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https://www.readbyqxmd.com/read/28317088/phase-i-trial-of-the-oral-smoothened-inhibitor-sonidegib-in-combination-with-paclitaxel-in-patients-with-advanced-solid-tumors
#1
A Stathis, D Hess, R von Moos, K Homicsko, G Griguolo, M Joerger, M Mark, C J Ackermann, S Allegrini, C V Catapano, A Xyrafas, M Enoiu, S Berardi, P Gargiulo, C Sessa
Purpose To establish a recommended phase II dose (RP2D) for the oral smoothened inhibitor sonidegib in combination with paclitaxel; secondary objectives include evaluation of safety, tolerability, markers of Hedgehog (Hh) signaling and preliminary antitumor activity. Methods Patients with advanced solid tumors were enrolled in cohorts of escalating sonidegib dose levels (400mg, 600mg and 800mg orally, once daily on days 1-28) in combination with paclitaxel 80 mg/m(2) on days 1, 8 and 15 in 4-weekly cycles. Dose-limiting toxicities (DLTs) were assessed using CTCAE v4...
March 20, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28302010/discovery-of-hedgehog-antagonists-for-cancer-therapy
#2
Harleen Khatra, Chandra Bose, Surajit Sinha
BACKGROUND: The evolutionarily conserved Hedgehog (Hh) signaling cascade is one of the key mediators of embryonic development of many metazoans. This pathway has been extensively targeted by small molecule inhibitors as its misregulation leads to various malignancies and developmental disorders. Thus, blocking this pathway can be a novel therapeutic avenue for the treatment of Hedgehog-dependent cancers. This review covers the mechanism of hedgehog signaling in vertebrate cells, provides an overview of reported small molecule Hh pathway inhibitors, with the synthetic routes and SAR studies of some of them discussed briefly...
March 16, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28286162/gli1-expression-in-cancer-stem-like-cells-predicts-poor-prognosis-in-patients-with-lung-squamous-cell-carcinoma
#3
Yan Cui, Chun-Ai Cui, Zhao-Ting Yang, Wei-Dong Ni, Yu Jin, Yan-Hua Xuan
PURPOSE: Glioma-associated oncogene homolog 1 (Gli1) is involved in cancer stem cell (CSC) maintenance in various tumors; however, its expression and clinical significance in lung squamous cell carcinoma (LSCC) has not been reported. In this study, we aimed to reveal the clinical significance of Gli1 in LSCC and investigate the potential of Gli1 as a CSC marker by comparing its expression with that of other stemness-related genes in LSCC. METHODS: We assessed the expressions of Gli1, LSD1, CD44, Sox9 and Sox2 by immunohistochemistry in the tissue specimens obtained from 101 patients with LSCC...
March 9, 2017: Experimental and Molecular Pathology
https://www.readbyqxmd.com/read/28277196/downregulation-of-rab23-in-prostate-cancer-inhibits-tumor-growth-in-vitro-and-in-vivo
#4
Junkai Chang, Weibo Xu, Guangchao Liu, Xinyi Du, Xiaodong Li
Rab23, a novel member of the Rab GTPase family, was found to be implicated in the progression of some human cancers. However, what role Rab23 plays in prostate cancer (PCa) remains to be illustrated. In the present study, we investigated the expression pattern and roles of Rab23 in PCa. The study results showed that Rab23 was upregulated in PCa tissues and cell lines. Moreover, downregulation of Rab23 remarkably suppressed the proliferation, migration, and invasion of PCa cells. In addition, downregulation of Rab23 significantly downregulated the protein expression levels of Shh and Gli1...
January 26, 2017: Oncology Research
https://www.readbyqxmd.com/read/28276480/selective-targeting-of-hdac1-2-elicits-anticancer-effects-through-gli1-acetylation-in-preclinical-models-of-shh-medulloblastoma
#5
Sonia Coni, Anna Barbara Mancuso, Laura Di Magno, Giulia Sdruscia, Simona Manni, Silvia Maria Serrao, Dante Rotili, Eleonora Spiombi, Francesca Bufalieri, Marialaura Petroni, Monika Kusio-Kobialka, Enrico De Smaele, Elisabetta Ferretti, Carlo Capalbo, Antonello Mai, Pawel Niewiadomski, Isabella Screpanti, Lucia Di Marcotullio, Gianluca Canettieri
SHH Medulloblastoma (SHH-MB) is a pediatric brain tumor characterized by an inappropriate activation of the developmental Hedgehog (Hh) signaling. SHH-MB patients treated with the FDA-approved vismodegib, an Hh inhibitor that targets the transmembrane activator Smoothened (Smo), have shown the rapid development of drug resistance and tumor relapse due to novel Smo mutations. Moreover, a subset of patients did not respond to vismodegib because mutations were localized downstream of Smo. Thus, targeting downstream Hh components is now considered a preferable approach...
