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Thiostrepton

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https://www.readbyqxmd.com/read/29707121/foxm1-is-an-independent-poor-prognostic-marker-and-therapeutic-target-for-advanced-middle-eastern-breast-cancer
#1
Abdul Khalid Siraj, Poyil Pratheeshkumar, Sandeep Kumar Parvathareddy, Zeeshan Qadri, Saravanan Thangavel, Saeeda Ahmed, Fouad Al-Dayel, Asma Tulbah, Dahish Ajarim, Khawla S Al-Kuraya
Breast cancer (BC) is the most common cause of cancer-related death in females in Saudi Arabia. BC in Saudi women tend to behave more aggressively than breast cancer in the West. Therefore, identification of new molecular targets and treatment strategies are highly warranted to improve patient outcome. FoxM1 has been shown to play a critical role in pathogenesis of various malignancies. In this study, we explored the prevalence and clinical implication of FoxM1 overexpression in Saudi breast cancer. FoxM1 protein overexpression was seen in 79% (770/975) of BC tissues and was associated with aggressive clinical parameters such as younger age (< 30 yrs) ( p = 0...
April 3, 2018: Oncotarget
https://www.readbyqxmd.com/read/29665004/thiostrepton-degrades-mutant-p53-by-eliciting-an-autophagic-response-in-sw480-cells
#2
Dhanya Kalathil, Manu Prasad, Maharrish Chelladurai, Samu John, Asha S Nair
Mutations in p53 gene are one of the hallmarks of tumor development. Specific targeting of mutant p53 protein has a promising role in cancer therapeutics. Our preliminary observation showed destabilization of mutant p53 protein in SW480, MiaPaCa and MDAMB231 cell lines upon thiostrepton treatment. In order to elucidate the mechanism of thiostrepton triggered mutant p53 degradation, we explored the impact of proteasome inhibition on activation of autophagy. Combined treatment of thiostrepton and cycloheximide/chloroquine prevented the degradation of mutant p53 protein, reinforcing autophagy as the means of mutant p53 destabilization...
April 17, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29664678/endothelial-and-smooth-muscle-cell-interaction-via-foxm1-signaling-mediates-vascular-remodeling-and-pulmonary-hypertension
#3
Zhiyu Dai, Maggie M Zhu, Yi Peng, Hua Jin, Narsa Machireddy, Zhijian Qian, Xianming Zhang, You-Yang Zhao
RATIONALE: Angioproliferative vasculopathy is a hallmark of pulmonary arterial hypertension (PAH). However, little is known how endothelial cell (EC) and smooth muscle cell (SMC) crosstalk regulates the angioproliferative vascular remodeling. OBJECTIVES: We aimed to investigate the role of EC and SMC interaction and underlying signaling pathways in PH development. METHODS: SMC-specific Foxm1 or Cxcr4 knockout mice, EC-specific Foxm1 or Egln1 knockout mice, as well as EC-specific Egln1/Cxcl12 double knockout mice were used to assess the role of FoxM1 on SMC proliferation and PH...
April 17, 2018: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/29606130/proteasome-inhibitors-modulate-anticancer-and-anti-proliferative-properties-via-nf-kb-signaling-and-ubiquitin-proteasome-pathways-in-cancer-cell-lines-of-different-organs
#4
Asaf A Qureshi, Eleanor G Zuvanich, Dilshad A Khan, Shahida Mushtaq, Neerupma Silswal, Nilofer Qureshi
BACKGROUND: Cancer is second most common cause of death in the United State. There are over 100 different types of cancer associated with different human organs, predominantly breast, liver, pancreas, prostate, colon, rectum, lung, and stomach. We have recently reported properties of pro-inflammatory (for treatment of various types of cancers), and anti-inflammatory (for cardiovascular disease and diabetes) compounds. The major problem associated with development of anticancer drugs is their lack of solubility in aqueous solutions and severe side effects in cancer patients...
April 2, 2018: Lipids in Health and Disease
https://www.readbyqxmd.com/read/29545475/olaparib-induced-adaptive-response-is-disrupted-by-foxm1-targeting-which-enhances-sensitivity-to-parp-inhibition
#5
Pingping Fang, Jill A Madden, Lisa Neums, K Ryan Moulder, M Laird Forrest, Jeremy Chien
FOXM1 transcription factor network is activated in over 84% of cases in high-grade serous ovarian cancer (HGSOC), and FOXM1 upregulates the expression of genes involved in the homologous recombination (HR) DNA damage and repair (DDR) pathway. However, the role of FOXM1 in poly (ADP-ribose) polymerase (PARP) inhibitor response has not yet been studied. The present study demonstrates that PARP inhibitor (PARPi), olaparib, induces the expression and nuclear localization of FOXM1. Based on ChIP-qPCR, olaparib enhances the binding of FOXM1 to genes involved in HR repair...
