Structure–activity relationship analysis of a novel necroptosis inhibitor, Necrostatin-5

Wang, Ke; Li, Jinfeng; Degterev, Alexei; Hsu, Emily; Yuan, Junying; Yuan, Chengye

doi:10.1016/j.bmcl.2006.11.056

Cited by 83 publications

(35 citation statements)

References 26 publications

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“…In addition, decitabine plus gefitinib exerted apoptotic effects, as indicated by the fact that the broad-spectrum caspase inhibitor z-VAD-fmk could prevent cells death as induced by these agents. However, cells death induced by decitabine combined with gefitinib failed to be blocked by necrostatin-1 or necrostatin-5, a novel class of potent small-molecule inhibitors of necroptosis [52], [53]. To further address the underlying mechanism of this enhanced cell apoptosis, the expression and processing of caspase 3 and PARP were examined in colon cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Combination of Gefitinib and DNA Methylation Inhibitor Decitabine Exerts Synergistic Anti-Cancer Activity in Colon Cancer Cells

et al. 2014

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Despite recent advances in the treatment of human colon cancer, the chemotherapy efficacy against colon cancer is still unsatisfactory. In the present study, effects of concomitant inhibition of the epidermal growth factor receptor (EGFR) and DNA methyltransferase were examined in human colon cancer cells. We demonstrated that decitabine (a DNA methyltransferase inhibitor) synergized with gefitinib (an EGFR inhibitor) to reduce cell viability and colony formation in SW1116 and LOVO cells. However, the combination of the two compounds displayed minimal toxicity to NCM460 cells, a normal human colon mucosal epithelial cell line. The combination was also more effective at inhibiting the AKT/mTOR/S6 kinase pathway. In addition, the combination of decitabine with gefitinib markedly inhibited colon cancer cell migration. Furthermore, gefitinib synergistically enhanced decitabine-induced cytotoxicity was primarily due to apoptosis as shown by Annexin V labeling that was attenuated by z-VAD-fmk, a pan caspase inhibitor. Concomitantly, cell apoptosis resulting from the co-treatment of gefitinib and decitabine was accompanied by induction of BAX, cleaved caspase 3 and cleaved PARP, along with reduction of Bcl-2 compared to treatment with either drug alone. Interestingly, combined treatment with these two drugs increased the expression of XIAP-associated factor 1 (XAF1) which play an important role in cell apoptosis. Moreover, small interfering RNA (siRNA) depletion of XAF1 significantly attenuated colon cancer cells apoptosis induced by the combination of the two drugs. Our findings suggested that gefitinib in combination with decitabine exerted enhanced cell apoptosis in colon cancer cells were involved in mitochondrial-mediated pathway and induction of XAF1 expression. In conclusion, based on the observations from our study, we suggested that the combined administration of these two drugs might be considered as a novel therapeutic regimen for treating colon cancer.

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Section: Discussionmentioning

confidence: 99%

Combination of Gefitinib and DNA Methylation Inhibitor Decitabine Exerts Synergistic Anti-Cancer Activity in Colon Cancer Cells

et al. 2014

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“…We recorded up to 12 parameters simultaneously using a Becton Dickinson LSRII flow cytometer equipped with 20 mW solid-state Nd-YAG (emission at 355 nm), 20 mW argon (emission at 488 nm), 10 mW diode pumped solid state yellow-green (emission 561 nm) and 16 mW helium-neon lasers (emission at 634 nm). Necrostatin-1 (34), necrostatin-5(35), and necrostatin-7 were obtained from Biovision (Milpitas, CA) and used to inhibit necrosis, as earlier described (36). Each patient’s cells were freshly isolated, stained and analyzed in parallel with a matched control.…”

Section: Methodsmentioning

confidence: 99%

Mechanistic Target of Rapamycin Activation Triggers IL-4 Production and Necrotic Death of Double-Negative T Cells in Patients with Systemic Lupus Erythematosus

Lai

Borsuk

Shadakshari

et al. 2013

The Journal of Immunology

135

132

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The mechanistic target of rapamycin (mTOR) is recognized as a sensor of mitochondrial dysfunction and effector of T-cell lineage development, however, its role in autoimmunity, including systemic lupus erythematosus, remains unclear. Here, we prospectively evaluated mitochondrial dysfunction and mTOR activation in PBL relative to SLE disease activity index (SLEDAI) during 274 visits of 59 patients and 54 matched healthy subjects. Partial least square-discriminant analysis identified 15 of 212 parameters that accounted for 70.2% of the total variance and discriminated lupus and control samples (p<0.0005); increased mitochondrial mass of CD3+/CD4−/CD8− double-negative (DN) T cells (p=1.1×10−22) and FoxP3 depletion in CD4+/CD25+ T cells were top contributors (p=6.7×10−7). Prominent necrosis and mTOR activation were noted in DN T cells during 15 visits characterized by flares (SLEDAI increase ≥4) relative to 61 visits of remission (SLEDAI decrease ≥4). mTOR activation in DN T cells was also noted at pre-flare visits of SLE patients relative to those of stable disease or healthy controls. DN lupus T cells showed increased production of IL-4, which correlated with depletion of CD25+/CD19+B cells. Rapamycin treatment in vivo blocked the IL-4 production and necrosis of DN T cells, increased the expression of FoxP3 in CD25+/CD4+T cells, and expanded CD25+/CD19+ B cells. These results identify mTOR activation to be a trigger of IL-4 production and necrotic death of DN T cells in patients with SLE.

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“…c) Necrostatin-4 [10, 172, 173]. d) Necrostatin-5 [10, 174]. e) Optimized Necrostatin-1s [10, 90, 175].…”

Section: Figurementioning

confidence: 99%

Complex Pathologic Roles of RIPK1 and RIPK3: Moving Beyond Necroptosis

Wegner

Saleh

Degterev

2017

Trends in Pharmacological Sciences

Self Cite

138

132

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A process of regulated necrosis, termed necroptosis, has been recognized as a major contributor to cell death and inflammation occurring under a wide range of pathologic settings. The core event in necroptosis is the formation of the detergent-insoluble “necrosome” complex of homologous Ser/Thr kinases Receptor Interacting Kinase 1 (RIPK1) and Receptor Interacting Kinase 3 (RIPK3), which promotes phosphorylation of a key pro-death effector Mixed Lineage Kinase Domain-like (MLKL) by RIPK3. Core necroptosis mediators are under multiple controls, which have been a subject of intense investigation. Additional, non-necroptotic functions of these factors, primarily in controlling apoptosis and inflammatory responses, have also begun to emerge. This review will provide an overview of the current understanding of the human disease relevance of this pathway, and potential therapeutic strategies, targeting necroptosis mediators in various pathologies.

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Structure–activity relationship analysis of a novel necroptosis inhibitor, Necrostatin-5

Cited by 83 publications

References 26 publications

Combination of Gefitinib and DNA Methylation Inhibitor Decitabine Exerts Synergistic Anti-Cancer Activity in Colon Cancer Cells

Combination of Gefitinib and DNA Methylation Inhibitor Decitabine Exerts Synergistic Anti-Cancer Activity in Colon Cancer Cells

Mechanistic Target of Rapamycin Activation Triggers IL-4 Production and Necrotic Death of Double-Negative T Cells in Patients with Systemic Lupus Erythematosus

Complex Pathologic Roles of RIPK1 and RIPK3: Moving Beyond Necroptosis

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