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gemcitabine resistance

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https://www.readbyqxmd.com/read/28548955/exploring-brusatol-as-a-new-anti-pancreatic-cancer-adjuvant-biological-evaluation-and-mechanistic-studies
#1
Zheng Lu, Zheng-Quan Lai, Albert W N Leung, Po Sing Leung, Zhao-Shen Li, Zhi-Xiu Lin
Pancreatic cancer is highly resistant to chemotherapeutic agents and is known to have a poor prognosis. The development of new therapeutic entities is badly needed for this deadly malignancy. In this study, we demonstrated for the first time that brusatol, a natural quassinoid isolated from a Chinese herbal medicine named Bruceae Fructus, possessed potent cytotoxic effect against different pancreatic adenocarcinoma cell lines. Its anti-pancreatic cancer effect was comparable to that of the first-line chemotherapeutic agents such as gemcitabine and 5-fluorouracil, with a more favorable safety profile...
May 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28537897/mek-inhibitors-cobimetinib-and-trametinib-regressed-a-gemcitabine-resistant-pancreatic-cancer-patient-derived-orthotopic-xenograft-pdox
#2
Kei Kawaguchi, Kentaro Igarashi, Takashi Murakami, Tasuku Kiyuna, Thinzar M Lwin, Ho Kyoung Hwang, Jonathan C Delong, Bryan M Clary, Michael Bouvet, Michiaki Unno, Robert M Hoffman
A pancreatic ductal adenocarcinoma (PDAC), obtained from a patient, was grown orthotopically in the pancreatic tail of nude mice to establish a patient-derived orthotopic (PDOX) model. Seven weeks after implantation, PDOX nude mice were divided into the following groups: untreated control (n = 7); gemcitabine (100 mg/kg, i.p., once a week for 2 weeks, n = 7); cobimetinib (5 mg/kg, p.o., 14 consecutive days, n = 7); trametinib (0.3 mg/kg, p.o., 14 consecutive days, n = 7); trabectedin (0.15 mg/kg, i.v., once a week for 2 weeks, n = 7); temozolomide (25 mg/kg, p...
May 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28536008/chemosensitization-and-inhibition-of-pancreatic-cancer-stem-cell-proliferation-by-overexpression-of-microrna-205
#3
Amit Kumar Chaudhary, Goutam Mondal, Virender Kumar, Krishna Kattel, Ram I Mahato
Treatment of pancreatic cancer with gemcitabine (GEM) is limited due to its rapid plasma metabolism and development of chemoresistance. MicroRNA (miRNA) regulates cancer stem cell (CSC) maintenance and induces chemoresistance in cancer cells. In this study, we observed differential downregulation of miR-205 (miR-205-5p) in human pancreatic cancer tissues and cells. Compared to GEM-sensitive MIA PaCa-2 cells, miR-205 was highly downregulated in GEM-resistant MIA PaCa-2R cells. Lentivirus-mediated overexpression of miR-205 inhibits MIA PaCa-2R cell proliferation after GEM-treatment...
May 20, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28500236/identification-of-the-serine-biosynthesis-pathway-as-a-critical-component-of-braf-inhibitor-resistance-of-melanoma-pancreatic-and-non-small-cell-lung-cancer-cells
#4
Kayleigh C Ross, Andrew J Andrews, Christopher D Marion, Timothy J Yen, Vikram Bhattacharjee
Metastatic melanoma cells commonly acquire resistance to BRAF V600E inhibitors (BRAFis). In this study, we identified serine biosynthesis as a critical mechanism of resistance. Proteomic assays revealed differential protein expression of serine biosynthetic enzymes PHGDH, PSPH, and PSAT1 following vemurafenib (BRAFi) treatment in sensitive versus acquired resistant melanoma cells. Ablation of PHGDH via siRNA sensitized acquired resistant cells to vemurafenib. Inhibiting the folate cycle, directly downstream of serine synthesis, with methotrexate also displayed similar sensitization...
