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cancer drug discovery

Seema Negi, Shashi Kala Singh, Sanjay Kumar, Subodh Kumar, Rakesh K Tyagi
Pregnane & Xenobiotic Receptor (PXR) is one of the 48 members of the ligand-modulated transcription factors belonging to nuclear receptor superfamily. Though PXR is now well-established as a 'xenosensor', regulating the central detoxification and drug metabolizing machinery, it has also emerged as a key player in several metabolic disorders. This makes PXR attractive to both, researchers and pharmaceutical industry since clinical success of small drug molecules can be pre-evaluated on PXR platform. At the early stages of drug discovery, cell-based assays are used for high-throughput screening of small molecules...
June 19, 2018: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Jenny Beebe, Jing-Yuan Liu, Jian-Ting Zhang
Signal transducer and activator of transcription 3 (STAT3) controls many biological processes including differentiation, survival, proliferation, and angiogenesis. In normal healthy cells, STAT3 is tightly regulated to maintain a momentary active state. However, aberrant or constitutively activated STAT3 has been observed in many different cancers and constitutively activated STAT3 has been shown to associate with poor prognosis and tumor progression. For this reason, STAT3 has been studied as a possible target in the treatment of many different types of cancers...
June 19, 2018: Pharmacology & Therapeutics
Alberto Bresciani, Ottavia Cecchetti, Antonino Missineo, Pier Giorgio Pacifici, Licia Tomei, Steven Rodems
Glycosylation is a key posttranslational modification that tags protein to membranes, organelles, secretory pathways, and degradation. Aberrant protein glycosylation is present both in acquired diseases, such as cancer and neurodegeneration, and in congenital disorders of glycosylation (CDGs). Consequently, the ability to interrogate the activity of enzymes that can modify protein glycan moieties is key for drug discovery projects aimed at finding modulators of these enzymes. To date, low-throughput technologies such as SDS-PAGE and mass spectrometry have been used, which are not suitable for compound screening in drug discovery...
June 1, 2018: SLAS Discovery
K C Nicolaou, Ruofan Li, Zhaoyong Lu, Emmanuel N Pitsinos, Lawrence B Alemany
Namenamicin is a rare natural product possessing potent cytotoxic properties that may prove useful as a lead compound for payloads of antibody-drug conjugates (ADCs). Its scarcity, coupled with the uncertainty of its full absolute configuration, elevates it to an attractive synthetic target. Herein we describe the total synthesis of the two C7'-epimers of namenamicin and assign its complete structure, opening the way for further chemical and biological studies toward the discovery of potent payloads for ADCs directed toward targeted cancer therapies...
June 22, 2018: Journal of the American Chemical Society
Alina D Nikotina, Lidia Koludarova, Elena Y Komarova, Elena R Mikhaylova, Nikolay D Aksenov, Roman Suezov, Viktor G Kartzev, Boris A Margulis, Irina V Guzhova
Combinational anticancer therapy demonstrates increased efficiency, as it targets different cell-survival mechanisms and allows the decrease of drug dosages that are often toxic to normal cells. Inhibitors of the heat shock response (HSR) are known to reduce the efficiency of proteostasis mechanisms in many cancerous cells, and therefore, may be employed as anti-tumor drug complements. However, the application of HSR inhibitors is limited by their cytotoxicity, and we suggested that milder inhibitors may be employed to sensitize cancer cells to a certain drug...
June 5, 2018: Oncotarget
Ricardo L Pereira, Isis C Nascimento, Ana P Santos, Isabella E Y Ogusuku, Claudiana Lameu, Günter Mayer, Henning Ulrich
Although the term 'cancer' was still over two thousand years away of being coined, the first known cases of the disease date back to about 3000BC, in ancient Egypt. Five thousand years later, still lacking a cure, it has become one of the leading causes of death, killing over half a dozen million people yearly. So far, monoclonal antibodies are the most successful immune-therapy tools when it comes to fighting cancer. The number of clinical trials that use them has been increasing steadily during the past few years, especially since the Food and Drug Administration greenlit the use of the first immune-checkpoint blockade antibodies...
June 1, 2018: Oncotarget
See-Hyoung Park, Jongsung Lee, Mi-Ae Kang, Kyu Yun Jang, Jung Ryul Kim
The outcome of chemotherapy for osteosarcoma have improved during the past decade and more patients have access to combination chemotherapy, but there has been no significant clinical progress in the patient survival rate. Recently, forkhead-box O3 (FOXO3) was identified as a pivotal transcription factor responsible for the transcriptional regulation of genes associated with suppression of cancer. The purpose of the present study was to screen small chemicals activating FOXO3 and elucidate their underlying mechanism...
