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https://www.readbyqxmd.com/read/29785875/egfr-tkis-in-non-small-cell-lung-cancer-focus-on-clinical-pharmacology-and-mechanisms-of-resistance
#1
Stefano Fogli, Beatrice Polini, Marzia Del Re, Iacopo Petrini, Antonio Passaro, Stefania Crucitta, Eleonora Rofi, Romano Danesi
The clinical introduction of EGFR-TKIs within the oncologic armamentarium has changed the therapeutic landscape of non-small-cell lung cancer (NSCLC) creating widespread expectations both in patients and clinicians. However, several gaps in current understanding leave open important questions regarding the use of these drugs in clinical practice. For instance, there is uncertainty in regard to which EGFR-TKI should be given first in naive patients with EGFR-driven malignancies since different generations of drugs are available with different pharmacological profiles...
May 22, 2018: Pharmacogenomics
https://www.readbyqxmd.com/read/29785088/insight-into-resistance-mechanism-of-anaplastic-lymphoma-kinase-to-alectinib-and-jh-viii-157-02-caused-by-g1202r-solvent-front-mutation
#2
Han Wang, Yao Wang, Wentao Guo, Bin Du, Xiaobing Huang, Riping Wu, Baoyu Yang, Xiaoyan Lin, Yilan Wu
Background: Mutated anaplastic lymphoma kinase (ALK) drives the development of advanced non-small cell lung cancer (NSCLC). Most reported small-molecule inhibitors targeting the ALK domain do not display good inhibition of the G1202R solvent front mutation. The solvent front mutation was assumed to hinder drug binding. However, a different fact could be uncovered by the simulations reported in this study through a structural analog of alectinib (JH-VIII-157-02), which demonstrated potent effects against the G1202R mutation...
2018: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/29784675/radiation-followed-by-ox40-stimulation-drives-local-and-abscopal-antitumor-effects-in-an-anti-pd1-resistant-lung-tumor-model
#3
Sharareh Niknam, Hampartsoum B Barsoumian, Jonathan E Schoenhals, Heather Jackson, Niranjan Yanamandra, Mauricio S Caetano, Ailin Li, Ahmed I Younes, Alexandra P Cadena, Taylor R Cushman, Joe Y Chang, Quynh Nguyen, Daniel R Gomez, Adi Diab, John V Heymach, Patrick Hwu, Maria Angelica Cortez, James W Welsh
PURPOSE: Radiation is used extensively to treat localized cancer, but improved understanding of its effects on the immune system have increased interest in its potential systemic (abscopal) effects, particularly in combination with checkpoint inhibitors such as anti-PD1. The majority of patients either do not respond or develop resistance to monotherapy over time. Here, we investigated the efficacy of OX40 (CD134) stimulation as an alternative immunotherapeutic approach in combination with radiotherapy (XRT) in a murine model of anti-PD1-resistant lung tumors...
May 21, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29784046/knockdown-of-annexin-a5-restores-gefitinib-sensitivity-by-promoting-g2-m-cell-cycle-arrest
#4
Jian Zhou, Meijia Chang, Jing Li, Tao Fang, Jie Hu, Chunxue Bai
BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, including gefitinib, are first-line drugs against advanced non-small cell lung cancer with activating EGFR mutations. However, the development of resistance to such drugs is a major clinical challenge. METHODS: The role of annexin A5 in resistance to EGFR tyrosine kinase inhibitors was investigated by qPCR and western blot of relevant molecules, by CCK8 and EdU assay of cell proliferation and viability, by annexin V/propidium iodide assay of apoptosis and cell cycle distribution, by JC-1 assay of mitochondrial integrity, and by xenograft assay of tumorigenicity...
May 21, 2018: Respiratory Research
https://www.readbyqxmd.com/read/29782563/repurposing-established-cyclic-adenosine-monophosphate-reducing-agents-for-the-prevention-and-therapy-of-epidermal-growth-factor-receptor-inhibitor-resistance-in-non-small-cell-lung-cancer
#5
EDITORIAL
https://www.readbyqxmd.com/read/29781034/specific-inhibitor-of-notch%C3%A2-3-enhances-the-sensitivity-of-nsclc-cells-to-gemcitabine
#6
Bi-Dan Hu, Jia Guo, Yuan-Zi Ye, Ting Du, Chun-Song Cheng, Qian Jiang, Ruo-Nan Liu, Yan-Bei Zhang
Notch‑3 is a receptor of the Notch signaling pathway and plays an important role in regulating self‑renewal, differentiation and apoptosis in cancer cells. Overexpression of Notch‑3 has been proved to be associated with resistance to gemcitabine (GEM) and poor patient prognosis for various malignant tumors. In the present study, two non‑small cell lung cancer (NSCLC) cell lines, H1299 and A549, were induced with GEM for two months and then were treated with various concentrations of a Notch signaling blocker, N‑[N‑(3,5‑difluorophenacetyl)‑L‑alanyl]‑S‑phenylglycine t‑butyl ester (DAPT), with the goal of reducing expression of Notch intracellular domain 3 (NICD3)...