May 12, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28496342/sialylation-facilitates-self-assembly-of-3d-multicellular-prostaspheres-by-using-cyclo-rgdfk-tpp-peptide
#5
Sabah Haq, Vanessa Samuel, Fiona Haxho, Roman Akasov, Maria Leko, Sergey V Burov, Elena Markvicheva, Myron R Szewczuk
BACKGROUND: Prostaspheres-based three dimensional (3D) culture models have provided insight into prostate cancer (PCa) biology, highlighting the importance of cell-cell interactions and the extracellular matrix (EMC) in the tumor microenvironment. Although these 3D classical spheroid platforms provide a significant advance over 2D models mimicking in vivo tumors, the limitations involve no control of assembly and structure with only limited spatial or glandular organization. Here, matrix-free prostaspheres from human metastatic prostate carcinoma PC3 and DU145 cell lines and their respective gemcitabine resistant (GemR) variants were generated by using cyclic Arg-Gly-Asp-D-Phe-Lys peptide modified with 4-carboxybutyl-triphenylphosphonium bromide (cyclo-RGDfK(TPP))...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28495087/gemcitabine-anti-proliferative-activity-significantly-enhanced-upon-conjugation-with-cell-penetrating-peptides
#6
Nuno Vale, Abigail Ferreira, Iva Fernandes, Cláudia Alves, Maria João Araújo, Nuno Mateus, Paula Gomes
Gemcitabine proven efficiency against a wide range of solid tumors and undergoes deamination to its inactive uridine metabolite, which underlies its low bioavailability, and tumour resistance was also associated with nucleoside transporter alterations. Hence, we have conjugated gemcitabine to cell-penetrating peptides (CPP), in an effort to both mask its aniline moiety and facilitate its delivery into cancer cells. Two CPP-drug conjugates have been synthesized and studied regarding both the time-dependent kinetics of gemcitabine release and their anti-proliferative activity on three different human cancer cell lines...
April 28, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28492560/mir-218-5p-restores-sensitivity-to-gemcitabine-through-prkce-mdr1-axis-in-gallbladder-cancer
#7
Hui Wang, Ming Zhan, Sun-Wang Xu, Wei Chen, Man-Mei Long, Yong-Heng Shi, Qiang Liu, Man Mohan, Jian Wang
Gallbladder cancer (GBC) is one of the most common malignancy of the biliary tract characterized by its high chemoresistant tendency. Although great progresses have been made in recent decades for treating many cancers with anticancer drugs, effective therapeutics methods for anti-GBC are still lacking. Therefore, investigations into identifying the mechanisms underlying the drug resistance of GBC are greatly needed. In this study, we show that miR-218-5p plays a critical role in gemcitabine resistance of GBC...
May 11, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28487979/trail-mutant-membrane-penetrating-peptide-alike-mur6-tr-enhances-the-antitumor-effects-of-trail-in-pancreatic-carcinoma-both-in-vitro-and-in-vivo
#8
Lei Sun, Chen Chen, Aijing Zhu, Ying Huang, Hong Zhu, Cheng Yi
To remedy the drug resistance of natural tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and enhance its antitumor effects, we prepared a type of TRAIL mutant membrane penetrating peptide alike (TMPPA)‑TRAIL mutant R6 (MuR6-TR) by mutating the N‑terminal of the soluble TRAIL gene sequence. The expressed MuR6‑TR protein was purified to treat pancreatic carcinoma cell lines BxPC‑3 and PANC‑1. The inhibitory effects on the proliferation of BxPC‑3 and PANC‑1 cells was assessed with CCK‑8 assay and compared with natural TRAIL...
June 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28477403/micro-rna-21-regulates-cancer-associated-fibroblast-mediated-frug-resistance-in-pancreatic-cancer
#9
Lulin Zhang, Jun Yao, Wenyao Li, Ce Zhang
Pancreatic adenocarcinoma (PDAC) is one of the leading cause of cancer death due to its highly aggressive biological nature and resistance to chemotherapies. Former study also indicated that miR-21 in cancer-associated fibroblasts (CAFs) is an important regulator of their activation. However, whether miR-21 in CAFs would regulate PDAC's tumor microenvironment and leading to drug resistance remain unknown. In this study, we evaluated the relationship among CAFs activation, miR-21 expression level and drug resistance using PDAC patient tumor samples...
May 5, 2017: Oncology Research
https://www.readbyqxmd.com/read/28469793/downregulation-of-mir-301a-3p-sensitizes-pancreatic-cancer-cells-to-gemcitabine-treatment-via-pten
#10
Xiang Xia, Kundong Zhang, Guangtao Luo, Gang Cen, Jun Cao, Kejian Huang, Zhengjun Qiu
BACKGROUND: We previously showed that miR-301a-3p affects the invasion and migration abilities of pancreatic cancer cells. Here, we explore the role of miR-301a-3p in chemoresistance, which represents a major obstacle in cancer treatment. METHODS: We tested the effects of miR-301a-3p ongemcitabine resistance in cytotoxicity assays in vitro and in vivo. We used quantitative real-time PCR (qRT-PCR) to measure miR-301a-3p expression in wild-type and gemcitabine-resistant pancreatic cancer cells...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28467612/high-mobility-group-a1-enhances-tumorigenicity-of-human-cholangiocarcinoma-and-confers-resistance-to-therapy
#11
Cristina Quintavalle, Katharina Burmeister, Salvatore Piscuoglio, Luca Quagliata, Eva Karamitopoulou, Romina Sepe, Alfredo Fusco, Luigi M Terracciano, Jesper B Andersen, Pierlorenzo Pallante, Matthias S Matter
High mobility group A1 (HMGA1) protein has been described to play an important role in numerous types of human carcinoma. By the modulation of several target genes HMGA1 promotes proliferation and epithelial-mesenchymal transition of tumor cells. However, its role in cholangiocarcinoma (CCA) has not been addressed yet. Therefore, we determined HMGA1 mRNA expression in CCA samples in a transcriptome array (n=104) and a smaller cohort (n=13) by qRT-PCR. Protein expression was evaluated by immunohistochemistry in a tissue microarray (n=67)...