March 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28275687/hedgehog-signaling-links-chronic-inflammation-to-gastric-cancer-precursor-lesions
#6
REVIEW
Juanita L Merchant, Lin Ding
Since its initial discovery in Drosophila, Hedgehog (HH) signaling has long been associated with foregut development. The mammalian genome expresses 3 HH ligands, with sonic hedgehog (SHH) levels highest in the mucosa of the embryonic foregut. More recently, interest in the pathway has shifted to improving our understanding of its role in gastrointestinal cancers. The use of reporter mice proved instrumental in our ability to probe the expression pattern of SHH ligand and the cell types responding to canonical HH signaling during homeostasis, inflammation, and neoplastic transformation...
March 2017: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28259943/sclareolide-enhances-gemcitabine%C3%A2-induced-cell-death-through-mediating-the-nicd-and-gli1-pathways-in-gemcitabine%C3%A2-resistant-human-pancreatic-cancer
#7
Sheng Chen, Ye Wang, Wen-Long Zhang, Mao-Sheng Dong, Jian-Hua Zhang
Pancreatic cancer is a type of cancer, which rapidly develops resistance to chemotherapy. Gemcitabine is the treatment used clinically, however, gemcitabine resistance leads to limited efficacy and patient survival rates of only a few months following diagnosis. The aim of the present study was to investigate the mechanisms underlying gemcitabine resistance in pancreatic cancer and to select targeted agents combined with gemcitabine to promote the treatment of pancreatic cancer. Panc‑1 and ASPC‑1 human pancreatic cancer cells (HPCCs) were used to establish the experimental model, and HPCCs were exposed to gemcitabine of serially increased concentrations to generate gemcitabine‑resistant cells (GR‑HPCCs)...
February 8, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28219952/enthesis-regeneration-a-role-for-gli1-progenitor-cells
#8
Andrea G Schwartz, Leesa M Galatz, Stavros Thomopoulos
The tendon enthesis originates from a specific pool of hedgehog-active Gli1+ progenitor cells that differentiate and produce mineralized fibrocartilage. The current study investigated the regenerative capacity of this cell population by comparing the responses of early postnatal and mature entheses to injury. Lineage tracing studies demonstrated that the original Gli1+ cell population had the capacity to heal immature entheses after injury but this capacity was lost after the cells differentiated into mature fibrochondrocytes...
February 20, 2017: Development
https://www.readbyqxmd.com/read/28213929/exploration-of-the-brn4-regulated-genes-enhancing-adult-hippocampal-neurogenesis-by-rna-sequencing
#9
Jingjing Guo, Xiang Cheng, Lei Zhang, Linmei Wang, Yongxin Mao, Guixiang Tian, Wenhao Xu, Yuhao Wu, Zhi Ma, Jianbing Qin, Meiling Tian, Guohua Jin, Wei Shi, Xinhua Zhang
Adult hippocampal neurogenesis is essential for learning and memory, and its dysfunction is involved in neurodegenerative diseases. However, the molecular mechanisms underlying adult hippocampal neurogenesis are still largely unknown. Our previous studies indicated that the transcription factor Brn4 was upregulated and promoted neuronal differentiation of neural stem cells (NSCs) in the surgically denervated hippocampus in rats. In this study, we use high-throughput RNA sequencing to explore the molecular mechanisms underlying the enhancement of adult hippocampal neurogenesis induced by lentivirus-mediated Brn4 overexpression in vivo...
February 18, 2017: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/28208838/the-effect-of-metformin-and-gant61-combinations-on-the-radiosensitivity-of-prostate-cancer-cells
#10
Annelies Gonnissen, Sofie Isebaert, Chad M McKee, Ruth J Muschel, Karin Haustermans
The anti-diabetes drug metformin has been shown to have anti-neoplastic effects in several tumor models through its effects on energy metabolism and protein synthesis. Recent studies show that metformin also targets Hedgehog (Hh) signaling, a developmental pathway re-activated in several tumor types, including prostate cancer (PCa). Furthermore, we and others have shown that Hh signaling is an important target for radiosensitization. Here, we evaluated the combination of metformin and the Hh inhibitor GANT61 (GLI-ANTagonist 61) with or without ionizing radiation in three PCa cell lines (PC3, DU145, 22Rv1)...
