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gemcitabine resistance

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https://www.readbyqxmd.com/read/28814832/combinatorial-and-sequential-delivery-of-gemcitabine-and-oseltamivir-phosphate-from-implantable-poly-d-l-lactic-co-glycolic-acid-cylinders-disables-human-pancreatic-cancer-cell-survival
#1
Stephanie Allison Logan, Amanda J Brissenden, Myron R Szewczuk, Ronald J Neufeld
Combination therapies against multiple targets are currently being developed to prevent resistance to a single chemotherapeutic agent and to extirpate pre-existing resistance in heterogeneous cancer cells in tumors due to selective pressure from the single agent. Gemcitabine (GEM), a chemotherapeutic agent, is the current standard of care for patients with pancreatic cancer. Patients with pancreatic cancer receiving GEM have a low progression-free survival. Given the poor response rate to GEM, cancer cells are known to develop rapid resistance to this drug...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28811332/de-novo-lipid-synthesis-facilitates-gemcitabine-resistance-through-endoplasmic-reticulum-stress-in-pancreatic-cancer
#2
Saber Tadros, Surendra K Shukla, Ryan J King, Venugopal Gunda, Enza Vernucci, Jaime Abrego, Nina CHaika, Fang Yu, Audrey J Lazenby, Lyudmyla Berim, Jean L Grem, Aaron Sasson, Pankaj K Singh
Pancreatic adenocarcinoma is moderately responsive to gemcitabine-based chemotherapy, the most widely used single agent therapy for pancreatic cancer. While the prognosis in pancreatic cancer remains grim in part due to poor response to therapy, previous attempts at identifying and targeting the resistance mechanisms have not been very successful. By leveraging TCGA dataset, we identified lipid metabolism as the metabolic pathway that most significantly correlated with poor gemcitabine response in pancreatic cancer patients...
August 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28808038/the-phosphatidylinositol-3-kinase-pathway-as-a-potential-therapeutic-target-in-bladder-cancer
#3
Shuxiong Zeng, Yanjun Zhu, Ai-Hong Ma, Weimin Yu, Hongyong Zhang, Tzu-Yin Lin, Wei Shi, Clifford G Tepper, Paul T Henderson, Susan Airhart, Jianming Guo, Chuanliang Xu, Ralph de Vere White, Chong-Xian Pan
PURPOSE: Activation of the phosphatidylinositol 3-kinase (PI3K) pathway occurs in over 40% of bladder urothelial cancers. The aim of this study is to determine the therapeutic potential, the underlying action and resistant mechanisms of drugs targeting the PI3K pathway. EXPERIMENTAL DESIGN: Urothelial cancer cell lines and patient-derived xenografts (PDXs) were analyzed for alterations of the PI3K pathway and for their sensitivity to the small molecule inhibitor pictilisib alone and in combination with cisplatin and/or gemcitabine...
August 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28801576/disrupting-glutamine-metabolic-pathways-to-sensitize-gemcitabine-resistant-pancreatic-cancer
#4
Ru Chen, Lisa A Lai, Yumi Sullivan, Melissa Wong, Lei Wang, Jonah Riddell, Linda Jung, Venu G Pillarisetty, Teresa A Brentnall, Sheng Pan
Pancreatic cancer is a lethal disease with poor prognosis. Gemcitabine has been the first line systemic treatment for pancreatic cancer. However, the rapid development of drug resistance has been a major hurdle in gemcitabine therapy leading to unsatisfactory patient outcomes. With the recent renewed understanding of glutamine metabolism involvement in drug resistance and immuno-response, we investigated the anti-tumor effect of a glutamine analog (6-diazo-5-oxo-L-norleucine) as an adjuvant treatment to sensitize chemoresistant pancreatic cancer cells...
