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Cancer pathways

Mahalaqua Nazli Khatib, Abhay Gaidhane, Shilpa Gaidhane, Zahiruddin Syed Quazi
Cachexia is a devastating complication of cancer and an important cause of morbidity and mortality and can have a great effect on quality of life, and sense of self-esteem. Unfortunately; there is no standard cure available for cancer cachexia. Ghrelin; a 28 amino acid orexigenic gut hormone and its mimetics have shown potential benefits in reversing the breakdown of protein and weight loss in catabolic states like cancer cachexia. Ghrelin has effects on several vital pathways in the regulation of appetite, and composition of the body...
August 15, 2018: Cellular Physiology and Biochemistry
Lin Yang, Cui Ma, Lixin Zhang, Min Zhang, Fei Li, Chen Zhang, Xiufeng Yu, Xiaoying Wang, Siyu He, Daling Zhu, Yinli Song
15-Lipoxygenase-2 (15-LOX-2) and 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) have been considered as latent mediators of diverse biological processes including cancer. However, their functions in lung adenocarcinoma (LAC) are unclear. In this study, we aimed to determine whether 15-LOX-2/15(S)-HETE is involved in the proliferation and migration of A549 cells and to identify the signaling pathways that participate in this process. We used immunohistochemistry to identify the expression levels of 15-LOX-2 in lung cancer tissue samples...
August 12, 2018: Prostaglandins & Other Lipid Mediators
Chie Kudo-Saito, Akiko Ishida, Yuji Shouya, Koji Teramoto, Tomoyuki Igarashi, Ryoko Kon, Kenji Saito, Chihiro Awada, Yamato Ogiwara, Masayoshi Toyoura
Immune dysfunction is a strong factor in the resistance of cancer to treatment. Blocking immune checkpoint pathways is a promising approach to improve anti-tumor immunity, but the clinical efficacies are still limited. We previously identified follistatin-like 1 (FSTL1) as a determinant of immune dysfunction mediated by mesenchymal stromal/stem cells (MSCs) and immunoregulatory cells. Here, we demonstrate that blocking FSTL1 but not immune checkpoint pathways significantly suppresses cancer progression and metastasis in several mouse tumor models with increased MSCs...
August 14, 2018: Cell Reports
Lavina Sierra Tay, Vaidehi Krishnan, Haresh Sankar, Yu Lin Chong, Linda Shyue Huey Chuang, Tuan Zea Tan, Arun Mouli Kolinjivadi, Dennis Kappei, Yoshiaki Ito
The Fanconi anemia (FA) pathway is a pivotal genome maintenance network that orchestrates the repair of DNA interstrand crosslinks (ICLs). The tumor suppressors RUNX1 and RUNX3 were shown to regulate the FA pathway independent of their canonical transcription activities, by controlling the DNA damage-dependent chromatin association of FANCD2. Here, in further biochemical characterization, we demonstrate that RUNX3 is modified by PARP-dependent poly(ADP-ribosyl)ation (PARylation), which in turn allows RUNX binding to DNA repair structures lacking transcription-related RUNX consensus motifs...
August 14, 2018: Cell Reports
Masanori Kawakami, Xi Liu, Ethan Dmitrovsky
Aneuploidy is a hallmark of cancer. Defects in chromosome segregation result in aneuploidy. Multiple pathways are engaged in this process, including errors in kinetochore-microtubule attachments, supernumerary centrosomes, spindle assembly checkpoint (SAC) defects, and chromosome cohesion defects. Although aneuploidy provides an adaptation and proliferative advantage in affected cells, excessive aneuploidy beyond a critical level can be lethal to cancer cells. Given this, enhanced chromosome missegregation is hypothesized to limit survival of aneuploid cancer cells, especially when compared to diploid cells...
August 15, 2018: Annual Review of Pharmacology and Toxicology
Ashley T Fancher, Yun Hua, Daniel P Camarco, David A Close, Christopher J Strock, Paul A Johnston
Twenty percent of prostate cancer (PCa) patients develop a noncurable drug-resistant form of the disease termed castration-resistant prostate cancer (CRPC). Overexpression of Androgen Receptor (AR) coactivators such as transcriptional intermediary factor 2 (TIF2) is associated with poor CRPC patient outcomes. We describe the implementation of the AR-TIF2 protein-protein interaction biosensor (PPIB) assay in a high-content screening (HCS) campaign of 143,535 compounds. The assay performed robustly and reproducibly and enabled us to identify compounds that inhibited dihydrotestosterone (DHT)-induced AR-TIF2 protein-protein interaction (PPI) formation or disrupted preexisting AR-TIF2 PPIs...
August 15, 2018: Assay and Drug Development Technologies
T Coxon, L Goldstein, B K Odhiambo
Increasing anthropogenic alteration has resulted in increased exposure to both point and nonpoint source pollution. These exposures are increasingly studied for their role in human diseases, including diseases with known genetic or lifestyle risk factors. This study analyzed associations between a variety of human diseases and trace metals, PCBs, and PAHs in soil, groundwater, sediment, and fish. Contaminant spatial data at the county level from Virginia were used in ArcGIS to identify these associations among socially vulnerable populations...
