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Drug resistance in melanoma

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https://www.readbyqxmd.com/read/28069687/adaptive-resistance-of-melanoma-cells-to-raf-inhibition-via-reversible-induction-of-a-slowly-dividing-de-differentiated-state
#1
Mohammad Fallahi-Sichani, Verena Becker, Benjamin Izar, Gregory J Baker, Jia-Ren Lin, Sarah A Boswell, Parin Shah, Asaf Rotem, Levi A Garraway, Peter K Sorger
Treatment of BRAF-mutant melanomas with MAP kinase pathway inhibitors is paradigmatic of the promise of precision cancer therapy but also highlights problems with drug resistance that limit patient benefit. We use live-cell imaging, single-cell analysis, and molecular profiling to show that exposure of tumor cells to RAF/MEK inhibitors elicits a heterogeneous response in which some cells die, some arrest, and the remainder adapt to drug. Drug-adapted cells up-regulate markers of the neural crest (e.g., NGFR), a melanocyte precursor, and grow slowly...
January 9, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28067893/vemurafenib-and-trametinib-reduce-expression-of-ctgf-and-il-8-in-v600e-braf-melanoma-cells
#2
Mariusz L Hartman, Michal Rozanski, Marta Osrodek, Izabela Zalesna, Malgorzata Czyz
Clinical evidence has revealed that while RAS/RAF/MEK/ERK pathway is a crucial component of melanomagenesis, other signaling pathways can also contribute to the malignant growth and development of resistance to targeted therapies. We explored the response of (V600E)BRAF melanoma cells derived from surgical specimens and grown in stem cell medium to vemurafenib and trametinib, drugs targeting the activity of (V600E)BRAF and MEK1/2, respectively. Cell growth and apoptosis were monitored by real-time imaging system, immunophenotype and cell cycle by flow cytometry, gene expression by quantitative real-time PCR, immunoblotting and enzyme-linked immunosorbent assay...
January 9, 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/28064546/targeting-protein-kinase-b3-akt3-signaling-in-melanoma
#3
SubbaRao V Madhunapantula, Gavin P Robertson
Deregulated Akt activity leading to apoptosis inhibition, enhanced proliferation and drug resistance has been shown to be responsible for 35-70% of advanced metastatic melanomas. Of the three isoforms, the majority of melanomas have elevated Akt3 expression and activity. Hence, potent inhibitors targeting Akt are urgently required, which is possible only if (a) the factors responsible for the failure of Akt inhibitors in clinical trials is known; and (b) the information pertaining to synergistically acting targeted therapeutics is available...
January 9, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28064454/hgf-met-in-cancer-progression-and-biomarker-discovery
#4
REVIEW
Kunio Matsumoto, Masataka Umitsu, Dinuka M De Silva, Arpita Roy, Donald P Bottaro
Signaling driven by hepatocyte growth factor (HGF) and MET receptor facilitates conspicuous biological responses such as epithelial cell migration, 3-D morphogenesis, and survival. The dynamic migration and promotion of cell survival induced by MET activation are bases respectively for invasion-metastasis and resistance against targeted drugs in cancers. Recent studies indicated that MET in tumor-derived exosomes facilitates metastatic niche formation and metastasis in malignant melanoma. In lung cancer, gene amplification-induced MET activation and ligand-dependent MET activation in autocrine/paracrine manner are causes for resistance to EGF receptor tyrosine kinase inhibitors and ALK inhibitors...
January 8, 2017: Cancer Science
https://www.readbyqxmd.com/read/28063902/application-of-aluminum-chloride-phthalocyanine-loaded-solid-lipid-nanoparticles-for-photodynamic-inactivation-of-melanoma-cells
#5
Patrícia L Goto, Marigilson P Siqueira-Moura, Antonio C Tedesco
Cutaneous melanoma is the most aggressive skin cancer and is particularly resistant to current therapeutic approaches. Photodynamic therapy (PDT) is a well-established photoprocess that is employed to treat some cancers, including non-melanoma skin cancer. Aluminum chloride phthalocyanine (ClAlPc) is used as a photosensitizer in PDT; however, its high hydrophobicity hampers its photodynamic activity under physiological conditions. The aim of this study was to produce solid lipid nanoparticles (SLN) containing ClAlPc using the direct emulsification method...