August 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28797284/gambogic-acid-sensitizes-gemcitabine-efficacy-in-pancreatic-cancer-by-reducing-the-expression-of-ribonucleotide-reductase-subunit-m2-rrm2
#5
Guanggai Xia, Hongcheng Wang, Ziliang Song, Qingcai Meng, Xiuyan Huang, Xinyu Huang
BACKGROUND: Pancreatic cancer is susceptible to gemcitabine resistance, and patients receive less benefit from gemcitabine chemotherapy. Previous studies report that gambogic acid possesses antineoplastic properties; however, to our knowledge, there have been no specific studies on its effects in pancreatic cancer. Therefore, the purpose of this study was to explore whether increases the sensitivity of pancreatic cancer to gemcitabine, and determine the synergistic effects of gambogic acid and gemcitabine against pancreatic cancer...
August 10, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28796151/potential-development-of-tumor-targeted-oral-anti-cancer-prodrugs-amino-acid-and-dipeptide-monoester-prodrugs-of-gemcitabine
#6
Yasuhiro Tsume, Adam J Drelich, David E Smith, Gordon L Amidon
One of the main obstacles for cancer therapies is to deliver medicines effectively to target sites. Since stroma cells are developed around tumors, chemotherapeutic agents have to go through stroma cells in order to reach tumors. As a method to improve drug delivery to the tumor site, a prodrug approach for gemcitabine was adopted. Amino acid and dipeptide monoester prodrugs of gemcitabine were synthesized and their chemical stability in buffers, resistance to thymidine phosphorylase and cytidine deaminase, antiproliferative activity, and uptake/permeability in HFF cells as a surrogate to stroma cells were determined and compared to their parent drug, gemcitabine...
August 10, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28795274/novel-gemcitabine-conjugated-albumin-nanoparticles-a-potential-strategy-to-enhance-drug-efficacy-in-pancreatic-cancer-treatment
#7
Varun Kushwah, Ashish Kumar Agrawal, Chander Parkash Dora, David Mallinson, Dimitrios A Lamprou, Ramesh C Gupta, Sanyog Jain
PURPOSE: The present study reports a novel conjugate of gemcitabine (GEM) with bovine serum albumin (BSA) and thereof nanoparticles (GEM-BSA NPs) to potentiate the therapeutic efficacy by altering physicochemical properties, improving cellular uptake and stability of GEM. METHODS: The synthesized GEM-BSA conjugate was extensively characterized by NMR, FTIR, MALDI-TOF and elemental analysis. Conjugation mediated changes in structural conformation and physicochemical properties were analysed by fluorescence, Raman and CD spectroscopy, DSC and contact angle analysis...
August 9, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28793246/endoglin-is-essential-for-the-maintenance-of-self-renewal-and-chemoresistance-in-renal-cancer-stem-cells
#8
Junhui Hu, Wei Guan, Peijun Liu, Jin Dai, Kun Tang, Haibing Xiao, Yuan Qian, Allison C Sharrow, Zhangqun Ye, Lily Wu, Hua Xu
Renal cell carcinoma (RCC) is a deadly malignancy due to its tendency to metastasize and resistance to chemotherapy. Stem-like tumor cells often confer these aggressive behaviors. We discovered an endoglin (CD105)-expressing subpopulation in human RCC xenografts and patient samples with a greater capability to form spheres in vitro and tumors in mice at low dilutions than parental cells. Knockdown of CD105 by short hairpin RNA and CRISPR/cas9 reduced stemness markers and sphere-formation ability while accelerating senescence in vitro...
August 8, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28778071/suppression-of-pancreatic-adenocarcinoma-upregulated-factor-pauf-increases-the-sensitivity-of-pancreatic-cancer-to-gemcitabine-and-5fu-and-inhibits-the-formation-of-pancreatic-cancer-stem-like-cells
#9
Jae Hee Cho, Sun A Kim, Soo Been Park, Hee Man Kim, Si Young Song
Pancreatic cancer stem cells (CSCs) play a crucial role in tumorigenesis and chemoresistance of pancreatic ductal adenocarcinoma. Pancreatic adenocarcinoma up-regulated factor (PAUF), a novel secretory protein, has been shown to contribute to cancer progression and metastasis. Because the clinical relationship between PAUF and pancreatic CSCs is largely unknown, we investigated the associations between the functional role of PAUF and pancreatic CSCs. Pancreatic cancer sphere cultured from the CFPAC-1 cells showed elevated expression of PAUF and pluripotent stemness genes (Oct4, Nanog, Stat3, and Sox2), and the mRNA of PAUF were increased in CD44+CD24+ESA+ pancreatic CSCs...