June 2018: Oncology Letters
Srinivasa Reddy Bonam, Seng Wu Yuan, Lakshmi Tunki, Ranjithkumar Chellian, Sampath Kumar Halmuthur M, Sylviane Muller, Vijayapandi Pandy
Several modern treatment strategies have been adopted to combat cancer with the aim of minimizing toxicity. Medicinal plant-based compounds with the potential to treat cancer have been widely studied in preclinical research and have elicited many innovative ways of leading-edge clinical research. In parallel, researchers have eagerly tried to reduce the toxicity of current chemotherapeutic agents either by combining them with herbals or in using herbals alone. The focus of this article is to present an update of medicinal plants and their bioactive compounds, or mere changes in the bioactive compounds, and herbal edibles, which display efficacy against diverse cancer cells and in anticancer therapy...
June 21, 2018: ChemMedChem
Gianluca Civenni, Giuseppina M Carbone, Carlo V Catapano
Prostate cancer (PCa) is the most common malignant visceral neoplasm in males in Western countries. Despite progress made in the early treatment of localized malignancies, there remains a need for therapies effective against advanced forms of the disease. Genetically engineered mouse (GEM) models are valuable tools for addressing this issue, particularly in defining the cellular and molecular mechanisms responsible for tumor initiation and progression. While cell and tissue culture systems are important models for this purpose as well, they cannot recapitulate the complex interactions within heterotypic cells and the tumor microenvironment that are crucial in the initiation and progression of prostate tumors...
June 7, 2018: Current Protocols in Pharmacology
Wolfram C M Dempke, Peter Uciechowski, Klaus Fenchel, Timothy Chevassut
Well-balanced levels of tyrosine phosphorylation, maintained by the reversible and coordinated actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), are critical for a wide range of cellular processes including growth, differentiation, metabolism, migration, and survival. Aberrant tyrosine phosphorylation, as a result of a perturbed balance between the activities of PTKs and PTPs, is linked to the pathogenesis of numerous human diseases, including cancer, suggesting that PTPs may be innovative molecular targets for cancer treatment...
June 20, 2018: Oncology
Signe Borgquist, Olöf Bjarnadottir, Siker Kimbung, Thomas P Ahern
Statin drugs have been used for more than two decades to treat hypercholesterolemia and as cardio-preventive drugs, resulting in a marked decrease in cardiovascular morbidity and mortality worldwide. Statins halt hepatic cholesterol biosynthesis by inhibiting the rate-limiting enzyme in the mevalonate pathway, hydroxymethylglutaryl-coenzyme A reductase (HMGCR). The mevalonate pathway regulates a host of biochemical processes in addition to cholesterol production. Attenuation of these pathways is likely responsible for the myriad benefits of statin therapy beyond cholesterol reduction-the so-called pleiotropic effects of statins...
June 20, 2018: Journal of Internal Medicine
Srinidi Mohan, Seema Patel, Ian Greenstein, Cathy Ng, Kelly Frazier, Giang Nguyen, Lisa Harding, David Barlow
We had shown Nw -hydroxy-L-arginine (NOHA) as a promising blood-based biomarker for estrogen-receptor-negative (ER - ) breast cancer (BC) that differentiates ER - BC based on grade and molecular phenotype. In this in vitro study, we assessed the metabolic relevance for ER- BC-specific NOHA modulation and correlated them with NOHA regulatory responses. This study aids future NOHA clinical utility in ER- BC diagnosis and therapy management and would prove useful for potential drug discovery and development process...
June 20, 2018: Amino Acids
Alison E Casey, Ankit Sinha, Rajat Singhania, Julie Livingstone, Paul Waterhouse, Pirashaanthy Tharmapalan, Jennifer Cruickshank, Mona Shehata, Erik Drysdale, Hui Fang, Hyeyeon Kim, Ruth Isserlin, Swneke Bailey, Tiago Medina, Genevieve Deblois, Yu-Jia Shiah, Dalia Barsyte-Lovejoy, Stefan Hofer, Gary Bader, Mathieu Lupien, Cheryl Arrowsmith, Stefan Knapp, Daniel De Carvalho, Hal Berman, Paul C Boutros, Thomas Kislinger, Rama Khokha
The mammary epithelium depends on specific lineages and their stem and progenitor function to accommodate hormone-triggered physiological demands in the adult female. Perturbations of these lineages underpin breast cancer risk, yet our understanding of normal mammary cell composition is incomplete. Here, we build a multimodal resource for the adult gland through comprehensive profiling of primary cell epigenomes, transcriptomes, and proteomes. We define systems-level relationships between chromatin-DNA-RNA-protein states, identify lineage-specific DNA methylation of transcription factor binding sites, and pinpoint proteins underlying progesterone responsiveness...
