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E6 inhibitor

Elizabeth A Nelson, Julie Dyall, Thomas Hoenen, Alyson B Barnes, Huanying Zhou, Janie Y Liang, Julia Michelotti, William H Dewey, Lisa Evans DeWald, Richard S Bennett, Patrick J Morris, Rajarshi Guha, Carleen Klumpp-Thomas, Crystal McKnight, Yu-Chi Chen, Xin Xu, Amy Wang, Emma Hughes, Scott Martin, Craig Thomas, Peter B Jahrling, Lisa E Hensley, Gene G Olinger, Judith M White
Phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) is a lipid kinase involved in endosome maturation that emerged from a haploid genetic screen as being required for Ebola virus (EBOV) infection. Here we analyzed the effects of apilimod, a PIKfyve inhibitor that was reported to be well tolerated in humans in phase 2 clinical trials, for its effects on entry and infection of EBOV and Marburg virus (MARV). We first found that apilimod blocks infections by EBOV and MARV in Huh 7, Vero E6 and primary human macrophage cells, with notable potency in the macrophages (IC50, 10 nM)...
April 12, 2017: PLoS Neglected Tropical Diseases
Julie Dyall, Brit J Hart, Elena Postnikova, Yu Cong, Huanying Zhou, Dawn M Gerhardt, Denise Freeburger, Julia Michelotti, Anna N Honko, Lisa Evans DeWald, Richard S Bennett, Gene G Olinger, Peter B Jahrling, Lisa E Hensley
Previous studies demonstrated little efficacy of interferons (IFNs) in animal models of Ebola virus disease. However, these studies were limited to a small number of Type I IFNs and, during the most recent outbreak of Ebola virus, questions regarding the suitability of the animal models to evaluate IFNs were raised. To address the potential that anti-Ebola virus activity was overlooked, Type I and Type II IFNs (α-2a, α-2b, -β, -γ, and -universal) were tested in a variety of cell types (Vero E6, Huh 7 cells, and human macrophages)...
March 22, 2017: Journal of Infectious Diseases
Amina Houddane, Laurent Bultot, Laura Novellasdemunt, Manuel Johanns, Marie-Agnès Gueuning, Didier Vertommen, Pierre G Coulie, Ramon Bartrons, Louis Hue, Mark H Rider
Proliferating cells depend on glycolysis mainly to supply precursors for macromolecular synthesis. Fructose 2,6-bisphosphate (Fru-2,6-P2) is the most potent positive allosteric effector of 6-phosphofructo-1-kinase (PFK-1), and hence of glycolysis. Mitogen stimulation of rat thymocytes with concanavalin A (ConA) led to time-dependent increases in lactate accumulation (6-fold), Fru-2,6-P2 content (4-fold), 6-phosphofructo-2-kinase (PFK-2)/fructose-2,6-bisphosphatase isoenzyme 3 and 4 (PFKFB3 and PFKFB4) protein levels (~2-fold and ~15-fold, respectively) and rates of cell proliferation (~40-fold) and protein synthesis (10-fold) after 68h of incubation compared with resting cells...
February 22, 2017: Cellular Signalling
S X Wu, X Y Ren, Y L Pan, D D Guan, S Liu, X Y Zou, C G Shi, Y Z Li, Y Z Zhang
Current treatments for high-grade cervical intraepithelial neoplasia (CIN) and persistent infection with high-risk human papillomavirus (HR-HPV) type are mainly surgical interventions. However, such treatments are associated with adverse side effects and pose risks for future pregnancies. In order to reduce the requirement for excisional procedures, an effective and noninvasive therapy is needed for women at reproductive age. ALA-PDT has proved to be effective in the treatment of HPV-associated disease in several clinical investigations...