January 4, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28052407/p21-activated-kinase-1-regulates-resistance-to-braf-inhibition-in-human-cancer-cells
#6
Mahamat Babagana, Sydney Johnson, Hannah Slabodkin, Wiam Bshara, Carl Morrison, Eugene S Kandel
BRAF is a commonly mutated oncogene in various human malignancies and a target of a new class of anti-cancer agents, BRAF-inhibitors (BRAFi). The initial enthusiasm for these agents, based on the early successes in the management of metastatic melanoma, is now challenged by the mounting evidence of intrinsic BRAFi-insensitivity in many BRAF-mutated tumors, by the scarcity of complete responses, and by the inevitable emergence of drug resistance in initially responsive cases. These setbacks put an emphasis on discovering the means to increase the efficacy of BRAFi and to prevent or overcome BRAFi-resistance...
January 4, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/28036292/therapeutic-potential-of-the-metabolic-modulator-phenformin-in-targeting-the-stem-cell-compartment-in-melanoma
#7
Tiziana Petrachi, Alessandra Romagnani, Adriana Albini, Caterina Longo, Giuseppe Argenziano, Giulia Grisendi, Massimo Dominici, Alessia Ciarrocchi, Katiuscia Dallaglio
Melanoma is the most dangerous and treatment-resistant skin cancer. Tumor resistance and recurrence are due to the persistence in the patient of aggressive cells with stem cell features, the cancer stem cells (CSC). Recent evidences have shown that CSC display a distinct metabolic profile as compared to tumor bulk population: a promising anti-tumor strategy is therefore to target specific metabolic pathways driving CSC behavior. Biguanides (metformin and phenformin) are anti-diabetic drugs able to perturb cellular metabolism and displaying anti-cancer activity...
December 28, 2016: Oncotarget
https://www.readbyqxmd.com/read/28035420/argininosuccinate-lyase-interacts-with-cyclin-a2-in-cytoplasm-and-modulates-growth-of-liver-tumor-cells
#8
Yu-Hsuan Hung, Hau-Lun Huang, Wei-Ching Chen, Meng-Chi Yen, Chien-Yu Cho, Tzu-Yang Weng, Chih-Yang Wang, Yi-Ling Chen, Li-Tzong Chen, Ming-Derg Lai
Arginine is a critical amino acid in specific cancer types including hepatocellular carcinoma (HCC) and melanoma. Novel molecular mechanisms and therapeutic targets in arginine metabolism-mediated cancer formation await further identification. Our laboratory has previously demonstrated that arginine metabolic enzyme argininosuccinate lyase (ASL) promoted HCC formation in part via maintenance of cyclin A2 protein expression and arginine production for channeling to nitric oxide synthase. In this study, we investigated the mechanism by which ASL regulates cyclin A2 expression...
December 23, 2016: Oncology Reports
https://www.readbyqxmd.com/read/28028438/hvtra-a-novel-trail-receptor-agonist-induces-apoptosis-and-sustained-growth-retardation-in-melanoma
#9
Karianne G Fleten, Vivi Ann Flørenes, Lina Prasmickaite, Oliver Hill, Jaromir Sykora, Gunhild M Mælandsmo, Birgit Engesæter
In recent years, new treatment options for malignant melanoma patients have enhanced the overall survival for selected patients. Despite new hope, most melanoma patients still relapse with drug-resistant tumors or experience intrinsic resistance to the therapy. Therefore, novel treatment modalities beneficial for subgroups of patients are needed. TRAIL receptor agonists have been suggested as promising candidates for use in cancer treatment as they preferentially induce apoptosis in cancer cells. Unfortunately, the first generation of TRAIL receptor agonists showed poor clinical efficacy...
2016: Cell Death Discovery
https://www.readbyqxmd.com/read/28003746/evaluation-of-%C3%AE-cyclodextrin-modified-gemini-surfactant-based-delivery-systems-in-melanoma-models
#10
Deborah Michel, Waleed Mohammed-Saeid, Heather Getson, Caitlin Roy, Masoomeh Poorghorban, Jackson M Chitanda, Ronald Verrall, Ildiko Badea
Novel drug delivery systems are developed to improve the biological behavior of poorly soluble drugs and to improve therapeutic outcomes. In melanoma therapy, the goal is efficient drug delivery and mitigation of drug resistance. Melphalan (Mel), a currently used therapeutic agent for melanoma, requires solvent system for solubilization, leading to poor chemical stability. Moreover, drug resistance often renders the drug inefficient in clinical setting. A novel β-cyclodextrin-modified gemini surfactant (CDgemini) delivery system was developed to incorporate Mel in order to improve its physicochemical and biological behavior...
