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https://www.readbyqxmd.com/read/29412166/efflux-inhibition-by-iwr-1-endo-confers-sensitivity-to-doxorubicin-effects-in-osteosarcoma-cells
#1
Carl T Gustafson, Tewodros Mamo, Avudaiappan Maran, Michael J Yaszemski
Osteosarcoma is the most common bone tumor that affects children and young adults. Despite advances in the use of combination chemotherapy regimens, response to neoadjuvant chemotherapy in osteosarcoma remains a key determinant of patient outcome. Recently, highly potent small molecule inhibitors of canonical Wnt signaling through the poly(ADP-ribose) polymerase (PARP)-family enzymes, tankyrases 1 & 2 (Tnks1/2), have been considered as possible chemotherapy sensitizing agents. The goal of this study was to determine the ability of the highly specific Tnks1/2 inhibitor IWR-1-endo to sensitize chemotherapy-resistant osteosarcoma to doxorubicin...
February 2, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29374194/2-phenylquinazolinones-as-dual-activity-tankyrase-kinase-inhibitors
#2
Yves Nkizinkiko, Jenny Desantis, Jarkko Koivunen, Teemu Haikarainen, Sudarshan Murthy, Luca Sancineto, Serena Massari, Federica Ianni, Ezeogo Obaji, Maria I Loza, Taina Pihlajaniemi, Jose Brea, Oriana Tabarrini, Lari Lehtiö
Tankyrases (TNKSs) are enzymes specialized in catalyzing poly-ADP-ribosylation of target proteins. Several studies have validated TNKSs as anti-cancer drug targets due to their regulatory role in Wnt/β-catenin pathway. Recently a lot of effort has been put into developing more potent and selective TNKS inhibitors and optimizing them towards anti-cancer agents. We noticed that some 2-phenylquinazolinones (2-PQs) reported as CDK9 inhibitors were similar to previously published TNKS inhibitors. In this study, we profiled this series of 2-PQs against TNKS and selected kinases that are involved in the Wnt/β-catenin pathway...
January 26, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29348564/inhibition-of-wnt-%C3%AE-catenin-signaling-under-serum-starvation-and-hypoxia-induces-adipocytic-transdifferentiation-in-human-leiomyoma-cells
#3
Hiroshi Harada, Yojiro Tsuda, Kei Yabuki, Eisuke Shiba, Kazuyoshi Uchihashi, Atsuji Matsuyama, Yoshihisa Fujino, Toru Hachisuga, Masanori Hisaoka
Fatty metamorphosis is an uncommon alteration in uterine leiomyoma (i.e., lipoleiomyoma), and the pathogenetic mechanisms underlying this phenomenon remain poorly understood. Because a conditional deletion of β-catenin, a major transducer of the canonical Wingless/integrated (WNT) pathway, in the developing mouse uterus can induce adipogenesis in the myometrium, it is hypothesized that inhibition of the WNT/β-catenin signaling may be also involved in the development of fat cells within uterine leiomyoma. In the current study, which was performed to address this point, intracytoplasmic lipid droplets were detectable in cultured human leiomyoma cells by treatment with a potent tankyrase inhibitor, XAV939, which antagonizes β-catenin, in a serum-starved culture medium without additional adipogenesis-inducing agents or supplements, and showed increasing accumulation in a time-dependent manner...
January 18, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29344117/wnt-inhibitor-xav939-suppresses-the-viability-of-small-cell-lung-cancer-nci-h446-cells-and-induces-apoptosis
#4
Wenxuan Guo, Fangzhen Shen, Wenjing Xiao, Jing Chen, Fei Pan
Small cell lung cancer (SCLC) is the most aggressive type of lung cancer due to a fast tumor doubling time and early hematogenous spread. Advances in the treatment of non-small cell lung cancer using targeted therapies having been made, but no targeted drugs for SCLC have been approved. The Wnt signaling pathway is associated with tumor progression and metastasis; therefore, the inhibition of Wnt/β-catenin signaling is a strategy for anticancer drugs. Tankyrase 1 (TNKS1) is overexpressed in a number of types of cancer and XAV939 is a small molecule inhibitor of TNKS1 which may inhibit tumor growth...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29316982/the-tankyrase-inhibitor-g007-lk-inhibits-small-intestine-lgr5-stem-cell-proliferation-without-altering-tissue-morphology
#5
Jens Henrik Norum, Ellen Skarpen, Andreas Brech, Raoul Kuiper, Jo Waaler, Stefan Krauss, Therese Sørlie
BACKGROUND: The WNT pathway regulates intestinal stem cells and is frequently disrupted in intestinal adenomas. The pathway contains several potential biotargets for interference, including the poly-ADP ribosyltransferase enzymes tankyrase1 and 2. LGR5 is a known WNT pathway target gene and marker of intestinal stem cells. The LGR5+ stem cells are located in the crypt base and capable of regenerating all intestinal epithelial cell lineages. RESULTS: We treated Lgr5-EGFP-Ires-CreERT2;R26R-Confetti mice with the tankyrase inhibitor G007-LK for up to 3 weeks to assess the effect on duodenal stem cell homeostasis and on the integrity of intestinal epithelium...