July 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28777668/therapeutic-tumor-control-of-her2-dna-vaccines-is-achieved-by-an-alteration-of-tumor-cells-and-tumor-microenvironment-by-gemcitabine-and-anti-gr-1-ab-treatment-in-a-her2-expressing-tumor-model
#10
Sayyed Nilofar Danishmalik, Jeong-Im Sin
Therapeutic control of tumors is challenging as they tend to alter their biological functions and microenvironment. In a CT26/HER2 tumor model, HER2 DNA vaccines and even anti-PD-L1 Abs failed to display antitumor therapeutic activity while inducing Ag-specific cytotoxic T lymphocyte (CTL) activity. To clarify this contradictory finding, we selected tumor cells (CT26/HER2-1) from one tumor-bearing animal in the therapeutic model. CT26/HER2-1 cells behaved similar to wild-type CT26/HER2 cells in their HER2 expression, immune cell stimulation for IFN-γ production, and antitumor immune sensitivity...
August 4, 2017: DNA and Cell Biology
https://www.readbyqxmd.com/read/28774899/89zr-anti-%C3%AE-h2ax-tat-but-not-18f-fdg-allows-early-monitoring-of-response-to-chemotherapy-in-a-mouse-model-of-pancreatic-ductal-adenocarcinoma
#11
James C Knight, Michael J Mosley, Luisa Contreras Bravo, Veerle Kersemans, Philip D Allen, Somnath Mukherjee, Eric O'Neill, Bart Cornelissen
Purpose: Late-stage, unresectable pancreatic ductal adenocarcinoma (PDAC) is largely resistant to chemotherapy and consequently has a very poor 5-year survival rate of < 5%. The ability to assess the efficacy of a treatment soon after its initiation would enable rapid switching to potentially more effective therapies if the current treatment is found to be futile. We have evaluated the ability of the PET imaging agent, (89)Zr-anti-γH2AX-TAT, to monitor DNA damage in response to fluouracil (5-FU), gemcitabine, or capecitabine treatment in a mouse model of pancreatic cancer...
August 3, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28765935/fbw7-increases-the-chemosensitivity-of-pancreatic-cancer-cells-to-gemcitabine-through-upregulation-of-ent1
#12
Qiangsheng Hu, Yi Qin, Bo Zhang, Chen Liang, Shunrong Ji, Si Shi, Wenyan Xu, Jinfeng Xiang, Dingkong Liang, Quanxing Ni, Xianjun Yu, Jin Xu
F-box and WD repeat domain-containing 7 (FBW7) has been characterized as a tumor suppressor, and its mutation or decreased expression has been observed in many types of human cancers. Our recent studies have uncovered that in pancreatic cancer, the KRAS mutation decreased FBW7 expression through phosphorylation and subsequent ubiquitination. Moreover, FBW7 inhibited aerobic glycolysis in pancreatic cancer via induction of thioredoxin-interacting protein (TXNIP), a mitochondrial localized tumor suppressor. The roles of FBW7 in anti-apoptosis and drug resistance via proteosomal degradation of myeloid cell leukemia-1 (MCL-1), which is an anti-apoptotic factor have been reported...
