Targeting Thioredoxin-1 by dimethyl fumarate induces ripoptosome-mediated cell death

Schroeder, Anne; Warnken, Uwe; Röth, Daniel; Klika, Karel D.; Vobis, Diana; Barnert, Andrea; Bujupi, Fatmire; Oberacker, Tina; Schnölzer, Martina; Nicolay, Jan P.; Krammer, Peter H.; Gülow, Karsten

doi:10.1038/srep43168

Cited by 23 publications

(26 citation statements)

References 49 publications

(65 reference statements)

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“…These findings point to Trx1 as a negative regulator of necroptosis by virtue of maintaining MLKL in a reduced, inactive state. In addition, Trx1 may also inhibit necroptotic signaling upstream of MLKL by interfering with the formation of necrosome-like complexes [93].…”

Section: Mlklmentioning

confidence: 99%

Oxidants, Antioxidants and Thiol Redox Switches in the Control of Regulated Cell Death Pathways

Benhar

2020

Antioxidants

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It is well appreciated that biological reactive oxygen and nitrogen species such as hydrogen peroxide, superoxide and nitric oxide, as well as endogenous antioxidant systems, are important modulators of cell survival and death in diverse organisms and cell types. In addition, oxidative stress, nitrosative stress and dysregulated cell death are implicated in a wide variety of pathological conditions, including cancer, cardiovascular and neurological diseases. Therefore, much effort is devoted to elucidate the molecular mechanisms linking oxidant/antioxidant systems and cell death pathways. This review is focused on thiol redox modifications as a major mechanism by which oxidants and antioxidants influence specific regulated cell death pathways in mammalian cells. Growing evidence indicates that redox modifications of cysteine residues in proteins are involved in the regulation of multiple cell death modalities, including apoptosis, necroptosis and pyroptosis. In addition, recent research suggests that thiol redox switches play a role in the crosstalk between apoptotic and necrotic forms of regulated cell death. Thus, thiol-based redox circuits provide an additional layer of control that determines when and how cells die.

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Section: Mlklmentioning

confidence: 99%

Oxidants, Antioxidants and Thiol Redox Switches in the Control of Regulated Cell Death Pathways

Benhar

2020

Antioxidants

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“…In details, several recent efforts have focused on the targeting of Trx/TrxR system [123–130]. Moreover, increasing evidences on a putative key role of HDAC inhibitors in the modulation of these pathways may deserve further investigations.…”

Section: Thioredoxin Glutathione Peroxidase and Superoxide Dismumentioning

confidence: 99%

Oxidative Stress Gene Expression Profile Correlates with Cancer Patient Poor Prognosis: Identification of Crucial Pathways Might Select Novel Therapeutic Approaches

Leone

Roca

Ciardiello

et al. 2017

Oxidative Medicine and Cellular Longevity

114

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The role of altered redox status and high reactive oxygen species (ROS) is still controversial in cancer development and progression. Intracellular levels of ROS are elevated in cancer cells suggesting a role in cancer initiation and progression; on the contrary, ROS elevated levels may induce programmed cell death and have been associated with cancer suppression. Thus, it is crucial to consider the double-face of ROS, for novel therapeutic strategies targeting redox regulatory mechanisms. In this review, in order to derive cancer-type specific oxidative stress genes' profile and their potential prognostic role, we integrated a publicly available oxidative stress gene signature with patient survival data from the Cancer Genome Atlas database. Overall, we found several genes statistically significant associated with poor prognosis in the examined six tumor types. Among them, FoxM1 and thioredoxin reductase1 expression showed the same pattern in four out of six cancers, suggesting their specific critical role in cancer-related oxidative stress adaptation. Our analysis also unveiled an enriched cellular network, highlighting specific pathways, in which many genes are strictly correlated. Finally, we discussed novel findings on the correlation between oxidative stress and cancer stem cells in order to define those pathways to be prioritized in drug development.

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“…We further elucidated mechanisms that suggest DMF can also be effective in other NF-kB-dependent malignancies. [17][18][19] Based on these findings, we are currently performing a clinical phase 2 study on DMF treatment in CTCL.…”

Section: Introductionmentioning

confidence: 99%

Combined inhibition of Bcl-2 and NFκB synergistically induces cell death in cutaneous T-cell lymphoma

Froehlich

Müller‐Decker²,

Braun

et al. 2019

Blood

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Therapeutic options for cutaneous T-cell lymphoma (CTCL) are limited and curative treatment regimens are not available. Thus, new targeted and well-tolerated therapeutic approaches are urgently needed. In this respect, we have recently shown that dimethyl fumerate (DMF) inhibits NF-κB acting as a survival factor in CTCL. Similarly, inhibition of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) has been shown to induce cell death in CTCL especially when combined with histone deacetylase inhibitors. Therefore, we hypothesized that inhibition of Bcl-2 should potentiate NF-κB inhibition in a novel combination treatment of CTCL. We show that, in vitro, the Bcl-2 inhibitors ABT-199 and ABT-263 induced specific cell death in primary CD4+ cells from CTCL patients as well as in the CTCL cell line SeAx, but not in T cells of healthy donors nor in the CTCL cell line HH, which lacks Bcl-2. Combined treatment with ABT-199 and DMF caused synergistic cell death specifically in CTCL cells engaging 2 independent signaling pathways. To verify these findings in vivo, we performed combined ABT-199 and DMF treatment in a xenograft mouse model for CTCL. The combined treatment effectively reduced tumor growth and increased overall survival via synergistic induction of CTCL cell death and suppression of tumor cell proliferation. Essentially, the combination treatment was superior to ABT-199 monotherapy with respect to both efficacy and tolerability. To sum up, our data provide proof of principle for the therapeutic potential of combining Bcl-2 and NF-κB inhibitors in treating CTCL. Next, this potential should be explored further in a clinical study.

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Targeting Thioredoxin-1 by dimethyl fumarate induces ripoptosome-mediated cell death

Cited by 23 publications

References 49 publications

Oxidants, Antioxidants and Thiol Redox Switches in the Control of Regulated Cell Death Pathways

Oxidants, Antioxidants and Thiol Redox Switches in the Control of Regulated Cell Death Pathways

Oxidative Stress Gene Expression Profile Correlates with Cancer Patient Poor Prognosis: Identification of Crucial Pathways Might Select Novel Therapeutic Approaches

Combined inhibition of Bcl-2 and NFκB synergistically induces cell death in cutaneous T-cell lymphoma

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