2016: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/28003325/nanoparticle-based-celecoxib-and-plumbagin-for-the-synergistic-treatment-of-melanoma
#11
Raghavendra Gowda, Gregory Kardos, Arati Sharma, Sanjay Singh, Gavin P Robertson
Using multiple drugs to kill cancer cells can decrease drug resistance development. However, this approach is frequently limited by the bioavailability and toxicity of the combined agents and delivery at ratios to specific locations that synergistically kill the cancer cells. Loading the individual agents into a nanoparticle that releases the drugs at synergizing ratios at a single location is one approach to resolve this concern. Celecoxib and Plumbagin are two drugs that were identified from a screen to synergistically kill melanoma cells compared to normal cells...
December 21, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28001152/peg-peptide-hydrogels-reveal-differential-effects-of-matrix-microenvironmental-cues-on-melanoma-drug-sensitivity
#12
Emi Y Tokuda, Caitlin E Jones, Kristi S Anseth
Metastatic melanoma is highly drug resistant, though the exact mechanisms of this resistance are not completely understood. One method to study melanoma drug responsiveness in vitro is through the use of multicellular spheroids, which have been found to exhibit decreased drug sensitivity compared to traditional 2D culture on various substrates. Because it is unclear whether dimensionality, cell-matrix interactions, and/or cell-cell contacts may influence melanoma drug responsiveness, we utilized a synthetic PEG-based hydrogel to compare the responses of cells cultured on top of or encapsulated within matrices with the same adhesive ligand density, polymer density, and material properties...
December 21, 2016: Integrative Biology: Quantitative Biosciences From Nano to Macro
https://www.readbyqxmd.com/read/27973568/yessotoxin-a-marine-toxin-exhibits-anti-allergic-and-anti-tumoural-activities-inhibiting-melanoma-tumour-growth-in-a-preclinical-model
#13
Araceli Tobío, Amparo Alfonso, Iris Madera-Salcedo, Luis M Botana, Ulrich Blank
Yessotoxins (YTXs) are a group of marine toxins produced by the dinoflagellates Protoceratium reticulatum, Lingulodinium polyedrum and Gonyaulax spinifera. They may have medical interest due to their potential role as anti-allergic but also anti-cancer compounds. However, their biological activities remain poorly characterized. Here, we show that the small molecular compound YTX causes a slight but significant reduction of the ability of mast cells to degranulate. Strikingly, further examination revealed that YTX had a marked and selective cytotoxicity for the RBL-2H3 mast cell line inducing apoptosis, while primary bone marrow derived mast cells were highly resistant...
2016: PloS One
https://www.readbyqxmd.com/read/27965097/braf-mutated-cells-activate-gcn2-mediated-integrated-stress-response-as-a-cytoprotective-mechanism-in-response-to-vemurafenib
#14
Ikuko Nagasawa, Kazuhiro Kunimasa, Satomi Tsukahara, Akihiro Tomida
In BRAF-mutated melanoma cells, the BRAF inhibitor, vemurafenib, induces phosphorylation of eukaryotic initiation factor 2α (eIF2α) and subsequent induction of activating transcription factor 4 (ATF4), the central regulation node of the integrated stress response (ISR). While the ISR supports cellular adaptation to various stresses, the role of vemurafenib-triggered ISR has not been fully characterized. Here, we showed that in response to vemurafenib, BRAF-mutated melanoma and colorectal cancer cells rapidly induced the ISR as a cytoprotective mechanism through activation of general control nonderepressible 2 (GCN2), an eIF2α kinase sensing amino acid levels...
January 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27934796/plga-loaded-nanomedicines-in-melanoma-treatment-future-prospect-for-efficient-drug-delivery
#15
REVIEW
Sreemanti Das, Anisur Rahman Khuda-Bukhsh
Current treatment methods for melanoma have some limitations such as less target-specific action, severe side effects and resistance to drugs. Significant progress has been made in exploring novel drug delivery systems based on suitable biochemical mechanisms using nanoparticles ranging from 10 to 400 nm for drug delivery and imaging, utilizing their enhanced penetration and retention properties. Poly-lactide-co-glycolide (PLGA), a copolymer of poly-lactic acid and poly-glycolic acid, provides an ideally suited performance-based design for better penetration into skin cells, thereby having a greater potential for the treatment of melanoma...
