Phosphatidylinositol 3-kinase inhibitor(LY294002) induces apoptosis of human nasopharyngeal carcinoma in vitro and in vivo

Treatment with the phosphatidylinositol 3-kinase inhibitor wortmannin promotes approximately 30% decrease in the steady-state number of cell-surface transferrin receptors. This effect is rapid and dose dependent, with maximal down-regulation elicited with 30 min of treatment and with an IC50 approximately 25 nM wortmannin. Wortmannin-treated cells display an increased endocytic rate constant for transferrin internalization and decreased exocytic rate constants for transferrin recycling. In addition to these effects in vivo, wortmannin is a potent inhibitor (IC50 approximately 15 nM) of a cell-free assay that detects the delivery of endocytosed probes into a common compartment. Inhibition of the in vitro assay involves the inactivation of a membrane-associated factor that can be recruited onto the surface of vesicles from the cytosol. Its effects on the cell-free assay suggest that wortmannin inhibits receptor sorting and/or vesicle budding required for delivery of endocytosed material to "mixing" endosomes. This idea is consistent with morphological changes induced by wortmannin, which include the formation of enlarged transferrin-containing structures and the disruption of the perinuclear endosomal compartment. However, the differential effects of wortmannin, specifically increased transferrin receptor internalization and inhibition of receptor recycling, implicate a role for phosphatidylinositol 3-kinase activity in multiple sorting events in the transferrin receptor's membrane traffic pathway.

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A sensitive HPLC-FLD method for the quantification of alpelisib, a novel phosphatidylinositol 3-kinase inhibitor, in rat plasma: Drug metabolism and pharmacokinetic evaluation in vitro and in vivo

Journal of Chromatography B ◽

10.1016/j.jchromb.2020.122508 ◽

2021 ◽

Vol 1163 ◽

pp. 122508

Author(s):

Seong-Wook Seo ◽

Ji-Min Kim ◽

Dong-Gyun Han ◽

Dongho Geum ◽

Hwayoung Yun ◽

...

Keyword(s):

Drug Metabolism ◽

Kinase Inhibitor ◽

Rat Plasma ◽

Plasma Drug ◽

Phosphatidylinositol 3 Kinase ◽

Pharmacokinetic Evaluation ◽

Phosphatidylinositol 3

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In Vitro Antimetastatic Effect of Phosphatidylinositol 3-Kinase Inhibitor ZSTK474 on Prostate Cancer PC3 Cells

International Journal of Molecular Sciences ◽

10.3390/ijms140713577 ◽

2013 ◽

Vol 14 (7) ◽

pp. 13577-13591 ◽

Cited By ~ 20

Author(s):

Wennan Zhao ◽

Wenzhi Guo ◽

Qianxiang Zhou ◽

Sheng-Nan Ma ◽

Ran Wang ◽

...

Keyword(s):

Prostate Cancer ◽

Kinase Inhibitor ◽

Phosphatidylinositol 3 Kinase ◽

Antimetastatic Effect ◽

Pc3 Cells ◽

Phosphatidylinositol 3

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Osthole sensitizes with radiotherapy to suppress tumorigenesis of human nasopharyngeal carcinoma in vitro and in vivo

Cancer Management and Research ◽

10.2147/cmar.s182798 ◽

2018 ◽

Vol Volume 10 ◽

pp. 5471-5477 ◽

Cited By ~ 2

Author(s):

Lin Peng ◽

Yi-Teng Huang ◽

Jian Chen ◽

Yi-Xuan Zhuang ◽

Fan Zhang ◽

...

Keyword(s):

Nasopharyngeal Carcinoma ◽

Human Nasopharyngeal Carcinoma

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Tyrosine 1101 of Tie2 Is the Major Site of Association of p85 and Is Required for Activation of Phosphatidylinositol 3-Kinase and Akt

Molecular and Cellular Biology ◽

10.1128/mcb.18.7.4131 ◽

1998 ◽

Vol 18 (7) ◽

pp. 4131-4140 ◽

Cited By ~ 154

Author(s):

Christopher D. Kontos ◽

Thomas P. Stauffer ◽

Wen-Pin Yang ◽

John D. York ◽

Liwen Huang ◽

...

