PTEN and PI-3 kinase inhibitors control LPS signaling and the lymphoproliferative response in the CD19+ B cell compartment

Singh, Alok R.; Peirce, Susan K.; Joshi, Shweta; Durden, Donald L.

doi:10.1016/j.yexcr.2014.05.016

Cited by 18 publications

(14 citation statements)

References 47 publications

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“…ConA and LPS are commonly used to promote B and T lymphocyte proliferation, with ConA‐ and LPS‐stimulated splenocyte proliferation being important indicators of humoral and cellular immunity, respectively . A number of xenobiotics inhibited ConA and LPS‐stimulated splenocyte proliferation and impaired adaptive immunity .…”

Section: Discussionmentioning

confidence: 99%

8:2 Fluorotelomer alcohol causes immunotoxicity and liver injury in adult male C57BL/6 mice

Wang

Kong

et al. 2018

Environmental Toxicology

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8:2 Fluorotelomer alcohol (8:2 FTOH) is widely used in houseware and industrial goods and is ubiquitous in the surrounding environment. 8:2 FTOH has been linked to hepatoxicity, nephrotoxicity, and reproductive toxicity, as well as endocrine-disrupting effects. However, as of yet, the research regarding immunotoxicity of 8:2 FTOH remains largely limited. In the present study, adult male C57BL/6 mice were administered with 10, 30, and 100 mg/kg/d 8:2 FTOH by gavage for 28 days to investigate its immunotoxicity in vivo. The results showed that exposure to 8:2 FTOH caused increases in liver weight and histological changes in the liver, including vacuolation, cell swelling, immune cell infiltration, karyopyknosis and nuclear swelling. No histological change in either the spleen or the thymus was observed after administration of 8:2 FTOH. In addition, exposure to 8:2 FTOH reduced the concentration of IL-1β in serum, and mRNA levels of IL-1β, IL-6, and TNF-α in both the thymus and spleen. CXCL-1 mRNA expression was downregulated in both the liver and thymus after 8:2 FTOH administration, while only IL-1β mRNA expression was upregulated in the liver. Moreover, the exposure of primary cultured splenocytes to 8:2 FTOH inhibited the ConA-stimulated proliferation of splenocytes at concentrations of 30 and 100 μM, and the LPS-stimulated proliferation of splenocytes at 100 μM. Furthermore, 8:2 FTOH inhibited the level of secreted IFN-γ in ConA-stimulated splenocytes. The results obtained in the study demonstrated that 8:2 FTOH posed potential immunotoxicity and liver injury in mice. Our findings will provide novel data for the health risk assessment of 8:2 FTOH. K E Y W O R D S 8:2 FTOH, immunotoxicity, liver injury, mice, oxidative stress 1 | INTRODUCTION Fluorotelomers, as fluorocarbon-based oligomers or telomers, have various applications in food packaging, home furnishings, fire-fighting foams, surfactants, textiles, adhesives, waxes, polishes, and leather. 1 It was reported that the market size of fluorotelomers was 26.5 kt in 2015, and its annual growth rate is estimated to be 12.7%. 2 Among fluorotelomers, fluorotelomer alcohol (FTOH) products dominate global consumption; these products reportedly made up approximately 32% of the overall volume of fluorotemomers in 2013. 3 8:2 FTOH is the most abundant FTOH homologue and is ubiquitous in the environment. 4 Chen et al. 5 detected FTOHs in several wastewater treatment plants in China, and the study also found that 8:2 FTOH was the primary FTOH in the influent, secondary effluent, and sludge, with the concentrations ranging from 2.10 to 11.0 ng/L, 3.05 to 12.4 ng/L, and 0.36 to 1.91 ng/g dry weight, respectively. Bach et al. 6 assessed 14 perfluorinated compounds (PFCs) in water samples in France and found that the concentrations of 8:2 FTOH were 117 ng/L and 213 ng/L in tap and surface water, respectively. Additionally, 8:2 FTOH was commonly detected in food contact materials (FCMs). For example, 8:2 FTOH was detected in most Chinese and American FCM samples at concentra...