July 28, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28765154/gemcitabine-induced-timp1-attenuates-therapy-response-and-promotes-tumor-growth-and-liver-metastasis-in-pancreatic-cancer
#13
Zenobia D'Costa, Keaton Jones, Abul Azad, Ruud van Stiphout, Su Y Lim, Ana L Gomes, Paul Kinchesh, Sean C Smart, W Gillies McKenna, Francesca M Buffa, Owen J Sansom, Ruth J Muschel, Eric O'Neill, Emmanouil Fokas
Gemcitabine constitutes one of the backbones for chemotherapy treatment in pancreatic ductal adenocarcinoma (PDAC), but patients often respond poorly to this agent. Molecular markers downstream of gemcitabine treatment in pre-clinical models may provide an insight into resistance mechanisms. Using cytokine arrays, we identified potential secretory biomarkers of gemcitabine resistance (response) in the transgenic KRasG12D; Trp53R172H; Pdx-1 Cre (KPC) mouse model of PDAC. We verified the oncogenic role of the cytokine tissue inhibitor of matrix metalloproteinases 1 (TIMP1) in primary pancreatic tumors and metastases using both in vitro techniques and animal models...
August 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/28743280/exosomes-derived-from-gemcitabine-resistant-cells-transfer-malignant-phenotypic-traits-via-delivery-of-mirna-222-3p
#14
Feng Wei, Chengyuan Ma, Tong Zhou, Xuechao Dong, Qinghua Luo, Li Geng, Lijuan Ding, Yandong Zhang, Li Zhang, Nan Li, Yang Li, Yan Liu
BACKGROUND: Although gemcitabine-based chemotherapy has been established as a core multimodal therapy for non-small cell lung cancer (NSCLC) treatment, its clinical efficacy remains limited by the development of acquired resistance following tumor metastasis and relapse. In this study, we investigated how gemcitabine-resistant (GR) cells contribute to the development of NSCLC tumor malignancy via exosome-mediated transfer of microRNAs. METHODS: We first studied the mechanism of exosome internalization via PKH-67 staining and an immunofluorescence assay, then confirmed our finding by transmission electron microscopy and western blot analysis...
July 25, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28738680/photothermal-effect-enhanced-cascade-targeting-strategy-for-improved-pancreatic-cancer-therapy-by-gold-nanoshell-mesoporous-silica-nanorod
#15
Ruifang Zhao, Xuexiang Han, Yiye Li, Hai Wang, Tianjiao Ji, Yuliang Zhao, Guangjun Nie
Pancreatic cancer, one of the leading causes of cancer-related mortality, is characterized by desmoplasia and hypovascular cancerous tissue, with a 5-year survival rate of less than 8%. To overcome the severe resistance of pancreatic cancer to conventional therapies, we synthesized gold nanoshell-coated rod-like mesoporous silica (GNRS) nanoparticles which integrated cascade tumor targeting (mediated by photothermal effect and molecular receptor binding) and photothermal treatment-enhanced gemcitabine chemotherapy, under mild near infrared laser irradiation condition...
July 24, 2017: ACS Nano
https://www.readbyqxmd.com/read/28733542/use-of-a-genome-wide-haploid-genetic-screen-to-identify-treatment-predicting-factors-a-proof-of-principle-study-in-pancreatic-cancer
#16
Yuk Ting Ma, Sarah M Leonard, Naheema Gordon, Jennifer Anderton, Claire James, David Huen, Ciaran B Woodman, Daniel H Palmer
The ability to develop a comprehensive panel of treatment predicting factors would significantly improve our ability to stratify patients for cytotoxic or targeted therapies, and prevent patients receiving ineffective treatments. We have investigated if a recently developed genome-wide haploid genetic screen can be used to reveal the critical mediators of response to anticancer therapy. Pancreatic cancer is known to be highly resistant to systemic therapy. Recently epigenetic changes have been shown to be a key determinant in the maintenance of subpopulations of cancer cells with high-level resistance to cytotoxic therapy...
