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https://www.readbyqxmd.com/read/28535439/critical-focus-on-mechanisms-of-resistance-and-toxicity-of-m-tor-inhibitors-in-pancreatic-neuroendocrine-tumors
#1
REVIEW
L Antonuzzo, M Del Re, V Barucca, F Spada, G Meoni, G Restante, R Danesi, F Di Costanzo, N Fazio
Pancreatic neuroendocrine tumors (pNETs) are rare neoplasms representing less than 2% of all pancreatic malignancies. The PI3K-AKT-mTOR pathway is often deregulated in pNETs and seems to play a key role in tumorigenesis. Everolimus, an inhibitor of the mTOR pathway, has demonstrated efficacy in the treatment of pNETs. Nevertheless de novo or acquired drug resistance is responsible for disease progression and represents a major obstacle to overcome by clinicians. Blocking the PI3K/AKT/mTOR pathway may cover the supposed main mechanisms of resistance to everolimus...
May 11, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28535181/everolimus-with-paclitaxel-and-carboplatin-as-first-line-treatment-for-metastatic-large-cell-neuroendocrine-lung-carcinoma-a-multicenter-phase-ii-trial
#2
P Christopoulos, W Engel-Riedel, C Grohé, C Kropf-Sanchen, J von Pawel, S Gütz, J Kollmeier, W Eberhardt, D Ukena, V Baum, I Nimmrich, C Sieder, P A Schnabel, M Serke, M Thomas
Background: Large cell neuroendocrine carcinoma of the lung (LCNEC) is a rare disease with poor prognosis and limited treatment options. Neuroendocrine tumors frequently show overactivation of the mTOR pathway. Based on the good activity of the mTOR inhibitor everolimus in different types of neuroendocrine tumors and the results of a previous phase I trial we evaluated the efficacy and safety of everolimus in combination with carboplatin and paclitaxel as upfront treatment for patients with advanced LCNEC...
May 23, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28534368/study-on-the-molecular-mechanism-of-rac3-on-regulating-autophagy-in-human-lung-cancer-cells
#3
Xuyang Xiao, Gebang Wang, Hongxu Liu
PURPOSE: Rac3 plays an important role in regulating tumorigenesis. Autophagy plays a vital role in tumorigenesis and tumor progression. The relationship between the two remains unclear. The objective of the present study was to determine the specific molecular mechanism of intracellular Rac3 in regulating autophagy and reveal the relationship between tumor cell autophagy and apoptosis. METHODS: A laser confocal microscope was used to photograph the accumulated EGFP-MAP1LC3 spots for investigating the relationship between Rac3 and autophagy at the cellular level...
March 2017: Journal of B.U.ON.: Official Journal of the Balkan Union of Oncology
https://www.readbyqxmd.com/read/28533436/metformin-synergizes-with-bcl-xl-bcl-2-inhibitor-abt-263-to-induce-apoptosis-specifically-in-p53-defective-cancer-cells
#4
Xinzhe Li, Bo Li, Zhenhong Ni, Peng Zhou, Bin Wang, Jintao He, Haojun Xiong, Fan Yang, Yaran Wu, Xilin Lyu, Yan Zhang, Yijun Zeng, Jiqin Lian, Fengtian He
p53 deficiency, a frequent event in multiple kinds of malignancies, decreases the sensitivity of diverse targeted chemotherapeutics including the BCL-XL/BCL-2 inhibitor ABT-263. Loss of p53 function can activate mTOR complex 1 (mTORC1), which may make it a vulnerable target. Metformin has shown anti-neoplastic efficiency partially through suppressing mTORC1. However, it remains unknown whether mTORC1 activation confers ABT-263 resistance and whether metformin can overcome it in the p53-defective contexts. In this study, we for the first time demonstrated that metformin and ABT-263 synergistically elicited remarkable apoptosis through orchestrating the pro-apoptotic machineries in various p53-defective cancer cells...
May 22, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28532580/sirt1-ameliorates-systemic-sclerosis-by-targeting-the-mtor-pathway
#5
Xiaoxia Zhu, Haiyan Chu, Shuai Jiang, Qingmei Liu, Lei Liu, Yu Xue, Shucong Zheng, Weiguo Wan, Jianhua Qiu, Jiucun Wang, Hejian Zou
BACKGROUND: Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by inflammation and fibrosis. Our previous research has indicated that Sirtuin1 (Sirt1) plays a role in the regulation of TNF-α-induced inflammation; however, whether Sirt1 may inhibit the progress of SSc by blocking inflammation remains unknown. OBJECTIVE: We aimed to investigate the function of Sirt1 in SSc. METHODS: The function and its mechanism of Sirt1 were evaluated in fibroblasts or scleroderma mice...
