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PI3K inhibitor

Michael L Schulte, Matthew R Hight, Gregory D Ayers, Qi Liu, Yu Shyr, M Kay Washington, H Charles Manning
PURPOSE: This study aimed to study whether cancer cells possess distinguishing metabolic features compared with surrounding normal cells, such as increased glutamine uptake. Given this, quantitative measures of glutamine uptake may reflect critical processes in oncology. Approximately, 10 % of patients with colorectal cancer (CRC) express BRAF (V600E) , which may be actionable with selective BRAF inhibitors or in combination with inhibitors of complementary signaling axes. Non-invasive and quantitative predictive measures of response to these targeted therapies remain poorly developed in this setting...
October 21, 2016: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
Eun-Young Nam, Sun Ah Kim, Heejung Kim, Su-Hyun Kim, Jae-Hyun Han, Ju-Hee Lee, Dong-Il Kim
ETHNOPHARMACOLOGICAL RELEVANCE: Evodiae Fructus (EF) is the dried, unripe fruit of Evodia rutaecarpa Benth., and one of the main components of traditional herbal prescriptions issued for the treatment of sterility caused by irregular menstruation in Korea. However, scientific evidence regarding the efficacy and action mechanism of EF is lacking. AIM OF THE STUDY: In this study, the authors established an in vitro screening tool to identify promising new drug candidates in herbal medicines for the prevention and treatment of premature ovarian failure...
October 18, 2016: Journal of Ethnopharmacology
Da-Shi Qi, Jin-Hao Tao, Lian-Qin Zhang, Mei Wang, Rui Qu, Lian-Qin Zhang, Pei Liu, Jian-Cheng Miu, Jing-Yi Ma, Xin-Yu Mei
Cilostazol(CTL) is a phosphodiesterase inhibitor, which has been widely used as anti-platelet agent. It also has preventive effects on various central nervous system (CNS) diseases, including ischemic stroke, Parkinson's disease and Alzheimer disease. However, the molecular mechanism underlying the protective effects of CTL is still unclear, and whether CTL can prevent I/R induced cognitive deficit has not been reported. Transient global brain ischemia was induced by 4-vessel occlusion in adult male Sprague-Dawley rats...
October 18, 2016: Brain Research
Lan Wei, Kuangfa Li, Xueli Pang, Bianqin Guo, Min Su, Yunxiu Huang, Nian Wang, Feihu Ji, Changli Zhong, Junhong Yang, Zhiqian Zhang, Yulin Jiang, Yifeng Liu, Tingmei Chen
BACKGROUND: Accumulating researches have shown that epithelial-mesenchymal transition (EMT) contributes to tumor metastasis. Leptin, a key adipokine secreted from adipocytes, shapes the tumor microenvironment, potentiates the migration of breast cancer cells and angiogenesis, and is also involved in EMT. However, the potential mechanism remains unknown. This study aims to explore the effect of leptin on EMT in breast cancer cells and the underlying mechanism. METHODS: With the assessment of EMT-associated marker expression in MCF-7, SK-BR-3, and MDA-MB-468 cells, the effect of leptin on breast cancer cells was analyzed...
October 21, 2016: Journal of Experimental & Clinical Cancer Research: CR
Yu Liu, Wen-Zhu Wan, Yan Li, Guan-Lian Zhou, Xin-Guang Liu
Phosphatidylinostitol-3-kinase (PI3K) is the potential anticancer target in the PI3K/Akt/ mTOR pathway. Here we reviewed the ATP-competitive small molecule PI3K inhibitors in the past few years, including the pan Class I PI3K inhibitors, the isoform-specific PI3K inhibitors and/or the PI3K/mTOR dual inhibitors.
October 18, 2016: Oncotarget
Silvia Laura Locatelli, Giuseppa Careddu, Giuliano Giuseppe Stirparo, Luca Castagna, Armando Santoro, Carmelo Carlo-Stella
PI3K/AKT and RAF/MEK/ERK pathways are constitutively activated in Hodgkin lymphoma (HL) patients, thus representing attractive therapeutic targets. Here we report that the PI3K/ERK dual inhibitor AEZS-136 induced significant cell proliferation inhibition in L-540, SUP-HD1, KM-H2 and L-428 HL cell lines, but a significant increase in necroptotic cell death was observed only in two out of four cell lines (L-540 and SUP-HD1). In these cells, AEZS-136-induced necroptosis was associated with mitochondrial dysfunction and reactive oxygen species (ROS) production...
October 21, 2016: Scientific Reports
Ming Yang, Haiyong Wang, Mo Zhou, Weilin Liu, Pengqun Kuang, Hao Liang, Qipeng Yuan
Lung cancer is one of the leading causes of cancer death worldwide. Isothiocyanates from cruciferous vegetables been shown to possess anticarcinogenic activities in lung malignances. We previously found sulforaphene (4-methylsufinyl-3-butenyl isothiocyanate, SFE), one new kind of isothiocyanates, existing in a relative high abundance in radish seeds. An efficient methodology based on macroporous resin and preparative high-performance liquid chromatography was developed to isolate SFE in reasonably large quantities, high purity and low cost...
