated groups. Taken together, our findings will be helpful to understanding E804-induced developmental toxicity and the underlying mechanism.

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“…As concerning the pathways, by which indirubins may exert their effects, multiple targets have been suggested including CDKs, GSK-3β, pRb, c-Src, FGF-R1, VEGFR, STAT3, c-Jun and JNK2 [23,24,25,26]. In melanoma cells, we have previously shown that indurubin derivatives enhance extrinsic apoptosis pathways as induced by TRAIL (TNF-related apoptosis-inducing ligand [27,28]. Extrinsic apoptosis pathways via caspase-8/caspase-3 are of particular importance for apoptosis regulation in CTCL cells [10,34].…”

Section: Discussionmentioning

confidence: 99%

“…Reactive oxygen species (ROS) play important roles in tissue damage and aging, and antioxidative strategies were established to prevent these negative effects. Besides this, ROS may also be involved in proapoptotic signaling in cancer cells [16,28,35,36]. As an example from the clinic, photodynamic therapy (PDT), used for the treatment of actinic keratosis, results in the production of high amounts of singlet oxygen.…”

Section: Discussionmentioning

confidence: 99%

“…Explaining the mode of action, a large number of intracellular targets have been described for indirubin derivatives, including cyclin-dependent kinases (CDK1, CDK2, CDK4 and CDK5), pRb, glycogen synthase kinase 3 (GSK-3), STAT3 (Signal transducer and activator of transcription), EGFR (Epidermal growth factor receptor), c-Jun, and JNK2 [23,24,25,26]. The activation of extrinsic apoptosis pathways by indirubin derivatives was found in melanoma cells [27,28]. To improve the anti-cancer activity of indirubin, we have previously introduced a series of chemical modifications [29,30,31].…”

Section: Introductionmentioning

confidence: 99%

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Key Role of Reactive Oxygen Species (ROS) in Indirubin Derivative-Induced Cell Death in Cutaneous T-Cell Lymphoma Cells

Soltan

Sumarni

Assaf

et al. 2019

IJMS

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Cutaneous T-cell lymphoma (CTCL) may develop a highly malignant phenotype in its late phase, and patients may profit from innovative therapies. The plant extract indirubin and its chemical derivatives represent new and promising antitumor strategies. This first report on the effects of an indirubin derivative in CTCL cells shows a strong decrease of cell proliferation and cell viability as well as an induction of apoptosis, suggesting indirubin derivatives for therapy of CTCL. As concerning the mode of activity, the indirubin derivative DKP-071 activated the extrinsic apoptosis cascade via caspase-8 and caspase-3 through downregulation of the caspase antagonistic proteins c-FLIP and XIAP. Importantly, a strong increase of reactive oxygen species (ROS) was observed as an immediate early effect in response to DKP-071 treatment. The use of antioxidative pre-treatment proved the decisive role of ROS, which turned out upstream of all other proapoptotic effects monitored. Thus, reactive oxygen species appear as a highly active proapoptotic pathway in CTCL, which may be promising for therapeutic intervention. This pathway can be efficiently activated by an indirubin derivative.

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Crucial role of reactive oxygen species (ROS) for the proapoptotic effects of indirubin derivative DKP‐073 in melanoma cells

Cited by 14 publications

References 51 publications

Countering TRAIL Resistance in Melanoma

Countering TRAIL Resistance in Melanoma

Evaluation of the Developmental Toxicity Induced by E804 in Zebrafish Embryos

Key Role of Reactive Oxygen Species (ROS) in Indirubin Derivative-Induced Cell Death in Cutaneous T-Cell Lymphoma Cells

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