May 3, 2017: Journal of Dermatological Science
https://www.readbyqxmd.com/read/28530127/an-oncolytic-adenovirus-expressing-snord44-and-gas5-exhibits-anti-tumor-effect-in-colorectal-cancer-cells
#6
Sujing Yuan, Yu Wu, Yigang Wang, Jianhua Chen, Liang Chu
SNORD44 is a C/D box small nucleolar RNA, and low expresses in breast cancer and head and neck squamous cell carcinoma tissues. Its host gene is growth arrest specific transcript 5 (GAS5), which is a long noncoding RNA. GAS5 is down-regulated in colorectal cancer (CRC), and overexpression of GAS5 suppresses cell proliferation. However, the function of SNORD44 in CRC remains largely unknown, and the application of SNORD44 combined with GAS5 in CRC treatment has not been reported. In this study, the expression levels of SNORD44 and GAS5 were measured in CRC tissues by qRT-PCR...
May 20, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28529994/rapamycin-increases-length-and-mechanosensory-function-of-primary-cilia-in-renal-epithelial-and-vascular-endothelial-cells
#7
Rinzhin T Sherpa, Kimberly F Atkinson, Viviana P Ferreira, Surya M Nauli
Primary cilia arebiophysically-sensitive organelles responsible for sensing fluid-flow and transducing this stimulus into intracellular responses. Previous studies have shown that the primary cilia mediate flow-induced calcium influx, and sensitivity of cilia function to flow is correlated to cilia length. Cells with abnormal cilia length or function can lead to a host of diseases that are collectively termed as ciliopathies. Rapamycin, a potent inhibitor of mTOR (mammalian target of rapamycin), has been demonstrated to be a potential pharmacological agent against the aberrant mTOR signaling seen in ciliopathies such as polycystic kidney disease (PKD) and tuberous sclerosis complex (TSC)...
December 2016: Int Educ Res J
https://www.readbyqxmd.com/read/28529550/hormonoresistance-in-advanced-breast-cancer-a-new-revolution-in-endocrine-therapy
#8
REVIEW
Paule Augereau, Anne Patsouris, Emmanuelle Bourbouloux, Carole Gourmelon, Sophie Abadie Lacourtoisie, Dominique Berton Rigaud, Patrick Soulié, Jean Sebastien Frenel, Mario Campone
Endocrine therapy is the mainstay of treatment of estrogen-receptor-positive (ER+) breast cancer with an overall survival benefit. However, some adaptive mechanisms in the tumor emerge leading to the development of a resistance to this therapy. A better characterization of this process is needed to overcome this resistance and to develop new tailored therapies. Mechanisms of resistance to hormone therapy result in activation of transduction signal pathways, including the cell cycle regulation with cyclin D/CDK4/6/Rb pathway...
May 2017: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/28528184/synergistic-antitumor-effect-of-nvp-bez235-and-cape-on-mda-mb-231-breast-cancer-cells
#9
Samira Torki, Amin Soltani, Hedayatollah Shirzad, Nafiseh Esmaeil, Mahdi Ghatrehsamani
Triple negative breast cancer (TNBC) is the most lethal and aggressive kind of breast cancer. Studies with TNBC cells suggest that tumor environmental cytokines such as Transforming Growth Factor β1 (TGF-β1) have important roles in tumors fate. In the present study, we aimed to investigate, the effect of phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway dual inhibitor, NVP-BEZ235 and Caffeic acid phenyl ester (CAPE) on TNBC cell line (MDA-MB-231), stimulated with TGF-β1 for 14days in vitro...
May 18, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28528119/autophagy-plays-a-dual-role-during-intracellular-sirna-delivery-by-lipoplex-and-polyplex-nanoparticles
#10
Wen Song, Zhiwei Ma, Yumei Zhang, Chuanxu Yang
Growing evidence indicates that autophagy plays a vital role during the intracellular DNA delivery mediated by lipoplex and polyplex nanoparticles. However, autophagy in intracellular siRNA delivery has not been well understood. In this study, lipofectamine 2000 and chitosan were used to formulate lipoplex and polyplex with siRNA for systematically investigating the interplay between siRNA delivery and autophagy. After transfection of H1299 cells with lipoplex and polyplex, the number of autophagic vacuoles was increased significantly indicated by the accumulation of monodansylcadaverine (MDC) staining...
