Latest Publications

@article{machala_colon_2019,

title = {Colon Cancer and Perturbations of the Sphingolipid Metabolism.},

author = {Miroslav Machala and Jiřina Procházková and Jiřina Hofmanová and Lucie Králiková and Josef Slavík and Zuzana Tylichová and Petra Ovesná and Alois Kozubík and Jan Vondráček},

doi = {10.3390/ijms20236051},

issn = {1422-0067},

year  = {2019},

date = {2019-11-01},

journal = {International journal of molecular sciences},

volume = {20},

number = {23},

abstract = {The development and progression of colorectal cancer (CRC), a major cause of cancer-related death in the western world, is accompanied with alterations of sphingolipid (SL) composition in colon tumors. A number of enzymes involved in the SL metabolism have been found to be deregulated in human colon tumors, in experimental rodent studies, and in human colon cancer cells in vitro. Therefore, the enzymatic pathways that modulate SL levels have received a significant attention, due to their possible contribution to CRC development, or as potential therapeutic targets. Many of these enzymes are associated with an increased sphingosine-1-phosphate/ceramide ratio, which is in turn linked with increased colon cancer cell survival, proliferation and cancer progression. Nevertheless, more attention should also be paid to the more complex SLs, including specific glycosphingolipids, such as lactosylceramides, which can be also deregulated during CRC development. In this review, we focus on the potential roles of individual SLs/SL metabolism enzymes in colon cancer, as well as on the pros and cons of employing the current in vitro models of colon cancer cells for lipidomic studies investigating the SL metabolism in CRC.},

note = {Place: Switzerland},

keywords = {*Gene Expression Regulation, Acid Ceramidase/genetics/metabolism, Alkaline Ceramidase/genetics/metabolism, Animal, Animals, Ceramides/metabolism, colon cancer (CRC) sphingolipidomics, colon cancer cells, Colonic Neoplasms/*enzymology/genetics/pathology, colorectal cancer, Cultured, Disease Models, glycosphingolipid, Humans, Lactosylceramide, Lactosylceramides/*metabolism, Lipid Metabolism/*genetics, Lysophospholipids/metabolism, Neoplastic, Neutral Ceramidase/genetics/metabolism, Phosphotransferases (Alcohol Group Acceptor)/genetics/metabolism, Proto-Oncogene Proteins c-akt/genetics/metabolism, sphingolipid, Sphingolipids/*metabolism, Sphingosine N-Acyltransferase/genetics/metabolism, sphingosine-1-phosphate, Sphingosine/analogs & derivatives/metabolism, Tumor Cells},

pubstate = {published},

tppubtype = {article}

}

@article{samadder_synthesis_2017,

title = {Synthesis and Profiling of a Novel Potent Selective Inhibitor of CHK1 Kinase Possessing Unusual N-trifluoromethylpyrazole Pharmacophore Resistant to Metabolic N-dealkylation.},

author = {Pounami Samadder and Tereza Suchánková and Ondřej Hylse and Prashant Khirsariya and Fedor Nikulenkov and Stanislav Drápela and Nicol Straková and Petr Vaňhara and Kateřina Vašíčková and Hana Kolářová and Lucia Binó and Miroslava Bittová and Petra Ovesná and Peter Kollár and Radek Fedr and Milan Ešner and Josef Jaroš and Aleš Hampl and Lumír Krejčí and Kamil Paruch and Karel Souček},

doi = {10.1158/1535-7163.MCT-17-0018},

issn = {1538-8514 1535-7163},

year  = {2017},

date = {2017-09-01},

journal = {Molecular cancer therapeutics},

volume = {16},

number = {9},

pages = {1831–1842},

abstract = {Checkpoint-mediated dependency of tumor cells can be deployed to selectively kill them without substantial toxicity to normal cells. Specifically, loss of CHK1, a serine threonine kinase involved in the surveillance of the G(2)-M checkpoint in the presence of replication stress inflicted by DNA-damaging drugs, has been reported to dramatically influence the viability of tumor cells. CHK1's pivotal role in maintaining genomic stability offers attractive opportunity for increasing the selectivity, effectivity, and reduced toxicity of chemotherapy. Some recently identified CHK1 inhibitors entered clinical trials in combination with DNA antimetabolites. Herein, we report synthesis and profiling of MU380, a nontrivial analogue of clinically profiled compound SCH900776 possessing the highly unusual N-trifluoromethylpyrazole motif, which was envisioned not to undergo metabolic oxidative dealkylation and thereby provide greater robustness to the compound. MU380 is a selective and potent inhibitor of CHK1 which sensitizes a variety of tumor cell lines to hydroxyurea or gemcitabine up to 10 times. MU380 shows extended inhibitory effects in cells, and unlike SCH900776, does not undergo in vivo N-dealkylation to the significantly less selective metabolite. Compared with SCH900776, MU380 in combination with GEM causes higher accumulation of DNA damage in tumor cells and subsequent enhanced cell death, and is more efficacious in the A2780 xenograft mouse model. Overall, MU380 represents a novel state-of-the-art CHK1 inhibitor with high potency, selectivity, and improved metabolic robustness to oxidative N-dealkylation. Mol Cancer Ther; 16(9); 1831-42. ©2017 AACR.},

note = {Place: United States},

keywords = {Animal, Animals, Antineoplastic Agents/*chemical synthesis/*pharmacology, Apoptosis/drug effects, Biomarkers, Cell Cycle Checkpoints/drug effects, Cell Cycle/drug effects, Cell Line, Checkpoint Kinase 1/*antagonists & inhibitors, Dealkylation/drug effects, Disease Models, Dose-Response Relationship, Drug, Drug resistance, Humans, Methylation, Mice, Molecular Structure, Neoplasm/*drug effects, Protein Kinase Inhibitors/*chemical synthesis/*pharmacology, Pyrazoles/pharmacology, Pyrimidines/pharmacology, Tumor, Xenograft Model Antitumor Assays},

pubstate = {published},

tppubtype = {article}

}