1,722,970 research outputs found
Image2_The XPO1 Inhibitor KPT-8602 Ameliorates Parkinson’s Disease by Inhibiting the NF-κB/NLRP3 Pathway.JPEG
No full textExportin 1 (XPO1) is an important transport receptor that mediates the nuclear export of various proteins and RNA. KPT-8602 is a second-generation inhibitor of XPO1, demonstrating the lowest level of side effects, and is currently in clinical trials for the treatment of cancers. Previous studies suggest that several first-generation inhibitors of XPO1 demonstrate anti-inflammation activities, indicating the application of this drug in inflammation-related diseases. In this study, our results suggested the potent anti-inflammatory effect of KPT-8602 in vitro and in vivo. KPT-8602 inhibited the activation of the NF-κB pathway by blocking the phosphorylation and degradation of IκBα, and the priming of NLRP3. Importantly, the administration of KPT-8602 attenuated both lipopolysaccharide (LPS)-induced peripheral inflammation and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neuroinflammation in vivo. In addition, the tissue damage was also ameliorated by KPT-8602, indicating that KPT-8602 could be used as a novel potential therapeutic agent for the treatment of inflammasome-related diseases such as Parkinson’s disease, through the regulation of the NF-κB signaling pathway and the NLRP3 inflammasome.</p
Image1_The XPO1 Inhibitor KPT-8602 Ameliorates Parkinson’s Disease by Inhibiting the NF-κB/NLRP3 Pathway.JPEG
No full textExportin 1 (XPO1) is an important transport receptor that mediates the nuclear export of various proteins and RNA. KPT-8602 is a second-generation inhibitor of XPO1, demonstrating the lowest level of side effects, and is currently in clinical trials for the treatment of cancers. Previous studies suggest that several first-generation inhibitors of XPO1 demonstrate anti-inflammation activities, indicating the application of this drug in inflammation-related diseases. In this study, our results suggested the potent anti-inflammatory effect of KPT-8602 in vitro and in vivo. KPT-8602 inhibited the activation of the NF-κB pathway by blocking the phosphorylation and degradation of IκBα, and the priming of NLRP3. Importantly, the administration of KPT-8602 attenuated both lipopolysaccharide (LPS)-induced peripheral inflammation and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neuroinflammation in vivo. In addition, the tissue damage was also ameliorated by KPT-8602, indicating that KPT-8602 could be used as a novel potential therapeutic agent for the treatment of inflammasome-related diseases such as Parkinson’s disease, through the regulation of the NF-κB signaling pathway and the NLRP3 inflammasome.</p
Supplemental data from The Second-Generation Exportin-1 Inhibitor KPT-8602 Demonstrates Potent Activity against Acute Lymphoblastic Leukemia
No full textSupplementary Table 1 - EC50 values for KPT-8602 and KPT-330 in different leukemia cells Supplementary Table 2 - EC50 values for KPT-8602 in wild-type versus XPO1C528S mutant cell lines Figure S1 - High content images of HeLa cells stably expressing the NLS-AcGFP-NES reporter treated with different concentrations KPT-330 or KPT-8602 Figure S2 - Effect of KPT-8602 treatment on normal peripheral blood cells of NSG mice</p
Next-Generation SINE Compound KPT−8602 Ameliorates Dystrophic Pathology in Zebrafish and Mouse Models of DMD
Full text linkDuchenne muscular dystrophy (DMD) is a progressive, X-linked childhood neuromuscular disorder that results from loss-of-function mutations in the DYSTROPHIN gene. DMD patients exhibit muscle necrosis, cardiomyopathy, respiratory failure, and loss of ambulation. One of the major driving forces of DMD disease pathology is chronic inflammation. The current DMD standard of care is corticosteroids; however, there are serious side effects with long-term use, thus identifying novel anti-inflammatory and anti-fibrotic treatments for DMD is of high priority. We investigated the next-generation SINE compound, KPT−8602 (eltanexor) as an oral therapeutic to alleviate dystrophic symptoms. We performed pre-clinical evaluation of the effects of KPT−8602 in DMD zebrafish (sapje) and mouse (D2-mdx) models. KPT−8602 improved dystrophic skeletal muscle pathologies, muscle architecture and integrity, and overall outcomes in both animal models. KPT−8602 treatment ameliorated DMD pathology in D2-mdx mice, with increased locomotor behavior and improved muscle histology. KPT−8602 altered the immunological profile of the dystrophic mice, and reduced circulating osteopontin serum levels. These findings demonstrate KPT−8602 as an effective therapeutic in DMD through by promotion of an anti-inflammatory environment and overall improvement of DMD pathological outcomes