May 3, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/28459992/mir-153-enhances-the-therapeutic-effect-of-gemcitabine-by-targeting-snail-in-pancreatic-cancer
#12
Feng Liu, Bin Liu, Jianmin Qian, Gang Wu, Jiawei Li, Zhenyu Ma
Pancreatic cancer (PC) is one of the most lethal cancers, with an overall 5 years survival rate of <5%. The clinical benefit of gemcitabine based chemotherapeutic strategy on PC was limited by its high drug resistance rate. Snail, one of the master regulators of epithelial-mesenchymal transition, has been implicated in the progression of various cancers. However, whether it is also linked to the development of chemosensitivity to gemcitabine in PC is unknown, and the regulatory pathways controlling Snail also need to be explored...
April 28, 2017: Acta Biochimica et Biophysica Sinica
https://www.readbyqxmd.com/read/28440469/clinical-significance-of-akt2-in-advanced-pancreatic-cancer-treated-with-erlotinib
#13
Eri Banno, Yosuke Togashi, Marco A de Velasco, Takuro Mizukami, Yu Nakamura, Masato Terashima, Kazuko Sakai, Yoshihiko Fujita, Ken Kamata, Masayuki Kitano, Masatoshi Kudo, Kazuto Nishio
Akt2 is an isoform of Akt, and an association between Akt2 and resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been suggested in pancreatic cancer (PC) in vitro. In this study, we investigated the association between Akt2 expression as evaluated using immunohistochemistry and the outcome of patients with advanced PC who had received treatment with erlotinib (an EGFR-TKI). Although the difference was not significant, patients with high levels of Akt2 expression tended to have a poorer response and a shorter progression-free survival period after treatment with erlotinib plus gemcitabine than those with low expression levels (P=0...
April 18, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28440428/inhibition-of-atr-potentiates-the-cytotoxic-effect-of-gemcitabine-on-pancreatic-cancer-cells-through-enhancement-of-dna-damage-and-abrogation-of-ribonucleotide-reductase-induction-by-gemcitabine
#14
Shuang Liu, Yubin Ge, Tingting Wang, Holly Edwards, Qihang Ren, Yiqun Jiang, Chengshi Quan, Guan Wang
Pancreatic cancer is a highly malignant disease with a dismal prognosis. Gemcitabine (GEM)-based chemotherapy is the first-line treatment for patients with advanced disease, although its efficacy is very limited, mainly due to drug resistance. Ataxia telangiectasia and Rad3-related (ATR) plays a critical role in the DNA damage response (DDR) which has been implicated in GEM resistance. Thus, targeting ATR represents a promising approach to enhance GEM antitumor activity. In the present study, we tested the antitumor activity of AZ20, a novel ATR-selective inhibitor, alone or combined with GEM in 5 pancreatic cancer cell lines...
April 19, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28428074/melittin-inhibits-tumor-growth-and-decreases-resistance-to%C3%A2-gemcitabine-by-downregulating-cholesterol-pathway-gene%C3%A2-clu%C3%A2-in%C3%A2-pancreatic-ductal-adenocarcinoma
#15
Xinjing Wang, Jing Xie, Xiongxiong Lu, Hongzhe Li, Chenlei Wen, Zhen Huo, Junjie Xie, Minmin Shi, Xiaomei Tang, Hao Chen, Chenghong Peng, Yuan Fang, Xiaxing Deng, Baiyong Shen
Melittin is a Chinese traditional medicine for treating chronic inflammation, immunological diseases and cancers, however, the efficacy of melittin and its mechanism for treating pancreatic ductal adenocarcinoma (PDAC) are still unknown. Here we investigated the anti-cancer activity of melittin and its regulated mechanism(s) in the PDAC models. Melittin was found to suppress tumor growth by promoting cell apoptosis and cell-cycle arrest. Interestingly, the microarray analyses demonstrated that melittin significantly regulated cholesterol biosynthesis pathway during treatment...