May 16, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29780357/altered-circadian-rhythms-and-breast-cancer-from-the-human-to-the-molecular-level
#7
REVIEW
Hui-Hsien Lin, Michelle E Farkas
Circadian clocks are fundamental, time-tracking systems that allow organisms to adapt to the appropriate time of day and drive many physiological and cellular processes. Altered circadian rhythms can result from night-shift work, chronic jet lag, exposure to bright lights at night, or other conditioning, and have been shown to lead to increased likelihood of cancer, metabolic and cardiovascular diseases, and immune dysregulation. In cases of cancer, worse patient prognoses and drug resistance during treatment have also been observed...
2018: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/29779013/treatment-of-sec62-over-expressing-tumors-by-thapsigargin-and-trifluoperazine
#8
Christina Körbel, Maximilian Linxweiler, Florian Bochen, Silke Wemmert, Bernhard Schick, Markus Meyer, Hans Maurer, Michael D Menger, Richard Zimmermann, Markus Greiner
Treatment with analogues of the SERCA-inhibitor Thapsigargin is a promising new approach for a wide variety of cancer entities. However, our previous studies on various tumor cells suggested resistance of SEC62 over-expressing tumors to this treatment. Therefore, we proposed the novel concept that e.g. lung-, prostate-, and thyroid-cancer patients should be tested for SEC62 over-expression, and developed a novel therapeutic strategy for a combinatorial treatment of SEC62 over-expressing tumors. The latter was based on the observations that treatment of SEC62 over-expressing tumor cells with SEC62-targeting siRNAs showed less resistance to Thapsigargin as well as a reduction in migratory potential and that the siRNA effects can be mimicked by the Calmodulin antagonist Trifluoperazine...
May 19, 2018: Biomolecular Concepts
https://www.readbyqxmd.com/read/29778798/discovery-of-antitumor-ursolic-acid-long-chain-diamine-derivatives-as-potent-inhibitors-of-nf-%C3%AE%C2%BAb
#9
Wei Jiang, Ri-Zhen Huang, Jing Zhang, Tong Guo, Meng-Ting Zhang, Xiao-Chao Huang, Bin Zhang, Zhi-Xin Liao, Jing Sun, Heng-Shan Wang
A series of inhibitors of NF-κB based on ursolic acid (UA) derivatives containing long-chain diamine moieties were designed and synthesized as well as evaluated the antitumor effects. These compounds exhibited significant inhibitory activity to the NF-κB with IC50 values at micromolar concentrations in A549 lung cancer cell line. Among them, compound 8c exerted potent activity against the test tumor cell lines including multidrug resistant human cancer lines, with the IC50 values ranged from 5.22 to 8.95 μM...
May 8, 2018: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29777004/development-of-a-novel-spect-tracer-to-image-c-met-expression-in-non-small-cell-lung-cancer-in-a-human-tumor-xenograft
#10
Zhaoguo Han, Yadi Xiao, Kai Wang, Ji Yan, Zunyu Xiao, Fang Fang, Zhongnan Jin, Yang Liu, Xilin Sun, Baozhong Shen
Rationale: Elevated expression of the c-Met receptor plays a crucial role in cancers. In non-small cell lung cancer (NSCLC), aberrant activation of c-Met signaling pathway contributes to tumorigenesis and cancer progression, and may mediate acquired resistance to epidermal growth factor receptor-targeted therapy. c-Met is therefore emerging as a promising therapeutic target for treating NSCLC, and the methods for noninvasive in vivo assessment of c-Met expression will improve NSCLC treatment and diagnosis. Methods: A new peptide-based (cMBP) radiotracer targeting c-Met, 99m Tc-hydrazine nicotinamide (HYNIC)-cMBP, was developed for single photon emission computed tomography (SPECT) imaging...
May 18, 2018: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/29776963/combined-vegf-and-pd-l1-blockade-displays-synergistic-treatment-effects-in-an-autochthonous-mouse-model-of-small-cell-lung-cancer
#11
Lydia Meder, Philipp Schuldt, Martin Thelen, Anna Schmitt, Felix Dietlein, Sebastian Klein, Sven Borchmann, Kerstin Wennhold, Ignacija Vlasic, Sebastian Oberbeck, Richard Riedel, Alexandra Florin, Kristina Golfmann, Hans Anton Schlößer, Margarete Odenthal, Reinhard Büttner, Juergen Wolf, Michael Hallek, Marco Herling, Michael von Bergwelt-Baildon, Hans Christian Reinhardt, Roland T Ullrich
Small cell lung cancer (SCLC) represents the most aggressive pulmonary neoplasm and is often diagnosed at late stage with limited survival, despite combined chemotherapies. We show in an autochthonous mouse model of SCLC that combined anti-VEGF/anti-PD-L1 targeted therapy synergistically improves treatment outcome compared to anti-PD-L1 and anti-VEGF monotherapy. Mice treated with anti-PD-L1 alone relapsed after 3 weeks and were associated with a tumor-associated PD-1/TIM-3 double positive exhausted T cell phenotype...