Nuclear Export Inhibitor KPT-8602 Synergizes with PARP Inhibitors in Escalating Apoptosis in Castration Resistant Cancer Cells
No full textAberrant nuclear protein transport, often observed in cancer, causes mislocalization-dependent inactivation of critical cellular proteins. Earlier we showed that overexpression of exportin 1 is linked to higher grade and Gleason score in metastatic castration resistant prostate cancer (mCRPC). We also showed that a selective inhibitor of nuclear export (SINE) selinexor and second generation eltanexor (KPT-8602) could suppress mCRPC growth, reduce androgen receptor (AR), and re-sensitize to androgen deprivation therapy. Here we evaluated the combination of KPT-8602 with PARP inhibitors (PARPi) olaparib, veliparib and rucaparib in 22rv1 mCRPC cells. KPT-8602 synergized with PARPi (CI < 1) at pharmacologically relevant concentrations. KPT-8602-PARPi showed superior induction of apoptosis compared to single agent treatment and caused up-regulation of pro-apoptotic genes BAX, TP53 and CASPASE 9. Mechanistically, KPT-8602-PARPi suppressed AR, ARv7, PSA and AR targets FOXA1 and UBE2C. Western blot analysis revealed significant down-regulation of AR, ARv7, UBE2C, SAM68, FOXA1 and upregulation of cleaved PARP and cleaved CASPASE 3. KPT-8602 with or without olaparib was shown to reduce homologous recombination-regulated DNA damage response targets including BRCA1, BRCA2, CHEK1, EXO1, BLM, RAD51, LIG1, XRCC3 and RMI2. Taken together, this study revealed the therapeutic potential of a novel combination of KPT-8602 and PARP inhibitors for the treatment of mCRPC
The XPO1 inhibitor KPT-8602 synergizes with dexamethasone in acute lymphoblastic Leukemia
Full text linkPurpose: KPT-8602 (Eltanexor) is a second-generation exportin-1 (XPO1) inhibitor with potent activity against acute lymphoblastic leukemia (ALL) in preclinical models and with minimal effects on normal cells. In this study, we evaluated whether KPT-8602 would synergize with dexamethasone, vincristine, or doxorubicin, three drugs currently used for the treatment of ALL. Experimental Design: First, we searched for the most synergistic combination of KPT-8602 with dexamethasone, vincristine, or doxorubicin in vitro in both B-ALL and T-ALL cell lines using proliferation and apoptosis as a readout. Next, we validated this synergistic effect by treatment of clinically relevant B- and T-ALL patient-derived xenograft models in vivo. Finally, we performed RNA-sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) to determine the mechanism of synergy. Results: KPT-8602 showed strong synergism with dexamethasone on human B-ALL and T-ALL cell lines as well as in vivo in three patient-derived ALL xenografts. Compared with single-drug treatment, the drug combination caused increased apoptosis and led to histone depletion. Mechanistically, integration of ChIP-seq and RNA-seq data revealed that addition of KPT-8602 to dexamethasone enhanced the activity of the glucocorticoid receptor (NR3C1) and led to increased inhibition of E2F-mediated transcription. We observed strong inhibition of E2F target genes related to cell cycle, DNA replication, and transcriptional regulation. Conclusions: Our preclinical study demonstrates that KPT-8602 enhances the effects of dexamethasone to inhibit B-ALL and T-ALL cells via NR3C1- and E2F-mediated transcriptional complexes, allowing to achieve increased dexamethasone effects for patients
California Poll: 8602 -- May 2-7, 1986
No full textThe Field Poll, established in 1945 as The California Poll by Mervin Field, has operated continuously as an independent, non-partisan, media-sponsored public opinion news service. Each year the Field Polls cover a wide range of political and social topics examining California public opinion. Continuing measures are made of voter support for leading political figures vying for major state and federal offices, job ratings of important political figures and reactions to significant political events. Voter awareness, understanding and predispositions of major campaign issues and salient statewide ballot propositions are also tracked over time. For poll 8602 N=1013
Supplementary Figure 4 from The XPO1 Inhibitor KPT-8602 Synergizes with Dexamethasone in Acute Lymphoblastic Leukemia
No full textSuppl. figure 4: KPT-8602 single treatment or combined treatment with dexamethasone does not lead to nuclear accumulation of IKBα nor to effects on NFκB target genes</p
Supplementary Figure 1 from The XPO1 Inhibitor KPT-8602 Synergizes with Dexamethasone in Acute Lymphoblastic Leukemia
No full textSuppl. figure 1: Doxorubicin and vincristine are not synergistic with KPT-8602 in diminishing proliferation of B-ALL and T-ALL</p
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