September 28, 2016: Oncotarget
Susan Heavey, Sinead Cuffe, Stephen Finn, Vincent Young, Ronan Ryan, Siobhan Nicholson, Niamh Leonard, Niall McVeigh, Martin Barr, Kenneth O'Byrne, Kathy Gately
Clinical PI3K inhibition has been somewhat disappointing, due to both inadequate patient stratification and compensatory cell signalling through bypass mechanisms. As such, investigation of PI3K-MEK co-targeted inhibition has been recommended. With high mortality rates and a clear need for new therapeutic intervention strategies, non-small cell lung cancer (NSCLC) is an important setting to investigate the effectiveness of this approach.Here, 174 NSCLC tumours were screened for 150 mutations by Fluidigm technology, with 15 patients being profiled for phosphoprotein expression...
October 19, 2016: Oncotarget
Xin-Shuang Yu, Juan Du, Yu-Jun Fan, Feng-Jun Liu, Li-Li Cao, Ning Liang, De-Guo Xu, Jian-Dong Zhang
OBJECTIVE: This study aims to investigate the effects of endoplasmic reticulum stress (ERS) on autophagy, apoptosis and chemoresistance of human small cell lung cancer (SCLC) cells via the PI3K/AKT/mTOR signaling pathway. RESULTS: The expressions of ERS-related proteins (PEAK, eIF2α and CHOP) up-regulated, autophagy-related proteins (LC3, LC3-II and Beclin1) and apoptosis-related proteins (Bax and procaspase-3) down-regulated in NCI-H446 and H69 cells after tunicamycin treatment for 24 h...
October 18, 2016: Oncotarget
Rick Morrison, Zhaohua Zheng, Ian G Jennings, Philip E Thompson, Jasim M A Al-Rawi
To continue our study of 2-morpholino-benzoxazine based compounds, which show useful activity against PI3K family enzymes or antiplatelet activity, we designed and synthesized a series of linear 6.7-fused, 5,6-angular fused and 7,8-angular fused-aryl-morpholino-naphth-oxazines. The compounds were prepared from substituted 2-hydroxynaphthoic acid to give the corresponding thioxo analogues 8, 9, 15 and 19. The thioxo products were then converted to the morpholino substituted analogue. The aryl group was introduced by Suzuki coupling of bromo precursors...
October 5, 2016: Bioorganic & Medicinal Chemistry Letters
Mª Carmen Herrero-Sánchez, Concepción Rodríguez-Serrano, Julia Almeida, Laura San Segundo, Susana Inogés, Ángel Santos-Briz, Jesús García-Briñón, Luis Antonio Corchete, Jesús F San Miguel, Consuelo Del Cañizo, Belén Blanco
BACKGROUND: Graft-versus-host disease (GvHD) remains the major obstacle to successful allogeneic hematopoietic stem cell transplantation, despite of the immunosuppressive regimens administered to control T cell alloreactivity. PI3K/AKT/mTOR pathway is crucial in T cell activation and function and, therefore, represents an attractive therapeutic target to prevent GvHD development. Recently, numerous PI3K inhibitors have been developed for cancer therapy. However, few studies have explored their immunosuppressive effect...
October 20, 2016: Journal of Hematology & Oncology
Anil Prasad, Nagina Khudaynazar, Ramana V Tantravahi, Amanda M Gillum, Benjamin S Hoffman
Squamous cell carcinoma of the head and neck (HNSCC) is characterized by high morbidity and mortality. Treatment failure, drug resistance and chemoradiation toxicity have necessitated the development of alternative treatment strategies. Styryl benzyl sulfones, a family of novel small molecule inhibitors, are being evaluated as anti-neoplastic agents in multiple clinical trials. The activity of these compounds has been well characterized in several preclinical tumor studies, but their activity has yet to be fully examined in HNSCC...
October 15, 2016: Oncotarget
Gang Bao, Chuankun Li, Lei Qi, Ning Wang, Baixiang He
Tetrandrine (TET) is a bis-benzylisoquinoline alkaloid, which is isolated from a Chinese medicinal herb with antioxidant and anti-inflammatory activities. In this study, we investigated the effects of TET on oxygen-glucose-serum deprivation/reoxygenation (OGSD/R)-induced injury in rat spinal cord astrocytes, which mimics hypoxic/ischemic conditions in vivo. MTT and LDH assays indicated that cell viability was distinctly reduced and LDH leakage was elevated after OGSD/R exposure, which were dose-dependently reversed by pretreatment with TET (0...
October 17, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Leonardo Romorini, Ximena Garate, Gabriel Neiman, Carlos Luzzani, Verónica Alejandra Furmento, Alejandra Sonia Guberman, Gustavo Emilio Sevlever, María Elida Scassa, Santiago Gabriel Miriuka
Human embryonic and induced pluripotent stem cells are self-renewing pluripotent stem cells (PSC) that can differentiate into a wide range of specialized cells. Basic fibroblast growth factor is essential for PSC survival, stemness and self-renewal. PI3K/AKT pathway regulates cell viability and apoptosis in many cell types. Although it has been demonstrated that PI3K/AKT activation by bFGF is relevant for PSC stemness maintenance its role on PSC survival remains elusive. In this study we explored the molecular mechanisms involved in the regulation of PSC survival by AKT...