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Section: Discussionmentioning

confidence: 99%

8:2 Fluorotelomer alcohol causes immunotoxicity and liver injury in adult male C57BL/6 mice

Wang

Kong

et al. 2018

Environmental Toxicology

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“…Moreover, SF1126 blocks c-Myc expression and displaces BRD4 from the MYC transcriptional start site in HCC cell lines. Moreover, the active moiety of SF1126, LY294002, blocks BRD4 interaction with acetylated lysine residues Histone H4 peptide (1–21) K5/8/12/16Ac-Biotin, it has been cocrystallized in the active site of BRD4 and we have executed extensive molecular modeling of this chemotype and compared it with JQ1 to develop additional more potent dual inhibitors of PI3K and BRD4 (48). Our data show that SF1126, either alone or in combination with sorafenib, significantly suppressed tumor growth in vivo in SK-Hep1 cells and Huh 7 cells.…”

Section: Discussionmentioning

confidence: 99%

“…The 3D structures of LY294002 and JQ1 (all hydrogens included) were docked using LeadIT's standard parameters. Compounds LY294002 and JQ1 were tested for BRD4-1 and BRD4-2 activity by using Histone H4 peptide (1–21) K5/8/12/16Ac-Biotin as a ligand in alpha screen binding assay. The test was performed in collaboration with Reaction Biology.…”

Section: Methodsmentioning

confidence: 99%

“…Water molecules are not displayed for clarity but they were included in the in silico docking experiments. Bottom, alpha screen binding assay showing BRD4 activity of LY294002 and JQ1 using Histone H4 peptide (1–21) K5/8/12/16Ac-Biotin as a ligand. B–E, Hep3B, HepG2, SK-Hep1, and Huh7 cells were treated with 10 and 20 µmol/L of SF1126 for 24 hours followed by RNA isolation and real time PCR analysis of c-Myc.…”

Section: Figurementioning

confidence: 99%

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Single Agent and Synergistic Activity of the “First-in-Class” Dual PI3K/BRD4 Inhibitor SF1126 with Sorafenib in Hepatocellular Carcinoma

Singh

Joshi

Burgoyne

et al. 2016

Molecular Cancer Therapeutics

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Deregulated PI3K/AKT/mTOR, Ras/Raf/MAPK, and c-Myc signaling pathways are of prognostic significance in hepatocellular carcinoma (HCC). Sorafenib, the only drug clinically approved for patients with advanced HCC, blocks the Ras/Raf/MAPK pathway but it does not inhibit the PI3K/AKT/mTOR pathway or c-Myc activation. Hence, there is an unmet medical need to identify potent PI3K/BRD4 inhibitors, which can be used either alone or in combination with sorafenib to treat patients with advanced HCC. Herein, we show that SF1126 (pan PI3K/BRD4 inhibitor) as single agent or in combination with sorafenib inhibited proliferation, cell cycle, apoptosis, and multiple key enzymes in PI3K/AKT/mTOR and Ras/Raf/MAPK pathway in Hep3B, HepG2, SK-Hep1, and Huh7 HCC cell lines. We demonstrate that the active moiety of the SF1126 prodrug LY294002 binds to and blocks BRD4 interaction with the acetylated histone-H4 chromatin mark protein and displaced BRD4 coactivator protein from the transcriptional start site of MYC in Huh7 and SK-Hep1 HCC cell lines. Moreover, SF1126 blocked expression levels of c-Myc in HCC cells. Treatment of SF1126 either alone or in combination with sorafenib showed significant antitumor activity in vivo. Our results establish that SF1126 is a dual PI3K/BRD4 inhibitor. This agent has completed a phase I clinical trial in humans with good safety profile. Our data support the potential future consideration of a phase II clinical trial of SF1126, a clinically relevant dual "first-in-class" PI3K/BRD4 inhibitor in advanced HCC, and a potential combination with sorafenib.

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“…SF1126 is a vascular-targeted pan-PI-3K inhibitor prodrug with antitumor and antiangiogenic activity [37]. We recently published that SF1126 can block lymphoproliferative response in mouse lymphoma model [64]. This drug has completed phase I clinical trial in solid tumors and B-cell malignancies [38].…”

Section: Discussionmentioning

confidence: 99%

Pan-PI-3 kinase inhibitor SF1126 shows antitumor and antiangiogenic activity in renal cell carcinoma

Joshi

Singh

Durden

2015

Cancer Chemother Pharmacol

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PTEN and PI-3 kinase inhibitors control LPS signaling and the lymphoproliferative response in the CD19+ B cell compartment

Cited by 18 publications

References 47 publications

8:2 Fluorotelomer alcohol causes immunotoxicity and liver injury in adult male C57BL/6 mice

8:2 Fluorotelomer alcohol causes immunotoxicity and liver injury in adult male C57BL/6 mice

Single Agent and Synergistic Activity of the “First-in-Class” Dual PI3K/BRD4 Inhibitor SF1126 with Sorafenib in Hepatocellular Carcinoma

Pan-PI-3 kinase inhibitor SF1126 shows antitumor and antiangiogenic activity in renal cell carcinoma

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