August 14, 2018: Environmental Geochemistry and Health
Maria Luisa Gasparri, Zein Mersini Besharat, Ammad Ahmad Farooqi, Sumbul Khalid, Katayoun Taghavi, Raad Aris Besharat, Claudia Sabato, Andrea Papadia, Pierluigi Benedetti Panici, Michael David Mueller, Elisabetta Ferretti
Ovarian cancer is a leading cause of death among gynecologic malignancies. This disappointing prognosis is closely related to intrinsic or acquired resistance to conventional platinum-based chemotherapy, which can affect a third of patients. As such, investigating relevant molecular targets is crucial in the fight against this disease. So far, many mutations involved in ovarian cancer pathogenesis have been identified. Among them, a few pathways were implicated. One such pathway is the P13K/AKT/mTOR with abnormalities found in many cases...
August 14, 2018: Journal of Cancer Research and Clinical Oncology
Anna L Means, Tanner J Freeman, Jing Zhu, Luke G Woodbury, Paula Marincola-Smith, Chao Wu, Anne R Meyer, Connie J Weaver, Chandrasekhar Padmanabhan, Hanbing An, Jinghuan Zi, Bronson C Wessinger, Rupesh Chaturvedi, Tasia D Brown, Natasha G Deane, Robert J Coffey, Keith T Wilson, J Joshua Smith, Charles L Sawyers, James R Goldenring, Sergey V Novitskiy, M Kay Washington, Chanjuan Shi, R Daniel Beauchamp
Background & Aims: Chronic inflammation is a predisposing condition for colorectal cancer. Many studies to date have focused on proinflammatory signaling pathways in the colon. Understanding the mechanisms that suppress inflammation, particularly in epithelial cells, is critical for developing therapeutic interventions. Here, we explored the roles of transforming growth factor β (TGFβ) family signaling through SMAD4 in colonic epithelial cells. Methods: The Smad4 gene was deleted specifically in adult murine intestinal epithelium...
2018: Cellular and Molecular Gastroenterology and Hepatology
Amber M D'Souza, Yanjun Jiang, Ashley Cast, Leila Valanejad, Mary Wright, Kyle Lewis, Meenasri Kumbaji, Sheeniza Shah, David Smithrud, Rebekah Karns, Soona Shin, Nikolai Timchenko
Background & Aims: Uncontrolled liver proliferation is a key characteristic of liver cancer; however, the mechanisms by which this occurs are not well understood. Elucidation of these mechanisms is necessary for the development of better therapy. The oncogene Gankyrin (Gank) is overexpressed in both hepatocellular carcinoma and hepatoblastoma. The aim of this work was to determine the role of Gank in liver proliferation and elucidate the mechanism by which Gank promotes liver proliferation...
2018: Cellular and Molecular Gastroenterology and Hepatology
Emira Bousoik, Hamidreza Montazeri Aliabadi
Janus tyrosine kinase (JAK) family of proteins have been identified as crucial proteins in signal transduction initiated by a wide range of membrane receptors. Among the proteins in this family JAK2 has been associated with important downstream proteins, including signal transducers and activators of transcription (STATs), which in turn regulate the expression of a variety of proteins involved in induction or prevention of apoptosis. Therefore, the JAK/STAT signaling axis plays a major role in the proliferation and survival of different cancer cells, and may even be involved in resistance mechanisms against molecularly targeted drugs...
2018: Frontiers in Oncology
Feifei Liu, Xiaotong Yang, Meiyu Geng, Min Huang
The mitogen-activated protein kinases (MAPK) pathway, often known as the RAS-RAF-MEK-ERK signal cascade, functions to transmit upstream signals to its downstream effectors to regulate physiological process such as cell proliferation, differentiation, survival and death. As the most frequently mutated signaling pathway in human cancer, targeting the MAPK pathway has long been considered a promising strategy for cancer therapy. Substantial efforts in the past decades have led to the clinical success of BRAF and MEK inhibitors...
July 2018: Acta Pharmaceutica Sinica. B
Brandon Bumbaca, Wei Li
Despite its good initial response and significant survival benefit in patients with castration-resistant prostate cancer (CRPC), taxane therapy inevitably encounters drug resistance in all patients. Deep understandings of taxane resistant mechanisms can significantly facilitate the development of new therapeutic strategies to overcome taxane resistance and improve CRPC patient survival. Multiple pathways of resistance have been identified as potentially crucial areas of intervention. First, taxane resistant tumor cells typically have mutated microtubule binding sites, varying tubulin isotype expression, and upregulation of efflux transporters...