2017: Neoplasma
Sarah E Rotschafer, Michelle R Allen-Sharpley, Karina S Cramer
Caspase-3 is a cysteine protease that is most commonly associated with cell death. Recent studies have shown additional roles in mediating cell differentiation, cell proliferation and development of cell morphology. We investigated the role of caspase-3 in the development of chick auditory brainstem nuclei during embryogenesis. Immunofluorescence from embryonic days E6-13 revealed that the temporal expression of cleaved caspase-3 follows the ascending anatomical pathway. The expression is first seen in the auditory portion of VIIIth nerve including central axonal regions projecting to nucleus magnocellularis (NM), then later in NM axons projecting to nucleus laminaris (NL), and subsequently in NL dendrites...
2016: Frontiers in Neural Circuits
Kanchan Vishnoi, Sutapa Mahata, Abhishek Tyagi, Arvind Pandey, Gaurav Verma, Mohit Jadli, Tejveer Singh, Sukh Mahendra Singh, Alok C Bharti
Viral oncoproteins E6/E7 play key oncogenic role in human papillomavirus (HPV)-mediated cervical carcinogenesis in conjunction with aberrant activation of cellular signaling events. GLI-signaling has been implicated in metastasis and tumor recurrence of cervical cancer. However, the interaction of GLI-signaling with HPV oncogenes is unknown. We examined this relationship in established HPV-positive and HPV-negative cervical cancer cell lines using specific GLI inhibitor, cyclopamine and HPVE6/E7 siRNAs. Cervical cancer cell lines showed variable expression of GLI-signaling components...
September 28, 2016: Scientific Reports
Daniele Viarisio, Karin Müller-Decker, Jessica C Hassel, Jean-Claude Alvarez, Christa Flechtenmacher, Michael Pawlita, Lutz Gissmann, Massimo Tommasino
No abstract text is available yet for this article.
January 2017: Journal of Investigative Dermatology
Marie Saghaeian Jazi, Saeed Mohammadi, Yaghoub Yazdani, Sima Sedighi, Ali Memarian, Mehrdad Aghaei
OBJECTIVES: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignant tumor. Administration of chemical compounds influencing apoptosis and T cell development has been discussed as promising novel therapeutic strategies. Valproic acid (VPA) as a recently emerged anti-neoplastic histone deacetylase (HDAC) inhibitor and pioglitazone (PGZ) as a high-affinity peroxisome proliferator-activated receptor-gamma (PPARγ) agonist have been shown to induce apoptosis and cell cycle arrest in different studies...
July 2016: Iranian Journal of Basic Medical Sciences
Katharine E Dooley, Alix Warburton, Alison A McBride
UNLABELLED: In cancer cells associated with human papillomavirus (HPV) infections, the viral genome is very often found integrated into the cellular genome. The viral oncogenes E6 and E7 are transcribed from the viral promoter, and integration events that alter transcriptional regulation of this promoter contribute to carcinogenic progression. In this study, we detected highly enriched binding of the super-enhancer markers Brd4, MED1, and H3K27ac, visible as a prominent nuclear focus by immunofluorescence, at the tandemly integrated copies of HPV16 in cells of the cervical neoplasia cell line W12 subclone 20861...
2016: MBio
Hiroe Nakamura, Ayumi Taguchi, Kei Kawana, Akira Kawata, Mitsuyo Yoshida, Asaha Fujimoto, Juri Ogishima, Masakazu Sato, Tomoko Inoue, Haruka Nishida, Hitomi Furuya, Kensuke Tomio, Satoko Eguchi, Mayuyo Mori-Uchino, Aki Yamashita, Katsuyuki Adachi, Takahide Arimoto, Osamu Wada-Hiraike, Katsutoshi Oda, Takeshi Nagamatsu, Yutaka Osuga, Tomoyuki Fujii
In cervical cancer, p53-induced apoptosis is abrogated by human papilloma virus (HPV)-derived oncoprotein E6. Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) provides tumor-specific apoptosis in various cancers, including cervical cancer, the sensitivity differs depending on the cell lines. Signal transducer and activator of transcription 3 (STAT3) is a hub molecule that shifts the cellular fate to apoptosis or survival in response to cellular stresses. However, the contribution of STAT3 activity to TRAIL-induced apoptosis in cervical cancer remains unknown...