February 13, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28195165/smoothened-is-a-poor-prognosis-factor-and-a-potential-therapeutic-target-in-glioma
#11
Yiming Tu, Mingshan Niu, Peng Xie, Chenglong Yue, Ning Liu, Zhenglei Qi, Shangfeng Gao, Hongmei Liu, Qiong Shi, Rutong Yu, Xuejiao Liu
Malignant gliomas are associated with a high mortality rate. Thus, there is an urgent need for the development of novel targeted therapeutics. Aberrant Hedgehog signaling has been directly linked to glioma. GDC-0449 is a novel small molecule inhibitor of Hedgehog signaling that blocks the activity of smoothened (Smo). In this study, we evaluated the in vitro and in vivo effects of the smoothened inhibitor GDC-0449 on cell proliferation in human gliomas. We found that high expression of smoothened in glioma is a predictor of short overall survival and poor patient outcome...
February 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28188758/a-role-for-the-hedgehog-effector-gli1-in-mediating-stent-induced-ureteral-smooth-muscle-dysfunction-and-aperistalsis
#12
Claudia Janssen, Ralph Buttyan, Chun Y Seow, Wolfgang Jäger, Dennis Solomon, Ladan Fazli, Ben H Chew, Dirk Lange
OBJECTIVES: To better understand the effects of Double J (JJ) stenting on ureteral physiology and function. MATERIALS AND METHODS: In total, twenty-four pigs (24) were stented cystoscopically unilaterally for 48h, 1, 2, 4 and 7 wks. Controls consisted of un-stented animals (n=4) or the contralateral un-stented ureter in pigs. Ureters were harvested and tested in tissue baths to evaluate their contractility. Ureteral inflammation and expression of Sonic Hedgehog (Shh) and the transcriptional activator Gli1 (the downstream target of active HH signaling) were assessed histologically and by immunohistochemistry, respectively...
February 8, 2017: Urology
https://www.readbyqxmd.com/read/28179296/itraconazole-inhibits-akt-mtor-signaling-and-proliferation-in-endometrial-cancer-cells
#13
Hiroshi Tsubamoto, Kayo Inoue, Kazuko Sakata, Tomoko Ueda, Ryu Takeyama, Hiroaki Shibahara, Takashi Sonoda
BACKGROUND: Itraconazole is a common antifungal agent that has demonstrated anticancer activity in preclinical and clinical studies. This study investigated whether itraconazole exerts this effect in endometrial cancer (EC) cells. MATERIALS AND METHODS: Cell viability was evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and gene and protein expression were assessed by microarray analysis and immunoblotting, respectively, in five EC cell lines...
2017: Anticancer Research
https://www.readbyqxmd.com/read/28167794/gata4-potentiates-second-heart-field-proliferation-and-hedgehog-signaling-for-cardiac-septation
#14
Lun Zhou, Jielin Liu, Menglan Xiang, Patrick Olson, Alexander Guzzetta, Ke Zhang, Ivan P Moskowitz, Linglin Xie
GATA4, an essential cardiogenic transcription factor, provides a model for dominant transcription factor mutations in human disease. Dominant GATA4 mutations cause congenital heart disease (CHD), specifically atrial and atrioventricular septal defects (ASDs and AVSDs). We found that second heart field (SHF)-specific Gata4 heterozygote embryos recapitulated the AVSDs observed in germline Gata4 heterozygote embryos. A proliferation defect of SHF atrial septum progenitors and hypoplasia of the dorsal mesenchymal protrusion, rather than anlage of the atrioventricular septum, were observed in this model...
February 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28167297/loss-of-pin1-suppresses-hedgehog-driven-medulloblastoma-tumorigenesis
#15
Tao Xu, Honglai Zhang, Sung-Soo Park, Sriram Venneti, Rork Kuick, Kimberly Ha, Lowell Evan Michael, Mariarita Santi, Chiyoko Uchida, Takafumi Uchida, Ashok Srinivasan, James M Olson, Andrzej A Dlugosz, Sandra Camelo-Piragua, Jean-François Rual
Medulloblastoma is the most common malignant brain tumor in children. Therapeutic approaches to medulloblastoma (combination of surgery, radiotherapy, and chemotherapy) have led to significant improvements, but these are achieved at a high cost to quality of life. Alternative therapeutic approaches are needed. Genetic mutations leading to the activation of the Hedgehog pathway drive tumorigenesis in ~30% of medulloblastoma. In a yeast two-hybrid proteomic screen, we discovered a novel interaction between GLI1, a key transcription factor for the mediation of Hedgehog signals, and PIN1, a peptidylprolyl cis/trans isomerase that regulates the postphosphorylation fate of its targets...