Keyword(s):

Fluorescent Protein ◽

Vascular Development ◽

Pi3 Kinase ◽

Pleckstrin Homology Domain ◽

Phosphatidylinositol 3 Kinase ◽

Lipid Kinase ◽

Embryonic Vascular Development ◽

Phosphatidylinositol 3

ABSTRACT Tie2 is an endothelium-specific receptor tyrosine kinase that is required for both normal embryonic vascular development and tumor angiogenesis and is thought to play a role in vascular maintenance. However, the signaling pathways responsible for the function of Tie2 remain unknown. In this report, we demonstrate that the p85 subunit of phosphatidylinositol 3-kinase (PI3-kinase) associates with Tie2 and that this association confers functional lipid kinase activity. Mutation of tyrosine 1101 of Tie2 abrogated p85 association both in vitro and in vivo in yeast. Tie2 was found to activate PI3-kinase in vivo as demonstrated by direct measurement of increases in cellular phosphatidylinositol 3-phosphate and phosphatidylinositol 3,4-bisphosphate, by plasma membrane translocation of a green fluorescent protein-Akt pleckstrin homology domain fusion protein, and by downstream activation of the Akt kinase. Activation of PI3-kinase was abrogated in these assays by mutation of Y1101 to phenylalanine, consistent with a requirement for this residue for p85 association with Tie2. These results suggest that activation of PI3-kinase and Akt may in part account for Tie2’s role in both embryonic vascular development and pathologic angiogenesis, and they are consistent with a role for Tie2 in endothelial cell survival.

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11C-Labeled Pictilisib (GDC-0941) as a Molecular Tracer Targeting Phosphatidylinositol 3-Kinase (PI3K) for Breast Cancer Imaging

Contrast Media & Molecular Imaging ◽

10.1155/2019/1760184 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 2

Author(s):

Na Han ◽

Yaqun Jiang ◽

Yongkang Gai ◽

Qingyao Liu ◽

Lujie Yuan ◽

...

Keyword(s):

Breast Cancer ◽

Pik3ca Mutation ◽

Phosphatidylinositol 3 Kinase ◽

Pet Tracer ◽

Positron Emission ◽

Pet Scans ◽

Mcf 7 ◽

Phosphatidylinositol 3

Pictilisib (GDC-0941) is an inhibitor of phosphatidylinositol 3-kinase (PI3K), part of a signaling cascade involved in breast cancer development. The purpose of this study was to evaluate the pharmacokinetics of pictilisib noninvasively by radiolabeling it with 11C and to assess the usability of the resulting [11C]-pictilisib as a positron-emission tomography (PET) tracer to screen for pictilisib-sensitive tumors. In this study, pictilisib was radiolabeled with [11C]-methyl iodide to obtain 11C-methylated pictilisib ([11C]-pictilisib) using an automated synthesis module with a high radiolabeling yield. Considerably higher uptake ratios were observed in MCF-7 (PIK3CA mutation, pictilisib-sensitive) cells than those in MDA-MB-231 (PIK3CA wild-type, pictilisib-insensitive) cells at all evaluated time points, indicating good in vitro binding of [11C]-pictilisib. Dynamic micro-PET scans in mice and biodistribution results showed that [11C]-pictilisib was mainly excreted via the hepatobiliary tract into the intestines. MCF-7 xenografts could be clearly visualized on the static micro-PET scans, while MDA-MB-231 tumors could not. Biodistribution results of two xenograft models showed significantly higher uptake and tumor-to-muscle ratios in the MCF-7 xenografts than those in MDA-MB-231 xenografts, exhibiting high in vivo targeting specificity. In conclusion, [11C]-pictilisib was first successfully prepared, and it exhibited good potential to identify pictilisib-sensitive tumors noninvasively, which may have a great impact in the treatment of cancers with an overactive PI3K/Akt/mTOR signal pathway. However, the high activity in hepatobiliary system and intestines needs to be addressed.

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Antigen-stimulated Activation of Phospholipase D1b by Rac1, ARF6, and PKCα in RBL-2H3 Cells

Molecular Biology of the Cell ◽

10.1091/mbc.01-05-0235 ◽

2002 ◽

Vol 13 (4) ◽

pp. 1252-1262 ◽

Cited By ~ 58

Author(s):

Dale J. Powner ◽

Matthew N. Hodgkin ◽

Michael J.O. Wakelam

Keyword(s):