March 15, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29464042/yap-associated-chromosomal-instability-and-cholangiocarcinoma-in-mice
#6
Sumera Rizvi, Samantha R Fischbach, Steven F Bronk, Petra Hirsova, Anuradha Krishnan, Renumathy Dhanasekaran, James B Smadbeck, Rory L Smoot, George Vasmatzis, Gregory J Gores
Deregulated Hippo pathway signaling is associated with aberrant activation of the downstream effector yes-associated protein (YAP), an emerging key oncogenic mediator in cholangiocarcinoma (CCA). In our prior work, we have demonstrated that biliary transduction of YAP along with Akt as a permissive factor induces CCA in mice. To further delineate the mechanisms associated with YAP-associated biliary oncogenesis, we have established seven malignant murine cell lines from our YAP-driven murine CCA model. These cells express the CCA markers SRY (Sex Determining Region Y)-Box 9 (SOX9), cytokeratin (CK)-7 and 19 but lack hepatocyte nuclear factor 4 alpha and alpha-smooth muscle actin, markers of hepatocellular carcinoma and cancer-associated fibroblasts, respectively...
January 19, 2018: Oncotarget
https://www.readbyqxmd.com/read/29423068/foxm1-and-%C3%AE-catenin-predicts-aggressiveness-in-middle-eastern-ovarian-cancer-and-their-co-targeting-impairs-the-growth-of-ovarian-cancer-cells
#7
Poyil Pratheeshkumar, Sasidharan Padmaja Divya, Sandeep Kumar Parvathareddy, Norah M Alhoshani, Ismail A Al-Badawi, Asma Tulbah, Fouad Al-Dayel, Abdul K Siraj, Khawla S Al-Kuraya
Epithelial ovarian cancer (EOC) is a highly lethal disease with poor prognosis especially in advanced stage tumor. Emerging evidence has reported that aberrant upregulation of FoxM1 and β-catenin are closely associated with aggressiveness of human cancer. However, interplay between these factors in the aggressiveness of EOC is not fully illustrated. In this study, we show that FoxM1 is frequently increased in Middle Eastern EOC and associated with high proliferative index ( p = 0.0007) and high grade tumor ( p = 0...
January 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29414039/untying-the-knot-of-transcription-factor-druggability-molecular-modeling-study-of-foxm1-inhibitors
#8
S Amirhossein Tabatabaei-Dakhili, Rodrigo Aguayo-Ortiz, Laura Domínguez, Carlos A Velázquez-Martínez
The FOXM1 protein is a relevant transcription factor involved in cancer cell proliferation. The direct or indirect inhibition of this protein's transcriptional activity by small molecule drugs correlates well with a potentially significant anti-cancer profile, making this macro molecule a promising drug target. There are a few drug molecules reported to interact with (and inhibit) the FOXM1 DNA binding domain (FOXM1-BD), causing downregulation of protein expression and cancer cell proliferation inhibition. Among these drug molecules are the proteasome inhibitor thiostrepton, the former antidiabetic drug troglitazone, and the new FDI-6 molecule...
March 2018: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29290032/foxm1-promotes-pulmonary-artery-smooth-muscle-cell-expansion-in-pulmonary-arterial-hypertension
#9
Alice Bourgeois, Caroline Lambert, Karima Habbout, Benoit Ranchoux, Stéphanie Paquet-Marceau, Isabelle Trinh, Sandra Breuils-Bonnet, Renée Paradis, Valérie Nadeau, Roxane Paulin, Steeve Provencher, Sébastien Bonnet, Olivier Boucherat
Pulmonary arterial hypertension (PAH) is a progressive vascular remodeling disease characterized by a persistent elevation of pulmonary artery pressure, leading to right heart failure and premature death. Exaggerated proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs) is a key component of vascular remodeling. Despite major advances in the field, current therapies for PAH remain poorly effective in reversing the disease or significantly improving long-term survival. Because the transcription factor FOXM1 is necessary for PASMC proliferation during lung morphogenesis and its overexpression stimulates proliferation and evasion of apoptosis in cancer cells, we thus hypothesized that upregulation of FOXM1 in PAH-PASMCs promotes cell expansion and vascular remodeling...