April 17, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28418923/osu-a9-inhibits-pancreatic-cancer-cell-lines-by-modulating-p38-jak-stat3-signaling
#16
Wan-Chi Tsai, Li-Yuan Bai, Yi-Jin Chen, Po-Chen Chu, Ya-Wen Hsu, Aaron M Sargeant, Jing-Ru Weng
Pancreatic cancer is an aggressive malignancy that is the fourth leading cause of death worldwide. Since there is a dire need for novel and effective therapies to improve the poor survival rates of advanced pancreatic cancer patients, we analyzed the antitumor effects of OSU-A9, an indole-3-carbinol derivative, on pancreatic cancer cell lines in vitro and in vivo. OSU-A9 exhibited a stronger antitumor effect than gemcitabine on two pancreatic cancer cell lines, including gemcitabine-resistant PANC-1 cells. OSU-A9 treatment induced apoptosis, the down-regulation of Akt phosphorylation, up-regulation of p38 phosphorylation and decreased phosphorylation of JAK and STAT3...
April 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28416665/hippo-pathway-mediates-resistance-to-cytotoxic-drugs
#17
Taranjit S Gujral, Marc W Kirschner
Chemotherapy is widely used for cancer treatment, but its effectiveness is limited by drug resistance. Here, we report a mechanism by which cell density activates the Hippo pathway, which in turn inactivates YAP, leading to changes in the regulation of genes that control the intracellular concentrations of gemcitabine and several other US Food and Drug Administration (FDA)-approved oncology drugs. Hippo inactivation sensitizes a diverse panel of cell lines and human tumors to gemcitabine in 3D spheroid, mouse xenografts, and patient-derived xenograft models...
May 2, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28407685/extra-pancreatic-invasion-induces-lipolytic-and-fibrotic-changes-in-the-adipose-microenvironment-with-released-fatty-acids-enhancing-the-invasiveness-of-pancreatic-cancer-cells
#18
Takashi Okumura, Kenoki Ohuchida, Masafumi Sada, Toshiya Abe, Sho Endo, Kazuhiro Koikawa, Chika Iwamoto, Daisuke Miura, Yusuke Mizuuchi, Taiki Moriyama, Kohei Nakata, Yoshihiro Miyasaka, Tatsuya Manabe, Takao Ohtsuka, Eishi Nagai, Kazuhiro Mizumoto, Yoshinao Oda, Makoto Hashizume, Masafumi Nakamura
Pancreatic cancer progression involves components of the tumor microenvironment, including stellate cells, immune cells, endothelial cells, and the extracellular matrix. Although peripancreatic fat is the main stromal component involved in extra-pancreatic invasion, its roles in local invasion and metastasis of pancreatic cancer remain unclear. This study investigated the role of adipose tissue in pancreatic cancer progression using genetically engineered mice (Pdx1-Cre; LSL-KrasG12D; Trp53R172H/+) and an in vitro model of organotypic fat invasion...
March 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28404939/%C3%AE-tocotrienol-a-natural-form-of-vitamin-e-inhibits-pancreatic-cancer-stem-like-cells-and-prevents-pancreatic-cancer-metastasis
#19
Kazim Husain, Barbara A Centeno, Domenico Coppola, Jose Trevino, Said M Sebti, Mokenge P Malafa
The growth, metastasis, and chemotherapy resistance of pancreatic ductal adenocarcinoma (PDAC) is characterized by the activation and growth of tumor-initiating cells in distant organs that have stem-like properties. Thus, inhibiting growth of these cells may prevent PDAC growth and metastases. We have demonstrated that δ-tocotrienol, a natural form of vitamin E (VEDT), is bioactive against cancer, delays progression, and prevents metastases in transgenic mouse models of PDAC. In this report, we provide the first evidence that VEDT selectively inhibits PDAC stem-like cells...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28365185/curcumin-and-its-cyclohexanone-analogue-inhibited-human-equilibrative-nucleoside-transporter-1-ent1-in-pancreatic-cancer-cells
#20
Jezrael L Revalde, Yan Li, Tharaka S Wijeratne, Piyush Bugde, Bill C Hawkins, Rhonda J Rosengren, James W Paxton
Our group investigated combining the phytochemical curcumin and gemcitabine in a liposome, to improve gemcitabine's activity against pancreatic tumours. While optimising the curcumin: gemcitabine ratio for co-encapsulation, we found that increasing curcumin concentrations relative to gemcitabine resulted in antagonistic interactions. As curcumin is a promiscuous transporter inhibitor; we suspected that increased resistance occurred via inhibition of Equilibrative nucleoside transporter 1 (ENT1)-mediated gemcitabine uptake...
May 15, 2017: European Journal of Pharmacology
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