July 2018: Acta Pharmaceutica Sinica. B
Hui Lyu, Amy Han, Erik Polsdofer, Shuang Liu, Bolin Liu
HER3 belongs to the human epidermal growth factor receptor (HER) family which also includes HER1/EGFR/erbB1, HER2/erbB2, and HER4/erbB4. As a unique member of the HER family, HER3 lacks or has little intrinsic tyrosine kinase activity. It frequently co-expresses and forms heterodimers with other receptor tyrosine kinases (RTKs) in cancer cells to activate oncogenic signaling, especially the PI-3K/Akt pathway and Src kinase. Elevated expression of HER3 has been observed in a wide variety of human cancers and associates with a worse survival in cancer patients with solid tumors...
July 2018: Acta Pharmaceutica Sinica. B
Wuji Sun, Shubiao Fang, Hong Yan
Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in tumor angiogenesis, and inhibition of the VEGFR-2 signaling pathway has emerged as an attractive target for cancer therapy. In our effort, a novel series of picolinamide-based derivatives were designed and synthesized as potent and effective VEGFR-2 inhibitors. All the newly prepared compounds were evaluated in vitro for their antiproliferative activity against A549 and HepG2 cell lines. Among the new compounds, 8j and 8l exhibited better activity against both A549 and HepG2 cell lines...
June 1, 2018: MedChemComm
Agnese C Pippione, Stefano Sainas, Antonella Federico, Elisa Lupino, Marco Piccinini, Michael Kubbutat, Jean-Marie Contreras, Christophe Morice, Alessandro Barge, Alex Ducime, Donatella Boschi, Salam Al-Karadaghi, Marco L Lolli
NF-κB-inducing kinase (NIK), an oncogenic drug target that is associated with various cancers, is a central signalling component of the non-canonical pathway. A blind screening process, which established that amino pyrazole related scaffolds have an effect on IKKbeta, led to a hit-to-lead optimization process that identified the aminopyrazole 3a as a low μM selective NIK inhibitor. Compound 3a effectively inhibited the NIK-dependent activation of the NF-κB pathway in tumour cells, confirming its selective inhibitory profile...
June 1, 2018: MedChemComm
Viola Previtali, Cristina Trujillo, Rebecca Amet, Daniela M Zisterer, Isabel Rozas
Considering our hypothesis that the guanidinium moiety in the protein kinase type III inhibitor 1 interacts with a phosphate of ATP within the hinge region, the nature of the interactions established between a model isouronium and the phosphate groups of ATP was computationally analysed indicating that an isouronium derivative of 1 will interact in a similar manner with ATP. Thus, a number of compounds were prepared to assess the effect of the guanidinium/isouronium substitution on cancer cell growth; additionally, the molecular shortening and conformational change induced by replacing the di-substituted guanidine-linker of 1 by an amide was explored...
April 1, 2018: MedChemComm
Xianling Ning, Yunqiao Li, Hailong Qi, Ridong Li, Yan Jin, Junyi Liu, Yuxin Yin
Tumor cells reprogram their cellular metabolism by switching from oxidative phosphorylation to aerobic glycolysis to support aberrant cell proliferation. Suppressing tumor cell metabolism has become an attractive strategy for treating cancer patients. In this study, we identified a 2,3-didithiocarbamate-substituted naphthoquinone 3i that inhibited the proliferation of tumor cells by disturbing their metabolism. Compound 3i reduced cancer cell viability with IC50 values from 50 nM to 150 nM against HCT116, MCF7, MDA-MB231, HeLa, H1299 and B16 cells...
April 1, 2018: MedChemComm
Marcel König, Daniel Siegmund, Lukasz J Raszeja, Aram Prokop, Nils Metzler-Nolte
Emerging resistances of tumors against multiple anti-cancer agents are a major concern in the chemotherapeutical treatment of various cancers. Clearly, this raises the need for novel therapeutics with new modes of action. Herein, we report on the favorable in vitro anti-proliferative properties of a phenanthridine-containing ReI (CO)3 complex (compound 1 , also abbreviated LR-166) and identify major contributions to its mode of action. The complex induces apoptosis in low micromolar concentrations even in drug-resistant Burkitt-like lymphoma (BJAB) and leukemia (Nalm-6) cell lines with known overexpression of p -glycoproteins as was confirmed by measuring the amount of hypodiploid DNA via FACS Scan analysis...
January 1, 2018: MedChemComm
Chetan Kumar, Reyaz Ur Rasool, Zainab Iqra, Yedukondalu Nalli, Prabhu Dutt, Naresh K Satti, Neha Sharma, Sumit G Gandhi, Anindya Goswami, Asif Ali
Herein, we report the isolation and synthetic modification of dehydrozingerone (DHZ, 1 ), a secondary metabolite present in the rhizome of Zingiber officinale . We synthesized O -propargylated dehydrozingerone, which was subsequently coupled by alkyne-azide cycloaddition ( 3-20 ) using click chemistry. The compounds ( 1-20 ) were evaluated for their in vitro cytotoxic activity in a panel of three cancer cell lines. Among all the DHZ derivatives, 3 , 6 , 7 , 8 , 9 and 15 displayed potent cytotoxic potential with an IC50 value ranging from 1...
November 1, 2017: MedChemComm
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