November 2016: International Journal of Oncology
Juan Luis Callejas-Valera, Ramiro Iglesias-Bartolome, Panomwat Amornphimoltham, Julia Palacios-Garcia, Daniel Martin, Joseph A Califano, Alfredo A Molinolo, J Silvio Gutkind
The rising incidence of human papillomavirus (HPV)-associated malignancies, especially for oropharyngeal cancers, has highlighted the urgent need to understand how the interplay between high-risk HPV oncogenes and carcinogenic exposure results in squamous cell carcinoma (SCC) development. Here, we describe an inducible mouse model expressing high risk HPV-16 E6/E7 oncoproteins in adults, bypassing the impact of these viral genes during development. HPV-16 E6/E7 genes were targeted to the basal squamous epithelia in transgenic mice using a doxycycline inducible cytokeratin 5 promoter (cK5-rtTA) system...
October 2016: Carcinogenesis
Xiaowei Wu, Lin Li, Yi Li, Zhihua Liu
Homologous to the E6-associated protein carboxyl terminus domain containing 3 (HECTD3) is an E3 ubiquitin ligase which ubiquitinates caspase-8, caspase-9 and promotes cancer cell survival. Aberrant HECTD3 expression is frequently involved in various types of cancer progression. However, to date, the regulation of HECTD3 remains unclear. Here, we demonstrated that miR-153 functions as a negative regulator of HECTD3 and sensitizes cisplatin-induced apoptosis in triple-negative breast cancer cells MDA-MB-231 and BT-549...
2016: American Journal of Cancer Research
Ruxing Xi, Shupei Pan, Xin Chen, Beina Hui, Li Zhang, Shenbo Fu, Xiaolong Li, Xuanwei Zhang, Tuotuo Gong, Jia Guo, Xiaozhi Zhang, Shaomin Che
High-risk human papillomavirus (HPV), especially HPV16, correlates with cancerogenesis of human esophageal squamous cell carcinoma (ESCC) and we have reported that HPV16 related with a poor prognosis of ESCC patients in China. We aim to investigate the potential role and mechanism of HPV16 in ESCC development and progress. Our following researches demonstrated that ESCC cells which were stably transfected by HPV16 E6-E7 lentiviral vector showed a remarkable cancer stem-like cells (CSCs) phenotype, such as: migration, invasion, spherogenesis, high expression of CSCs marker in ESCC---p75NTR, chemoresistance, radioresistance, anti-apoptosis ability in vitro and cancerogenesis in vivo...
August 30, 2016: Oncotarget
J Yuan, Y-L Han, T-Y Wang, S Wu, L Tong, L-X Lin, M Li, L-L Wei, Z-H Zhong, G-M Zhang, Y Wang
OBJECTIVE: Inhibitor of growth 4 (ING4) is a candidate tumor suppressor which plays an important role in multiple processes including DNA repair, apoptosis, cell cycle control, tumor metastasis and angiogenesis. However, clinical data about the role of ING4 in the development and progression of cervical cancer are still limited. This study aimed to examine ING4 expression in cervical cancer and analyze its correlation with the progression of the malignancy. PATIENTS AND METHODS: RT-PCR, Western blot and immunohistochemistry analysis were performed to determine ING4 expression in 18 clinical specimens from cervical cancer patients...
July 2016: European Review for Medical and Pharmacological Sciences
Cristian Ruiz-Moreno, Marlene Jimenez-Del-Rio, Ligia Sierra-Garcia, Betty Lopez-Osorio, Carlos Velez-Pardo
D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) is a water-soluble derivative of natural vitamin E commonly used as a drug delivery agent. Recently, TPGS alone has been reported to induce cell death in lung, breast and prostate cancer. However, the effect of TPGS on cancer cell viability remains unclear. Thus, this study was aimed to evaluate the cytotoxic effect of TPGS on human periphral blood lymphocytes (PBL) and on T cell acute lymphocytic leukemia (ALL) Jurkat clone E6-1 cells and its possible mechanism of action...