February 2018: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/29230202/development-of-a-novel-escherichia-coli-kocuria-shuttle-vector-using-the-cryptic-pkpal3-plasmid-from-k-palustris-ipufs-1-and-its-utilization-in-producing-enantiopure-s-styrene-oxide
#10
Hiroshi Toda, Nobuya Itoh
The novel cryptic pKPAL3 plasmid was isolated from the Gram-positive microorganism Kocuria palustris IPUFS-1 and characterized in detail. pKPAL3 is a circular plasmid that is 4,443 bp in length. Open reading frame (ORF) and homology search analyses indicated that pKPAL3 possesses four ORFs; however, there were no replication protein coding genes predicted in the plasmid. Instead, there were two nucleotide sequence regions that showed significant identities with untranslated regions of K. rhizophila DC2201 (NBRC 103217) genomic sequences, and these sequences were essential for autonomous replication of pKPAL3 in Kocuria cells...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29109448/identification-of-claudin-4-binder-that-attenuates-tight-junction-barrier-function-by-tr-fret-based-screening-assay
#11
Akihiro Watari, Miki Kodaka, Koji Matsuhisa, Yuta Sakamoto, Kota Hisaie, Norihito Kawashita, Tatsuya Takagi, Yoshiaki Yamagishi, Hidehiko Suzuki, Hirofumi Tsujino, Kiyohito Yagi, Masuo Kondoh
Claudins are key functional and structural components of tight junctions (TJs) in epithelial cell sheets. The C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) binds to claudin-4 and reversibly modulates intestinal TJ seals, thereby enhancing paracellular transport of solutes. However, the use of C-CPE as an absorption enhancer is limited by the molecule's immunogenicity and manufacturing cost. Here, we developed a high-throughput screening system based on the Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) method to identify claudin-4 binders in a library collection of 32,560 compounds...
November 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29038577/morphology-engineering-of-streptomyces-coelicolor-m145-by-sub-inhibitory-concentrations-of-antibiotics
#12
Hu Wang, Guoping Zhao, Xiaoming Ding
Growth of Streptomyces in submerged culture is characterized by the formation of complex mycelial particles, known as pellets or clumps, which strongly influence antibiotic production. Also, many bioactive molecules produced by Streptomyces have great potential to modulate soil bacteria morphological development. However, there has been no effort directed at engineering mycelial morphology using these small molecules. Here, thiostrepton was identified, using a combination of qRT-PCR, semi-preparative HPLC, and MALDI-TOF MS, as a pellet-inducing compound produced by S...
October 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28975793/site-and-stereoselective-chemical-editing-of-thiostrepton-by-rh-catalyzed-conjugate-arylation-new-analogues-and-collateral-enantioselective-synthesis-of-amino-acids
#13
Hanna M Key, Scott J Miller
The synthesis of complex, biologically active molecules by catalyst-controlled, selective functionalization of complex molecules is an emerging capability. We describe the application of Rh-catalyzed conjugate arylation to the modification of thiostrepton, a complex molecule with potent antibacterial properties for which few analogues are known. By this approach, we achieve the site- and stereoselective functionalization of one subterminal dehydroalanine residue (Dha16) present in thiostrepton. The broad scope of this method enabled the preparation and isolation of 24 new analogues of thiostrepton, the biological testing of which revealed that the antimicrobial activity of thiostrepton tolerates the alteration of Dha16 to a range of amino acids...
November 1, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28930155/identification-of-agents-active-against-methicillin-resistant-staphylococcus-aureus-usa300-from-a-clinical-compound-library
#14
Hongxia Niu, Rebecca Yee, Peng Cui, Lili Tian, Shuo Zhang, Wanliang Shi, David Sullivan, Bingdong Zhu, Wenhong Zhang, Ying Zhang
Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant threat for effective treatment of several difficult-to-treat infections in humans. To identify potential new treatment options for MRSA infections, we screened a clinical compound library consisting of 1524 compounds using a growth inhibition assay in 96-well plates. We identified 34 agents which are either bacteriostatic or bactericidal against log-phase clinical MRSA strain USA300. Among them, 9 candidates (thonzonium, cetylpyridinium, trilocarban, benzododecinium, bithionol, brilliant green, chlorquinaldol, methylbenzethonium and green violet) are known antiseptics, 11 candidates are known antibiotics currently recommended for the treatment of MRSA...
September 20, 2017: Pathogens
https://www.readbyqxmd.com/read/28894754/natural-modulators-of-endosomal-toll-like-receptor-mediated-psoriatic-skin-inflammation
#15
REVIEW
Chao-Yang Lai, Yu-Wen Su, Kuo-I Lin, Li-Chung Hsu, Tsung-Hsien Chuang
Psoriasis is a chronic inflammatory autoimmune disease that can be initiated by excessive activation of endosomal toll-like receptors (TLRs), particularly TLR7, TLR8, and TLR9. Therefore, inhibitors of endosomal TLR activation are being investigated for their ability to treat this disease. The currently approved biological drugs adalimumab, etanercept, infliximab, ustekinumab, ixekizumab, and secukizumab are antibodies against effector cytokines that participate in the initiation and development of psoriasis...