June 19, 2018: Journal of Cell Biology
Tayaba Ismail, Hyun-Kyung Lee, Chowon Kim, Taejoon Kwon, Tae Joo Park, Hyun-Shik Lee
The lysine-specific histone demethylase 1A (KDM1A) was the first demethylase to challenge the concept of the irreversible nature of methylation marks. KDM1A, containing a flavin adenine dinucleotide (FAD)-dependent amine oxidase domain, demethylates histone 3 lysine 4 and histone 3 lysine 9 (H3K4me1/2 and H3K9me1/2). It has emerged as an epigenetic developmental regulator and was shown to be involved in carcinogenesis. The functional diversity of KDM1A originates from its complex structure and interactions with transcription factors, promoters, enhancers, oncoproteins, and tumor-associated genes (tumor suppressors and activators)...
June 19, 2018: Epigenetics & Chromatin
Michael W Mullowney, Ryan A McClure, Matthew T Robey, Neil L Kelleher, Regan J Thomson
Covering: up to 2018Thioester reductase domains catalyze two- and four-electron reductions to release natural products following assembly on nonribosomal peptide synthetases, polyketide synthases, and their hybrid biosynthetic complexes. This reductive off-loading of a natural product yields an aldehyde or alcohol, can initiate the formation of a macrocyclic imine, and contributes to important intermediates in a variety of biosyntheses, including those for polyketide alkaloids and pyrrolobenzodiazepines. Compounds that arise from reductase-terminated biosynthetic gene clusters are often reactive and exhibit biological activity...
June 19, 2018: Natural Product Reports
J M Rothenstein, N Chooback
The treatment of advanced non-small-cell lung cancer (nsclc) has undergone a paradigm shift since the early 2000s. The identification of molecular subtypes of the disease, based on oncogenic drivers, has led to the development of personalized medicine and the ability to deliver molecularly targeted therapies to patients. In the 10 years that have elapsed since the discovery of the ALK gene in a patient with nsclc, several active drugs have moved rapidly from bench to bedside, and multiple others are currently in clinical trials...
June 2018: Current Oncology
Jessie Peh, Matthew W Boudreau, Hannah M Smith, Paul J Hergenrother
The discovery of mutant or fusion kinases that drive oncogenesis, and the subsequent approval of specific inhibitors for these enzymes, has been instrumental in the management of some cancers. However, acquired resistance remains a significant problem in the clinic, limiting the long-term effectiveness of most of these drugs. Here we demonstrate a general strategy to overcome this resistance through drug-induced MEK cleavage (via direct procaspase-3 activation) combined with targeted kinase inhibition. This combination effect is shown to be general across diverse tumor histologies (melanoma, lung cancer, and leukemia) and driver mutations (mutant BRAF or EGFR, fusion kinases EML4-ALK and BCR-ABL)...
May 18, 2018: Cell Chemical Biology
Neil D Young, Robin B Gasser
Opisthorchiasis is a neglected tropical disease of major proportion, caused by the carcinogenic, Asian liver fluke, Opisthorchis viverrini. This hepatobiliary disease is known to be associated with malignant cancer (cholangiocarcinoma, CCA) and affects millions of people in Southeast Asia. No vaccine is available, and only one drug (praziquantel) is routinely employed against the parasite. Despite technological advances, little is known about the molecular biology of the fluke itself and the disease complex that it causes in humans...
2018: Advances in Parasitology
H Saari, E Lisitsyna, K Rautaniemi, T Rojalin, L Niemi, O Nivaro, T Laaksonen, M Yliperttula, E Vuorimaa-Laukkanen
In response to physiological and artificial stimuli, cells generate nano-scale extracellular vesicles (EVs) by encapsulating biomolecules in plasma membrane-derived phospholipid envelopes. These vesicles are released to bodily fluids, hence acting as powerful endogenous mediators in intercellular signaling. EVs provide a compelling alternative for biomarker discovery and targeted drug delivery, but their kinetics and dynamics while interacting with living cells are poorly understood. Here we introduce a novel method, fluorescence lifetime imaging microscopy (FLIM) to investigate these interaction attributes...
June 12, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Guanhua Rao, In-Kyu Kim, Fabio Conforti, Jing Liu, Yu-Wen Zhang, Giuseppe Giaccone
PURPOSE: Oncogenic KRAS mutations occur frequently in solid tumours, but no clinically applicable targeted strategy is yet available for treating human cancers with mutant KRAS. Here we aimed to identify a strategy for the treatment of KRAS-driven cancers. EXPERIMENTAL DESIGN: Cell viability and colony forming assays were used to assess the in vitro effect of dasatinib and trametinib as single agents or in combination. Western blot was used to analyse the phosphorylated protein and total protein levels...
June 11, 2018: European Journal of Cancer
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