September 2016: Apoptosis: An International Journal on Programmed Cell Death
A A Clancy, J N Spaans, J I Weberpals
BACKGROUND: The incidence of vulvar squamous cell carcinoma (VSCC) has been on the rise since the 1990s. There has been no new treatment for advanced and recurrent disease in decades, with most women succumbing to the disease. Despite two distinct etiologies of VSCC, human papillomavirus (HPV)-associated and HPV-independent disease, there is no difference in therapeutic options. METHODS: A literature review was carried out by searching EMBASE and Medline databases between January 1990 and March 2016 by pairing the keywords of vulvar carcinoma, vulva cancer, vulvar and vulva with molecular markers involved in the cell cycle, apoptosis and angiogenesis...
September 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Sung Jong Lee, Andrew Yang, T C Wu, Chien Fu Hung
Cervical cancer is the fourth most lethal women's cancer worldwide. Current treatments against cervical cancer include surgery, radiotherapy, chemotherapy, and anti-angiogenic agents. However, despite the various treatments utilized for the treatment of cervical cancer, its disease burden remains a global issue. Persistent infection of human papillomavirus (HPV) has been identified as an essential step of pathogenesis of cervical cancer and many other cancers, and nation-wide HPV screening as well as preventative HPV vaccination program have been introduced globally...
September 2016: Journal of Gynecologic Oncology
Juri Kwak, Joo Hee Shim, Indira Tiwari, Kyung Lib Jang
The E6-associated protein (E6AP) is a ubiquitin ligase that mediates ubiquitination and proteasomal degradation of hepatitis C virus (HCV) core protein. Given the role of HCV core protein as a major component of the viral nucleocapsid, as well as a multifunctional protein involved in viral pathogenesis and hepatocarcinogenesis, HCV has likely evolved a strategy to counteract the host anti-viral defense mechanism of E6AP and maximize its potential to produce infectious virus particles. In the present study, we found that HCV core protein derived from either ectopic expression or HCV infection inhibits E6AP expression via promoter hypermethylation in human hepatocytes...
September 28, 2016: Cancer Letters
Amy K Sheaffer, Min S Lee, Huilin Qi, Susan Chaniewski, Xiaofan Zheng, Glen A Farr, Kim Esposito, David Harden, Ming Lei, Liang Schweizer, Jacques Friborg, Michele Agler, Fiona McPhee, Robert Gentles, Brett R Beno, Lou Chupak, Stephen Mason
A phenotypic high-throughput cell culture screen was performed to identify compounds that prevented proliferation of the human Papilloma virus type 16 (HPV-16) transformed cell line Ca Ski. A series of quinoxaline compounds exemplified by Compound 1 was identified. Testing against a panel of cell lines demonstrated that Compound 1 selectively inhibited replication of all HPV-16, HPV-18, and HPV-31 transformed cell lines tested with 50% Inhibitory Concentration (IC50) values of 2 to 8 μM relative to IC50 values of 28 to 73 μM in HPV-negative cell lines...
2016: PloS One
Annika Stiasny, Christina Kuhn, Doris Mayr, Christoph Alexiou, Christina Janko, Irmi Wiest, Udo Jeschke, Bernd Kost
BACKGROUND/AIM: High-risk human papillomavirus (HPV) subtypes (i.e. 16 and 18) lead to uterine cervical cancer as well as HPV-positive oropharyngeal cancer (OSCC), a form of head and neck cancer. The induction of HPV-induced cancer is driven by virus-specific oncoproteins E6 and E7. E6 protein of HPV types 16 and 18 interacts with the E3 ubiquitin protein ligase, resulting in ubiquitination and proteolysis of tumor protein p53. E7 inactivates retinoblastoma protein (Rb) by phosphorylation followed by an increase of free eukaryotic transcription factor E2F (E2F) in the cell...
June 2016: Anticancer Research
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