Plasma Membrane ◽

Cell Types ◽

Enzyme Activation ◽

Dominant Negative ◽

Ph Domain ◽

Phosphatidylinositol 3 Kinase ◽

Stimulation Of ◽

Phosphatidylinositol 3

Phospholipase D (PLD) activity can be detected in response to many agonists in most cell types; however, the pathway from receptor occupation to enzyme activation remains unclear. In vitro PLD1b activity is phosphatidylinositol 4,5-bisphosphate dependent via an N-terminal PH domain and is stimulated by Rho, ARF, and PKC family proteins, combinations of which cooperatively increase this activity. Here we provide the first evidence for the in vivo regulation of PLD1b at the molecular level. Antigen stimulation of RBL-2H3 cells induces the colocalization of PLD1b with Rac1, ARF6, and PKCα at the plasma membrane in actin-rich structures, simultaneously with cooperatively increasing PLD activity. Activation is both specific and direct because dominant negative mutants of Rac1 and ARF6 inhibit stimulated PLD activity, and surface plasmon resonance reveals that the regulatory proteins bind directly and independently to PLD1b. This also indicates that PLD1b can concurrently interact with a member from each regulator family. Our results show that in contrast to PLD1b's translocation to the plasma membrane, PLD activation is phosphatidylinositol 3-kinase dependent. Therefore, because inactive, dominant negative GTPases do not activate PLD1b, we propose that activation results from phosphatidylinositol 3-kinase–dependent stimulation of Rac1, ARF6, and PKCα.

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Construction and identification of small hairpin RNA plasmids targeting neuropilin-1 gene and their inhibitory effect on human nasopharyngeal carcinoma CNE-2Z cell proliferation in vitro and in vivo

European Archives of Oto-Rhino-Laryngology ◽

10.1007/s00405-015-3873-5 ◽

2016 ◽

Vol 273 (9) ◽

pp. 2541-2547 ◽

Cited By ~ 1

Author(s):

Jin Sun ◽

Liang Wang ◽

Wei-hua Lou ◽

Hua Cao ◽

Xiu-fen Tian ◽

...

Keyword(s):

Cell Proliferation ◽

Nasopharyngeal Carcinoma ◽

Inhibitory Effect ◽

Hairpin Rna ◽

Small Hairpin Rna ◽

Human Nasopharyngeal Carcinoma ◽

Neuropilin 1 ◽

Proliferation In Vitro

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Aquaporins and Fetal Membranes From Diabetic Parturient Women: Expression Abnormalities and Regulation by Insulin

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2015-2057 ◽

2015 ◽

Vol 100 (10) ◽

pp. E1270-E1279 ◽

Cited By ~ 8

Author(s):

Damien Bouvier ◽

Marion Rouzaire ◽

Geoffroy Marceau ◽

Cécile Prat ◽

Bruno Pereira ◽

...

Keyword(s):

Intracellular Signaling ◽

Kinase Inhibitor ◽

Fetal Membranes ◽

Phosphatidylinositol 3 Kinase ◽

Intracellular Signaling Pathway ◽

The Impact ◽

Phosphatidylinositol 3

Context: During pregnancy, aquaporins (AQPs) expressed in fetal membranes are essential for controlling the homeostasis of the amniotic volume, but their regulation by insulin was never explored in diabetic women. Objective: The aim of our study was to investigate the involvement of AQPs 1, 3, 8, and 9 expressed in fetal membranes in diabetic parturient women and the control of their expression by insulin. Design and Participants: From 129 fetal membranes in four populations (controls, type 1, type 2 [T2D], and gestational diabetes [GD]), we established an expression AQP profile. In a second step, the amnion was used to study the control of the expression and functions of AQPs 3 and 9 by insulin. Main Outcomes and Measures: The expression of transcripts and proteins of AQPs was studied by quantitative RT-PCR and ELISA. We analyzed the regulation by insulin of the expression of AQPs 3 and 9 in the amnion. A tritiated glycerol test enabled us to measure the impact of insulin on the functional characteristics. Using an inhibitor of phosphatidylinositol 3-kinase, we analyzed the insulin intracellular signaling pathway. Results: The expression of AQP3 protein was significantly weaker in groups T2D and GD. In nondiabetic fetal membranes, we showed for the amnion (but not for the chorion) a significant repression by insulin of the transcriptional expression of AQPs 3 and 9, which was blocked by a phosphatidylinositol 3-kinase inhibitor. Conclusion: In fetal membranes, the repression of AQP3 protein expression and functions observed in vivo is allowed by the hyperinsulinism described in pregnant women with T2D or GD.

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