May 18, 2018: Cancer Research
https://www.readbyqxmd.com/read/29776953/the-landscape-of-actionable-genomic-alterations-in-cell-free-circulating-tumor-dna-from-21-807-advanced-cancer-patients
#12
Oliver A Zill, Kimberly C Banks, Stephen R Fairclough, Stefanie Mortimer, James V Vowles, Reza Mokhtari, David R Gandara, Philip C Mack, Justin I Odegaard, Rebecca J Nagy, Arthur M Baca, Helmy Eltoukhy, Darya I Chudova, Richard B Lanman, AmirAli Talasaz
PURPOSE: Cell-free DNA (cfDNA) sequencing provides a non-invasive method for obtaining actionable genomic information to guide personalized cancer treatment, but the presence of multiple alterations in circulation related to treatment and tumor heterogeneity complicate the interpretation of the observed variants. Experimental Design: We describe the somatic mutation landscape of 70 cancer genes from cfDNA deep-sequencing analysis of 21,807 patients with treated, late-stage cancers across >50 cancer types...
May 18, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29774072/twist-promotes-tumor-metastasis-in-basal-like-breast-cancer-by-transcriptionally-upregulating-ror1
#13
Jingying Cao, Xin Wang, Tao Dai, Yuanzhong Wu, Meifang Zhang, Renxian Cao, Ruhua Zhang, Gang Wang, Rou Jiang, Binhua P Zhou, Jian Shi, Tiebang Kang
Rationale: Twist is a key transcription factor for induction of epithelial-mesenchymal transition (EMT), which promotes cell migration, invasion, and cancer metastasis, confers cancer cells with stem cell-like characteristics, and provides therapeutic resistance. However, the functional roles and targeted genes of Twist in EMT and cancer progression remain elusive. Methods: The potential targeted genes of Twist were identified from the global transcriptomes of T47D/Twist cells by microarray analysis. EMT phenotype was detected by western blotting and immunofluorescence of marker proteins...
2018: Theranostics
https://www.readbyqxmd.com/read/29774063/dual-target-gene-therapy-to-eml4-alk-nsclc-by-a-gold-nanoshell-based-system
#14
Siwen Li, Yuxi Liu, Yalan Rui, Liping Tang, Samuel Achilefu, Yueqing Gu
Although EML4-ALK transforming fusion gene is represented in only 8% of non-small cell lung cancer (NSCLC) cases, its expression is partly responsive for the failure of current NSCLC treatments. Preventing secondary mutation of the ALK protein through direct gene manipulation could overcome NSCLC drug resistance. Method: In this study, we developed a gold nanoshell (HAuNs) drug carrier for delivery and selective photo-thermal release of genes that target ALK and microRNA-301 in NSCLC. Additionally, the densely-coated nanoshell adsorbed high amounts of the positively-charged anticancer drug doxorubicin (DOX), generating an exciting multidimensional treatment strategy that includes gene-, thermal- and chemo- therapy...
2018: Theranostics
https://www.readbyqxmd.com/read/29773172/seleno-l-methionine-and-l-ascorbic-acid-differentiate-the-biological-activity-of-doxorubicin-and-its-metal-complexes-as-a-new-anticancer-drugs-candidate
#15
Marzena Matejczyk, Grzegorz Świderski, Renata Świsłocka, Stanisław Józef Rosochacki, Włodzimierz Lewandowski
The most important problems of anti-cancer therapy include the toxicity of the drugs applied to healthy cells and the multi-drug cells resistance to chemotherapeutics. One of the most commonly used anticancer drugs is doxorubicin (DOX) used to treat certain leukemias and non-Hodgkin's lymphomas, as well as bladder, breast, stomach, lung, ovarian, thyroid, multiple myeloma and other cancers. Preliminary studies showed that metal complex with DOX improve its cytostatic activity with changes in their molecular structure and distribution of electrons, resulting in a substantial change of its biological activity (including antitumor activity)...