August 2016: Indian Journal of Medical Research
https://www.readbyqxmd.com/read/27934295/activity-based-protein-profiling-shows-heterogeneous-signaling-adaptations-to-braf-inhibition
#16
Ritin Sharma, Inna Fedorenko, Paige T Spence, Vernon K Sondak, Keiran S M Smalley, John M Koomen
Patients with BRAF V600E mutant melanoma are typically treated with targeted BRAF kinase inhibitors, such as vemurafenib and dabrafenib. Although these drugs are initially effective, they are not curative. Most of the focus to date has been upon genetic mechanisms of acquired resistance; therefore, we must better understand the global signaling adaptations that mediate escape from BRAF inhibition. In the current study, we have used activity-based protein profiling (ABPP) with ATP-analogue probes to enrich kinases and other enzyme classes that contribute to BRAF inhibitor (BRAFi) resistance in four paired isogenic BRAFi-naïve/resistant cell line models...
December 2, 2016: Journal of Proteome Research
https://www.readbyqxmd.com/read/27927748/axl-receptor-signalling-suppresses-p53-in-melanoma-through-stabilization-of-the-mdmx-mdm2-complex
#17
Anna de Polo, Zhongling Luo, Casimiro Gerarduzzi, Xiang Chen, John B Little, Zhi-Min Yuan
Deregulation of the tyrosine kinase signalling is often associated with tumour progression and drug resistance, but its underlying mechanisms are only partly understood. In this study, we investigated the effects of the receptor tyrosine kinase AXL on the stability of the MDMX-MDM2 heterocomplex and the activity of p53 in melanoma cells. Our data demonstrated that AXL overexpression or activation through growth arrest-specific 6 (Gas6) ligand stimulation increases MDMX and MDM2 protein levels and decreases p53 activity...
November 9, 2016: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/27926505/antitumor-effect-of-combination-of-the-inhibitors-of-two-new-oncotargets-proton-pumps-and-reverse-transcriptase
#18
Luana Lugini, Ilaria Sciamanna, Cristina Federici, Elisabetta Iessi, Enrico Pierluigi Spugnini, Stefano Fais
Tumor therapy needs new approaches in order to improve efficacy and reduce toxicity of the current treatments. The acidic microenvironment and the expression of high levels of endogenous non-telomerase reverse transcriptase (RT) are common features of malignant tumor cells. The anti-acidic proton pump inhibitor Lansoprazole (LAN) and the non-nucleoside RT inhibitor Efavirenz (EFV) have shown independent antitumor efficacy. LAN has shown to counteract drug tumor resistance. We tested the hypothesis that combination of LAN and EFV may improve the overall antitumor effects...
December 3, 2016: Oncotarget
https://www.readbyqxmd.com/read/27917404/the-emerging-role-of-cdk5-in-cancer
#19
Karine Pozo, James A Bibb
Cdk5 is an atypical cyclin-dependent kinase that is well characterized for its role in the central nervous system rather than in the cell cycle. However Cdk5 has been recently implicated in the development and progression of a variety of cancers including breast, lung, colon, pancreatic, melanoma, thyroid and brain tumors. This broad pro-tumorigenic role makes Cdk5 a promising drug target for the development of new cancer therapies. Here we review the contribution of Cdk5 to molecular mechanisms that confer upon tumors the ability to grow, proliferate and disseminate to secondary organs, as well as resistance to chemotherapies...
October 2016: Trends in Cancer
https://www.readbyqxmd.com/read/27903184/microinvasive-tumor-endoresection-in-combination-with-ocular-stereotactic-radiosurgery
#20
Oleg A Sinyavskiy, Roman L Troyanovsky, Pavel I Ivanov, Alexandr S Golovin, Andrey V Tibilov, Svetlana N Solonina, Anna M Astapenko, Irina S Zubatkina
OBJECTIVE The use of Gamma Knife radiosurgery (GKRS) as monotherapy in the treatment of uveal melanoma (UM) allows clinicians to achieve high local tumor control with low recurrence but does not prevent secondary enucleation due to glaucoma in cases of large tumors. The authors analyzed indications for tumor endoresection (ER), the time interval between irradiation and surgery, and the features and results of performing ER for UM after GKRS. METHODS Thirty-seven patients between 28 and 78 years of age (16 male and 11 female patients) with UM underwent GKRS with a dose of 70 to 80 Gy that was applied to the center of the tumor with complete immobilization of the eye during the procedure...
December 2016: Journal of Neurosurgery
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