October 20, 2016: Scientific Reports
Liping Liu, Tiedong Sun, Feng Xin, Wei Cui, Jianquan Guo, Jian Hu
AIMS: To study whether autophagy participates in the neuroprotective effect of nerve growth factor (NGF) on neurons treated with alcohol. METHODS: The autophagy-related markers were used to explore the role of autophagy in PC12 cells exposed to alcohol or pre-incubated with NGF before initiating the treatment with alcohol (100 mM; 6 h). PC12 cells were pre-incubated with 3-methyladenine (3-MA) (10 mM; 1 h) or rapamycin (100 nM; 1 h) before co-incubated with alcohol (100 mM; 6 h) in order to investigate the relationship between apoptosis and autophagy...
October 19, 2016: Alcohol and Alcoholism: International Journal of the Medical Council on Alcoholism
David R Driscoll, Saadia A Karim, Makoto Sano, David M Gay, Wright Jacob, Jun Yu, Yusuke Mizukami, Aarthi Gopinathan, Duncan I Jodrell, T R Jeffry Evans, Nabeel Bardeesy, Michael N Hall, Brian J Quattrochi, David S Klimstra, Simon T Barry, Owen J Sansom, Brian C Lewis, Jennifer P Morton
mTOR signaling controls several critical cellular functions and is deregulated in many cancers, including pancreatic cancer. To date, most efforts have focused on inhibiting the mTORC1 complex. However, clinical trials of mTORC1 inhibitors in pancreatic cancer have failed, raising questions about this therapeutic approach. We employed a genetic approach to delete the obligate mTORC2 subunit Rictor and identified the critical times during which tumorigenesis requires mTORC2 signaling. Rictor deletion resulted in profoundly delayed tumorigenesis...
October 6, 2016: Cancer Research
Xiang-Jun Tang, Kuan-Ming Huang, Hui Gui, Jun-Jie Wang, Jun-Ti Lu, Long-Jun Dai, Li Zhang, Gang Wang
As one of the natural herbal flavonoids, myricetin has attracted much research interest, mainly owing to its remarkable anticancer properties and negligible side effects. It holds great potential to be developed as an ideal anticancer drug through improving its bioavailability. This study was performed to investigate the effects of Pluronic-based micelle encapsulation on myricetin-induced cytotoxicity and the mechanisms underlying its anticancer properties in human glioblastoma cells. Cell viability was assessed using a methylthiazol tetrazolium assay and a real-time cell analyzer...
2016: International Journal of Nanomedicine
Jeffrey D Cooney, Ricardo C T Aguiar
Phosphodiesterase 4 (PDE4) inhibition restores the suppressive effects of cyclic-AMP in lymphocytes. In this concise review, we detail how PDE4 inhibition downmodulates the B-cell receptor (BCR)-related kinases SYK and PI3K, inhibits VEGFA secretion by tumor cells, inducing cancer cell apoptosis and blocking angiogenesis in the microenvironment. We describe the successful clinical repurposing of PDE4 inhibitors in B-cell malignancies, and propose that given their anti-inflammatory/immunomodulatory activity, these agents will suppress BCR signals without the toxicity associated with other targeted biological doublets...
October 18, 2016: Blood
Qi Zhang, Manyi Yang, Zhan Qu, Jixiang Zhou, Qin Jiang
Molecule-targeted therapy has become the research focus for hepatocellular carcinoma (HCC). Persistent PI3K-AKT activation is often detected in HCC, representing a valuable oncotarget for treatment. Here, we tested the anti-HCC activity by a potent AKT inhibitor: AKT inhibitor 1/2 (AKTi-1/2). In both established (HepG2 and Huh-7) and primary human HCC cells, treatment with AKTi-1/2 inhibited cell survival and proliferation, but induced cell apoptosis. AKTi-1/2 blocked AKT-mTOR activation, yet simultaneously provoked cytoprotective autophagy in HCC cells...
October 15, 2016: Biochemical and Biophysical Research Communications
X Liu, X Zhang, K Ma, R Zhang, P Hou, B Sun, S Yuan, Z Wang, Z Liu
Matrine is a quinolizidine alkaloid derived from the herb Radix Sophorae Flavescentis, and possesses anti-oxidant, anti-inflammatory and anti-tumoral properties. However, its effectiveness against subarachnoid hemorrhage (SAH) is not well known. In this study, we investigated the effects of matrine on early brain injury (EBI) and the related potential mechanisms following SAH in rats. Our results showed that matrine pretreatment partially alleviated SAH-induced EBI, including neurological deficit, severity of SAH grade, brain edema, and blood-brain barrier (BBB) disruption in rats...
September 30, 2016: Cellular and Molecular Biology
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