July 2018: Journal of Trace Elements in Medicine and Biology
https://www.readbyqxmd.com/read/29772677/lambertianic-acid-sensitizes-non-small-cell-lung-cancers-to-trail-induced-apoptosis-via-inhibition-of-xiap-nf-%C3%AE%C2%BAb-and-activation-of-caspases-and-death-receptor-4
#16
Deok Soo Ahn, Hyo Jung Lee, Jisung Hwang, Hyukgyu Han, Bonglee Kim, BumSang Shim, Sung-Hoon Kim
Lambertianic acid (LA) is a biologically active compound from the leaves of Pinus koraiensis. In the present study, apoptotic mechanisms of LA plus TNF-related apoptosis-inducing ligand (TRAIL) were elucidated in non-small cell lung cancer cells (NSCLCs). Cytotoxicity assay, flow cytometry, immunoprecipitation, and Western blotting were performed. Here, combined treatment of LA and TRAIL increased cytotoxicity, sub-G1 population, cleaved poly (ADP-ribose) polymerase (PARP), and caspase3/8/9 in A549 and H1299 cells compared to LA or TRAIL alone...
May 16, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29771007/dichlorophenylacrylonitriles-as-ahr-ligands-displaying-selective-breast-cancer-cytotoxicity-in-vitro
#17
Jennifer R Baker, Jayne Gilbert, Stefan Paula, Xiao Zhu, Jennette A Sakoff, Adam McCluskey
Knoevenagel condensation of 3,4-dichloro- and 2,6-dichloro- phenylacetonitriles gave a library of dichlorophenylacrylonitriles. Our leads 5 and 6 displayed 0.56±0.03 and 0.127±0.04 μM growth inhibition (GI₅₀) and 260-fold selectivity for the MCF-7 breast cancer cell line. A 2,6-dichlorophenyl moiety saw a 10-fold potency loss; additional nitrogen moieties (-NO₂) enhanced activity (26 and 27), with the corresponding -NH₂ analogues (29 and 30) more potent. Despite this, both 29 (2.8±0.03 μM) and 30 (2...
May 17, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29770894/efficacy-of-punarnavine-in-restraining-organ-specific-tumour-progression-in-4t1-induced-murine-breast-tumour-model
#18
Gilcy George Kallivalappil, Girija Kuttan
Most of the breast cancer deaths occur when cancer cells depart from their tumour of origin and spread systemically and colonise distant organs. The present study was to find out whether punarnavine, the quinolizidine alkaloid, with already proven antimetastatic effect on spontaneous B16F10 pulmonary metastasis has got any effect on a drastic organ-specific breast cancer spread. For the study, we selected a syngenic mouse 4T1 breast tumour model that mimics stage four of human breast cancer. The metastatic progression of 4T1 to lymph nodes, lungs, and liver was reduced by punarnavine (40 mg/kg body weight) administration in BALB/c mice...
May 17, 2018: Inflammopharmacology
https://www.readbyqxmd.com/read/29770798/combined-treatment-with-apatinib-and-docetaxel-in-a549-xenograft-mice-and-its-cellular-pharmacokinetic-basis
#19
Si-Qi Feng, Guang-Ji Wang, Jing-Wei Zhang, Yuan Xie, Run-Bin Sun, Fei Fei, Jing-Qiu Huang, Ying Wang, Ji-Ye Aa, Fang Zhou
Apatinib, a small-molecule inhibitor of VEGFR-2, has attracted much attention due to its encouraging anticancer activity in third-line clinical treatment for many malignancies, including non-small cell lung cancer (NSCLC). Its usage in second-line therapy with chemotherapeutic drugs is still under exploration. In this study we investigated the antitumor effect of apatinib combined with docetaxel against NSCLC and its cellular pharmacokinetic basis. A549 xenograft nude mice were treated with apatinib (100 mg/kg every day for 20 days) combined with docetaxel (8 mg/kg, ip, every four days for 5 times)...
May 17, 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29768255/asiatic-acid-aa-sensitizes-multidrug-resistant-human-lung-adenocarcinoma-a549-ddp-cells-to-cisplatin-ddp-via-downregulation-of-p-glycoprotein-mdr1-and-its-targets
#20
Qilai Cheng, Meixiang Liao, Haibo Hu, Hongliang Li, Longhuo Wu
BACKGROUND/AIMS: P-glycoprotein (P-gp, i.e., MDR1) is associated with the phenotype of multidrug resistance (MDR) and causes chemotherapy failure in the management of cancers. Searching for effective MDR modulators and combining them with anticancer drugs is a promising strategy against MDR. Asiatic acid (AA), a natural triterpene isolated from the plant Centella asiatica, may have an antitumor activity. The present study assessed the reversing effect of AA on MDR and possible molecular mechanisms of AA action in MDR1-overexpressing cisplatin (DDP)-resistant lung cancer cells, A549/DDP...
May 11, 2018: Cellular Physiology and Biochemistry
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