Doxorubicin and daunorubicin induce processing and release of interleukin-1β through activation of the NLRP3 inflammasome

Sauter, Kristin A.; Wood, Lisa J.; Wong, John; Iordanov, Mihail S.; Magun, Bruce E.

doi:10.4161/cbt.11.12.15540

Cited by 180 publications

(155 citation statements)

References 44 publications

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“…91 Additionally, the anthracycline doxorubicin induces systemic inflammation associated with IL-1b release, mediated by NLRP3 inflammasome activation, which is controlled by co-treatment with ROS inhibitors or by cultivation of cells with high levels of extracellular K 1 . 92 Lysosomal destabilization and activation of the NLRP3 inflammasome In addition to ROS and K 1 efflux, disruption of the lysosomal membrane, caused by phagocytosis of particulate matter or live pathogens or by sterile lysosomal damage (without crystals), results in NLRP3 activation. 55,57 In agreement with this, proton pump inhibitors (used for neutralization of lysosomal pH) or blockade of cathepsin(s) significantly inhibits NLRP3 inflammasome activation.…”

Section: Molecular Mechanisms Of the Canonical Activation Of The Nlrpmentioning

confidence: 99%

Molecular mechanisms regulating NLRP3 inflammasome activation

et al. 2015

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Section: Molecular Mechanisms Of the Canonical Activation Of The Nlrpmentioning

confidence: 99%

Molecular mechanisms regulating NLRP3 inflammasome activation

et al. 2015

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“…These paracrine effects include the promotion of tumor formation (1), stimulation of angiogenesis (2,3), metastasis (4), tumor resistance to chemotherapy (5), and secretion of multiple tumor-promoting cytokines in vivo (6) and in vitro (7). These damage responses also occur in the stromal components of solid tumors (endothelial cells and fibroblasts), where they are mediated by p53 (8,9).…”

mentioning

confidence: 99%

Cyclin-dependent kinase 8 mediates chemotherapy-induced tumor-promoting paracrine activities

Porter

Farmaki

Altilia

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

156

197

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Conventional chemotherapy not only kills tumor cells but also changes gene expression in treatment-damaged tissues, inducing production of multiple tumor-supporting secreted factors. This secretory phenotype was found here to be mediated in part by a damage-inducible cell-cycle inhibitor p21 (CDKN1A). We developed small-molecule compounds that inhibit damage-induced transcription downstream of p21. These compounds were identified as selective inhibitors of a transcription-regulating kinase CDK8 and its isoform CDK19. Remarkably, p21 was found to bind to CDK8 and stimulate its kinase activity. p21 and CDK8 also cooperate in the formation of internucleolar bodies, where both proteins accumulate. A CDK8 inhibitor suppresses damage-induced tumor-promoting paracrine activities of tumor cells and normal fibroblasts and reverses the increase in tumor engraftment and serum mitogenic activity in mice pretreated with a chemotherapeutic drug. The inhibitor also increases the efficacy of chemotherapy against xenografts formed by tumor cell/fibroblast mixtures. Microarray data analysis revealed striking correlations between CDK8 expression and poor survival in breast and ovarian cancers. CDK8 inhibition offers a promising approach to increasing the efficacy of cancer chemotherapy.transcriptional damage response | senescence | tumor microenvironment | nucleolus | chemical genomics

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“…Doxorubicin is the classical cardiotoxic drug, which is still used in clinical practice due to its unsurpassed cancer killing effects in specific cancers. The pro-inflammatory effects of doxorubicin are mediated by the NLRP3 inflammasome [42], the production of mature IL-1β correlates with the intensity of cardiac injury [43], and treatment with IL-1 receptor antagonist (anakinra) protected against doxorubicin-induced cardiac injury [44]. IL-1 appears to be involved also in radiation-induced myocardial injury and systolic dysfunction (E. Mezzaroma; S. Toldo; R.J. …”

Section: Response Of the Myocardium To Non-ischemic Injurymentioning

confidence: 99%

Inflammasome: a new villain in heart disease

Sonnino¹,

Toldo²,

Mezzaroma³

et al. 2014

Inflammasome

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Many cardiac diseases have an inflammatory component by which the initial injury is amplified by an overzealous inflammatory response leading to further tissue injury, and impairing the recovery of cardiac function. The formation of the inflammasome in the heart represents a newly identified amplifying step in the pathogenesis and pathophysiology of different cardiovascular conditions. Initial experimental animal studies and small pilot clinical studies suggest that targeting the inflammasome in its different components interrupts this amplification process and promotes more favorable healing. The inflammasome represents therefore a new villain in the fight against heart disease.

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Doxorubicin and daunorubicin induce processing and release of interleukin-1β through activation of the NLRP3 inflammasome

Cited by 180 publications

References 44 publications

Molecular mechanisms regulating NLRP3 inflammasome activation

Molecular mechanisms regulating NLRP3 inflammasome activation

Cyclin-dependent kinase 8 mediates chemotherapy-induced tumor-promoting paracrine activities

Inflammasome: a new villain in heart disease

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