May 17, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28526540/sodium-dependent-glucose-transporters-sglt-in-human-ischemic-heart-a-new-potential-pharmacological-target
#11
Alessandra Di Franco, Giulia Cantini, Alessia Tani, Raffaele Coppini, Sandra Zecchi-Orlandini, Laura Raimondi, Michaela Luconi, Edoardo Mannucci
BACKGROUND: Empagliflozin is reported to reduce cardiovascular mortality and the rate of hospitalization for heart failure in type 2 diabetic patients with prior cardiovascular events. The mechanisms underlying the cardiac effects of this sodium/glucose transporter 2 (SGT2) inhibitor have not yet been clarified, though a direct action of the drug on the cardiomyocytes could be hypothesized. The aim of the present study is to assess the relative expression of SGLT2 and SGLT1, the two most relevant members of the SGLT family being potentially responsive to empagliflozin, in normal, ischemic and hypertrophic human hearts...
May 9, 2017: International Journal of Cardiology
https://www.readbyqxmd.com/read/28524213/-update-on-the-treatment-of-rasopathies
#12
A Duat-Rodriguez, A Hernandez-Martin
INTRODUCTION: The term 'RASopathies' covers a series of diseases that present mutations in the genes that code for the proteins of the RAS/MAPK pathway. These diseases include neurofibromatosis type 1, Noonan syndrome, Legius syndrome, LEOPARD syndrome, Costello syndrome and cardiofaciocutaneous syndrome. Involvement of the RAS/MAPK pathway not only increases predisposition to develop tumours, but also determines the presence of phenotypic anomalies and alterations in learning processes...
May 17, 2017: Revista de Neurologia
https://www.readbyqxmd.com/read/28524116/inhibition-of-autophagy-promotes-salinomycin-induced-apoptosis-via-reactive-oxygen-species-mediated-pi3k-akt-mtor-and-erk-p38-mapk-dependent-signaling-in-human-prostate-cancer-cells
#13
Kwang-Youn Kim, Kwang-Il Park, Sang-Hun Kim, Sun-Nyoung Yu, Sul-Gi Park, Young Woo Kim, Young-Kyo Seo, Jin-Yeul Ma, Soon-Cheol Ahn
Recently, the interplay between autophagy and apoptosis has become an important factor in chemotherapy for cancer treatment. Inhibition of autophagy may be an effective strategy to improve the treatment of chemo-resistant cancer by consistent exposure to chemotherapeutic drugs. However, no reports have clearly elucidated the underlying mechanisms. Therefore, in this study, we assessed whether salinomycin, a promising anticancer drug, induces apoptosis and elucidated potential antitumor mechanisms in chemo-resistant prostate cancer cells...
May 18, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28523933/the-pazoreal-noninterventional-study-to-assess-effectiveness-and-safety-of-pazopanib-and-everolimus-in-the-changing-metastatic-renal-cell-carcinoma-treatment-landscape
#14
Peter J Goebell, Christian Doehn, Carsten Grüllich, Viktor Grünwald, Thomas Steiner, Rainer Ehneß, Manfred Welslau
VEGFR and mTOR inhibitors are broadly used in metastatic renal cell carcinoma (mRCC) therapy, and sequential first-line pazopanib (VEGFR inhibitor) and second-line everolimus (mTOR inhibitor) is a standard treatment option. Nivolumab and lenvatinib/everolimus combination was recently approved in Europe for use in mRCC after previous therapy. Prospective routine data on sequential therapy including nivolumab and/or lenvatinib are missing. This is a prospective, noninterventional study, which evaluates the effectiveness, tolerability, safety and quality of life following 450 patients with mRCC starting either on pazopanib as first-line therapy or third-line everolimus plus/minus lenvatinib following nivolumab...
May 19, 2017: Future Oncology
https://www.readbyqxmd.com/read/28522586/antitumor-synergism-and-enhanced-survival-with-a-tumor-vasculature-targeted-enzyme-prodrug-system-rapamycin-and-cyclophosphamide
#15
John J Krais, Needa Virani, Partick H McKernan, Quang Nguyen, Kar-Ming Fung, Vassilios I Sikavitsas, Carla D Kurkjian, Roger G Harrison
Mutant cystathionine gamma-lyase was targeted to phosphatidylserine exposed on tumor vasculature through fusion with annexin A1 or annexin A5.  Cystathionine gamma-lyase E58N, R118L, and E338N mutations impart non-native methionine gamma-lyase activity, resulting in tumor-localized generation of highly toxic methylselenol upon systemic administration of non-toxic selenomethionine.  The described therapeutic system circumvents systemic toxicity issues using a novel drug delivery/generation approach and avoids the administration of non-native proteins and/or DNA required with other enzyme prodrug systems...