February 3, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28161934/identification-of-diverse-adenosine-to-inosine-rna-editing-subtypes-in-colorectal-cancer
#16
Si-Hyun Lee, Hwang-Phill Kim, Jun-Kyu Kang, Sang-Hyun Song, Sae-Won Han, Tae-You Kim
Purpose: RNA editing generates protein diversity by altering RNA sequences in coding regions without changing the overall DNA sequence. Adenosine-to-Inosine (A-to-I) RNA editing events have recently been reported in some types of cancer, but they are rare in human colorectal cancer. Therefore, this study was conducted to identify diverse RNA editing in colorectal cancer. Materials and Methods: We compared transcriptome data of 39 colorectal cancer (CRC) samples and paired adjacent tissues from The Cancer Genome Atlas database to identify RNA editing patterns in CRC, focusing on canonical A-to-I RNA edits in coding sequence regions...
January 25, 2017: Cancer Research and Treatment: Official Journal of Korean Cancer Association
https://www.readbyqxmd.com/read/28160546/expression-and-role-of-anion-exchanger-1-in-esophageal-squamous-cell-carcinoma
#17
Atsushi Shiozaki, Michihiro Kudou, Daisuke Ichikawa, Hiroki Shimizu, Tomohiro Arita, Toshiyuki Kosuga, Hirotaka Konishi, Shuhei Komatsu, Hitoshi Fujiwara, Kazuma Okamoto, Mitsuo Kishimoto, Yoshinori Marunaka, Eigo Otsuji
Recent studies have described important roles for the anion exchanger (AE) in epithelial carcinogenesis and tumor behavior. The objectives of the present study were to investigate the role of AE1 in the regulation of genes involved in tumor progression and the clinicopathological significance of its expression in esophageal squamous cell carcinoma (ESCC). An immunohistochemical analysis was performed on 61 primary tumor samples obtained from ESCC patients who underwent esophagectomy. AE1 was primarily located in the cell membranes or cytoplasm of carcinoma cells, and its distribution pattern was related to the histological degree of the differentiation of SCC or the pT category...
January 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28159470/hedgehog-pathway-plays-a-vital-role-in-hiv-induced-epithelial-mesenchymal-transition-of-podocyte
#18
Xiqian Lan, Hongxiu Wen, Kang Cheng, Andrei Plagov, Seyedeh Shadafarin Marashi Shoshtari, Ashwani Malhotra, Pravin C Singhal
HIV-associated nephropathy (HIVAN) is characterized by heavy proteinuria, rapidly progressive renal failure, and distinct morphological features in the kidney. HIV-induced epithelial-mesenchymal transition (EMT) is critically important for the progression of kidney injury. In this study, we tested the role of hedgehog pathway in the HIV-induced EMT and fibrosis of kidney. We used the Tg26 mice, the abundantly used HIVAN mouse model, to investigate the activation of hedgehog pathway by HIV. Western blotting and real time PCR results showed that renal tissue expression of hedgehog pathway related molecules, including hedgehog homologous (Shh, Ihh, Dhh), PTCH, and Gli1, were increased in HIVAN (Tg26) mice; while immunofluorescent staining displayed localization PTCH expression in podocytes...
March 15, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28148565/pirfenidone-exerts-antifibrotic-effects-through-inhibition-of-gli-transcription-factors
#19
Miroslava Didiasova, Rajeev Singh, Jochen Wilhelm, Grazyna Kwapiszewska, Lukasz Wujak, Dariusz Zakrzewicz, Liliana Schaefer, Philipp Markart, Werner Seeger, Matthias Lauth, Malgorzata Wygrecka
Pirfenidone is an antifibrotic drug, recently approved for the treatment of patients suffering from idiopathic pulmonary fibrosis (IPF). Although pirfenidone exhibits anti-inflammatory, antioxidant, and antifibrotic properties, the molecular mechanism underlying its protective effects remains unknown. Here, we link pirfenidone action with the regulation of the profibrotic hedgehog (Hh) signaling pathway. We demonstrate that pirfenidone selectively destabilizes the glioma-associated oncogene homolog (GLI)2 protein, the primary activator of Hh-mediated gene transcription...
February 1, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28148279/aberrant-activation-of-hedgehog-signaling-promotes-cell-proliferation-via-the-transcriptional-activation-of-forkhead-box-m1-in-colorectal-cancer-cells
#20
DeJie Wang, Guohui Hu, Ying Du, Cheng Zhang, Quqin Lu, Nonghua Lv, Shiwen Luo
BACKGROUND: Recent evidence suggests that the aberrant activation of Hedgehog (Hh) signaling by Gli transcription factors is characteristic of a variety of aggressive human carcinomas, including colorectal cancer (CRC). Forkhead box M1 (FoxM1) controls the expression of a number of cell cycle regulatory proteins, and FoxM1 expression is elevated in a broad range of human malignancies, which suggests that it plays a crucial role in tumorigenesis. However, the mechanisms underlying FoxM1 expression are not fully understood...
February 2, 2017: Journal of Experimental & Clinical Cancer Research: CR
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