June 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28733220/pan-mtor-inhibitor-mln0128-is-effective-against-intrahepatic-cholangiocarcinoma-induced-in-mice-by-akt-and-yap-co-expression
#17
Shanshan Zhang, Xinhua Song, Dan Cao, Zhong Xu, Biao Fan, Li Che, Junjie Hu, Bin Chen, Mingjie Dong, Maria G Pilo, Antonio Cigliano, Katja Evert, Silvia Ribback, Frank Dombrowski, Rosa M Pascale, Antonio Cossu, Gianpaolo Vidili, Alberto Porcu, Maria M Simile, Giovanni M Pes, Gianluigi Giannelli, John Gordan, Lixin Wei, Matthias Evert, Wenming Cong, Diego F Calvisi, Xin Chen
BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (ICC) is a lethal malignancy without effective treatment options. MLN0128, a second-generation pan-mTOR inhibitor, shows efficacy for multiple tumor types. METHODS: We established a novel ICC mouse model via hydrodynamic transfection of activated forms of AKT (myr-AKT) and Yap (YapS127A) protooncogenes (that will be referred to as AKT/YapS127A). Genetic approaches were applied to study the requirement of mTORC1 and mTORC2 in mediating AKT/YapS127A driven tumorigenesis...
July 18, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28722177/metformin-induced-alterations-in-nucleotide-metabolism-cause-5-fluorouracil-resistance-but-gemcitabine-susceptibility-in-oesophageal-squamous-cell-carcinoma
#18
Charissa Mynhardt, Leonard Howard Damelin, Rupal Jivan, Jade Peres, Sharon Prince, Robin Bruce Veale, Demetra Mavri-Damelin
5-Fluorouracil (5-FU) is a chemotherapeutic agent used to treat a variety of gastric cancers including oesophageal squamous cell carcinoma (OSCC), for which the 5-year mortality rate exceeds 85%. Our study investigated the effects of metformin, an antidiabetic drug with established anti-cancer activity, in combination with 5-FU as a novel chemotherapy strategy, using the OSCC cell lines, WHCO1 and WHCO5. Our results indicate that metformin treatment induces significant resistance to 5-FU in WHCO1 and WHCO5 cells, by more than 5-fold and 6-fold respectively, as assessed by MTT assay...
July 19, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28720574/fructose-1-6-bisphosphatase-inhibits-erk-activation-and-bypasses-gemcitabine-resistance-in-pancreatic-cancer-by-blocking-iqgap1-mapk-interaction
#19
Xin Jin, Yunqian Pan, Liguo Wang, Tao Ma, Lizhi Zhang, Amy H Tang, Daniel D Billadeau, Heshui Wu, Haojie Huang
Dysregulation of the MAPK pathway correlates with progression of pancreatic ductal adenocarcinoma (PDAC) progression. IQ motif containing GTPase-activating protein 1 (IQGAP1) is a MAPK scaffold that directly regulates the activation of RAF, MEK, and ERK. Fructose-1,6-bisphosphatase (FBP1), a key enzyme in gluconeogenesis, is transcriptionally downregulated in various cancers, including PDAC. Here, we demonstrate that FBP1 acts as a negative modulator of the IQGAP1-MAPK signaling axis in PDAC cells. FBP1 binding to the WW domain of IQGAP1 impeded IQGAP1-dependent ERK1/2 phosphorylation (pERK1/2) in a manner independent of FBP1 enzymatic activity...
August 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28719220/egfr-targeted-cationic-polymeric-mixed-micelles-for-codelivery-of-gemcitabine-and-mir-205-for-treating-advanced-pancreatic-cancer
#20
Goutam Mondal, Saud Almawash, Amit Kumar Chaudhary, Ram I Mahato
Gemcitabine (GEM), a first-line chemotherapy for pancreatic cancer undergoes rapid metabolism and develops chemoresistance after repeated administration. We previously demonstrated that the combination of GEM and miR-205 provides an effective therapeutic strategy to sensitize GEM-resistant pancreatic cancer cells. Since epidermal growth factor receptor (EGFR) is overexpressed in pancreatic cancer cells, in this study, we aimed to deliver mixed micelles containing GEM and miR-205 decorated with EGFR-targeting cetuximab (C225) monoclonal antibody for targeted therapy...
July 31, 2017: Molecular Pharmaceutics
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