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/28820583/processing-2-methyl-l-tryptophan-through-tandem-transamination-and-selective-oxygenation-initiates-indole-ring-expansion-in-the-biosynthesis-of-thiostrepton
#16
Zhi Lin, Jia Ji, Shuaixiang Zhou, Fang Zhang, Jiequn Wu, Yinlong Guo, Wen Liu
Thiostrepton (TSR), an archetypal member of the family of ribosomally synthesized and post-translationally modified thiopeptide antibiotics, possesses a biologically important quinaldic acid (QA) moiety within the side-ring system of its characteristic thiopeptide framework. QA is derived from an independent l-Trp residue; however, its associated transformation process remains poorly understood. We here report that during the formation of QA, the key expansion of an indole to a quinoline relies on the activities of the pyridoxal-5'-phosphate-dependent protein TsrA and the flavoprotein TsrE...
August 23, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28747433/efficient-methylation-of-c2-in-l-tryptophan-by-the-cobalamin-dependent-radical-s-adenosylmethionine-methylase-tsrm-requires-an-unmodified-n1-amine
#17
Anthony J Blaszczyk, Bo Wang, Alexey Silakov, Jackson V Ho, Squire J Booker
TsrM catalyzes the methylation of C2 in l-tryptophan (Trp). This reaction is the first step in the biosynthesis of the quinaldic acid moiety of the thiopeptide antibiotic thiostrepton, which exhibits potent activity against Gram-positive pathogens. TsrM is a member of the radical S -adenosylmethionine (SAM) superfamily of enzymes, but it does not catalyze the formation of 5'-deoxyadenosin-5'-yl or any other SAM-derived radical. In addition to a [4Fe-4S] cluster, TsrM contains a cobalamin cofactor that serves as an intermediate methyl carrier in its reaction...
September 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28692634/targeting-foxm1-improves-cytotoxicity-of-paclitaxel-and-cisplatinum-in-platinum-resistant-ovarian-cancer
#18
Gina L Westhoff, Yi Chen, Nelson N H Teng
OBJECTIVE: Aberrantly activated FOXM1 (forkhead box protein M1) leading to uncontrolled cell proliferation and dysregulation of FOXM1 transcription network occurs in 84% of ovarian cancer cases. It was demonstrated that thiostrepton, a thiazole antibiotic, decreases FOXM1 expression. We aimed to determine if targeting the FOXM1 pathway with thiostrepton could improve the efficacy of paclitaxel and cisplatin in human ovarian cancer ascites cells ex vivo. METHODS: Human ovarian cancer cell lines and patients' ascites cells were treated with paclitaxel, cisplatin, and thiostrepton or a combination for 48 hours, and cytotoxicity was assessed...
October 2017: International Journal of Gynecological Cancer
https://www.readbyqxmd.com/read/28588757/identification-of-neuron-selective-androgen-receptor-inhibitors
#19
Maya Otto-Duessel, Ben Yi Tew, Steven Vonderfecht, Roger Moore, Jeremy O Jones
AIM: To identify neuron-selective androgen receptor (AR) signaling inhibitors, which could be useful in the treatment of spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease, a neuromuscular disorder in which deterioration of motor neurons leads to progressive muscle weakness. METHODS: Cell lines representing prostate, kidney, neuron, adipose, and muscle tissue were developed that stably expressed the CFP-AR-YFP FRET reporter. We used these cells to screen a library of small molecules for cell type-selective AR inhibitors...
May 26, 2017: World Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28498253/targeting-foxm1-improves-cytotoxicity-of-paclitaxel-and-cisplatinum-in-platinum-resistant-ovarian-cancer
#20
Gina L Westhoff, Yi Chen, Nelson N H Teng
OBJECTIVE: Aberrantly activated FOXM1 (forkhead box protein M1) leading to uncontrolled cell proliferation and dysregulation of FOXM1 transcription network occurs in 84% of ovarian cancer cases. It was demonstrated that thiostrepton, a thiazole antibiotic, decreases FOXM1 expression. We aimed to determine if targeting the FOXM1 pathway with thiostrepton could improve the efficacy of paclitaxel and cisplatin in human ovarian cancer ascites cells ex vivo. METHODS: Human ovarian cancer cell lines and patients' ascites cells were treated with paclitaxel, cisplatin, and thiostrepton or a combination for 48 hours, and cytotoxicity was assessed...
June 2017: International Journal of Gynecological Cancer
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