May 18, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28522584/cooperative-targets-of-combined-mtor-hdac-inhibition-promote-myc-degradation
#16
John K Simmons, Aleksandra M Michalowski, Benjamin J Gamache, Wendy DuBois, Jyoti Patel, Ke Zhang, Joy Gary, Shuling Zhang, Snehal Gaikwad, Daniel Connors, Nicholas Watson, Elena Leon, Jin-Qiu Chen, W Michael Kuehl, Maxwell P Lee, Adriana Zingone, Ola Landgren, Peter Ordentlich, Jing Huang, Beverly A Mock
Cancer treatments often require combinations of molecularly targeted agents to be effective. mTORi (rapamycin) and HDACi (MS-275/entinostat) inhibitors have been shown to be effective in limiting tumor growth, and here we define part of the cooperative action of this drug combination. More than 60 human cancer cell lines responded synergistically (CI<1) when treated with this drug combination compared to single agents.  In addition, a breast cancer patient-derived xenograft, and a BCL-XL plasmacytoma mouse model both showed enhanced responses to the combination compared to single agents...
May 18, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28520214/mtorc1-inhibits-nf-%C3%AE%C2%BAb-nfatc1-signaling-and-prevents-osteoclast-precursor-differentiation-in-vitro-and-in-mice
#17
Yue Zhang, Song Xu, Kai Li, Kang Tan, Kangyan Liang, Jian Wang, Junhui Shen, Wenchong Zou, Le Hu, Daozhang Cai, Changhai Ding, Mangmang Li, Guozhi Xiao, Bin Liu, Anling Liu, Xiaochun Bai
The mechanistic target of rapamycin complex 1 (mTORC1) is a critical sensor for bone homeostasis and bone formation; however, the role of mTORC1 in osteoclast development and the underlying mechanisms have not yet been fully established. Here, we found that mTORC1 activity declined during osteoclast precursors differentiation in vitro and in vivo. We further targeted deletion of Raptor (mTORC1 key component) or Tsc1 (mTORC1 negative regulator) to constitutively inhibit or activate mTORC1 in osteoclast precursors (monocytes/macrophages), using LyzM-cre mice...
May 18, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/28518408/s-adenosylmethionine-mediated-apoptosis-is-potentiated-by-autophagy-inhibition-induced-by-chloroquine-in-human-breast-cancer-cells
#18
Donatella Delle Cave, Vincenzo Desiderio, Laura Mosca, Concetta Paola Ilisso, Luigi Mele, Michele Caraglia, Giovanna Cacciapuoti, Marina Porcelli
The naturally-occurring sulfonium compound S-adenosyl-L-methionine (AdoMet) is an ubiquitous sulfur-nucleoside that represents the main methyl donor in numerous methylation reactions. In recent years, it has been shown that AdoMet possesses antiproliferative properties in various cancer cells, but the molecular mechanisms at the basis of the effect induced by AdoMet have been only in part investigated. In the present study, we found that AdoMet strongly inhibited the proliferation of breast cancer cells MCF-7 by inducing both autophagy and apoptosis...
May 18, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28518150/cycloheximide-promotes-paraptosis-induced-by-inhibition-of-cyclophilins-in-glioblastoma-multiforme
#19
Lin Wang, Justin H Gundelach, Richard J Bram
Cancer is the second leading cause of death worldwide. Current treatment strategies based on multi-agent chemotherapy and/or radiation regimens have improved overall survival in some cases. However, resistance to apoptosis often develops in cancer cells, and its occurrence is thought to contribute to treatment failure. Non-apoptotic cell death mechanisms have become of great interest, therefore, in hopes that they would bypass tumor cell resistance. Glioblastoma multiforme (GBM), a grade IV astrocytic tumor is the most frequent brain tumor in adults, and has a high rate of mortality...
May 18, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28514765/bmx-etk-promotes-cell-proliferation-and-tumorigenicity-of-cervical-cancer-cells-through-pi3k-akt-mtor-and-stat3-pathways
#20
Yuanyuan Li, Nan Cui, Peng-Sheng Zheng, Wen-Ting Yang
Bone marrow X-linked kinase (BMX, also known as Etk) has been reported to be involved in cell proliferation, differentiation, apoptosis, migration and invasion in several types of tumors, but its role in cervical carcinoma remains poorly understood. In this study, we showed that BMX expression exhibits a gradually increasing trend from normal cervical tissue to cervical cancer in situ and then to invasive cervical cancer tissue. Through BMX-IN-1, a potent and irreversible BMX kinase inhibitor, inhibited the expression of BMX, the cell proliferation was significantly decreased...
April 27, 2017: Oncotarget
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