January 9, 2018: Biological Research
https://www.readbyqxmd.com/read/29250169/therapeutic-strategies-against-cancer-stem-cells-in-human-colorectal-cancer
#6
Magdalena Szaryńska, Agata Olejniczak, Jarosław Kobiela, Piotr Spychalski, Zbigniew Kmieć
Colorectal cancer (CRC) is the third most frequent malignancy and represents the fourth most common cause of cancer-associated mortalities in the world. Despite many advances in the treatment of CRC, the 5-year survival rate of patients with CRC remains unsatisfactory due to tumor recurrence and metastases. Recently, cancer stem cells (CSCs), have been suggested to be responsible for the initiation and relapse of the disease, and have been identified in CRC. Due to their basic biological features, which include self-renewal and pluripotency, CSCs may be novel therapeutic targets for CRC and other cancer types...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29222171/tankyrase-inhibition-enhances-the-anti-proliferative-effect-of-pi3k-and-egfr-inhibition-mutually-affecting-%C3%AE-catenin-and-akt-signaling-in-colorectal-cancer
#7
Nina T Solberg, Jo Waaler, Kaja Lund, Line Mygland, Petter A Olsen, Stefan Krauss
Over-activation of the WNT/β-catenin signaling axis is a common denominator in colorectal cancer (CRC). Currently there is no available WNT inhibitor in clinical practice. Although tankyrase inhibitors have been proposed as promising candidates there are many CRC models that do not respond positively to tankyrase inhibition in vitro and in vivo. Therefore, a combinatorial therapeutic approach combining a tankyrase inhibitor (G007-LK) with PI3K (BKM120) and EGFR (Erlotinib) inhibitors in CRC was investigated...
December 8, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29179156/radiosensitization-with-an-inhibitor-of-poly-adp-ribose-glycohydrolase-a-comparison-with-the-parp1-2-3-inhibitor-olaparib
#8
Polly Gravells, James Neale, Emma Grant, Amit Nathubhai, Kate M Smith, Dominic I James, Helen E Bryant
Upon DNA binding the poly(ADP-ribose) polymerase family of enzymes (PARPs) add multiple ADP-ribose subunits to themselves and other acceptor proteins. Inhibitors of PARPs have become an exciting and real prospect for monotherapy and as sensitizers to ionising radiation (IR). The action of PARPs are reversed by poly(ADP-ribose) glycohydrolase (PARG). Until recently studies of PARG have been limited by the lack of an inhibitor. Here, a first in class, specific, and cell permeable PARG inhibitor, PDD00017273, is shown to radiosensitize...
November 22, 2017: DNA Repair
https://www.readbyqxmd.com/read/29168093/application-of-two-dimensional-binary-fingerprinting-methods-for-the-design-of-selective-tankyrase-i-inhibitors
#9
B S Muddukrishna, Vasudev Pai, Richard Lobo, Aravinda Pai
In the present study, five important binary fingerprinting techniques were used to model novel flavones for the selective inhibition of Tankyrase I. From the fingerprints used: the fingerprint atom pairs resulted in a statistically significant 2D QSAR model using a kernel-based partial least square regression method. This model indicates that the presence of electron-donating groups positively contributes to activity, whereas the presence of electron withdrawing groups negatively contributes to activity. This model could be used to develop more potent as well as selective analogues for the inhibition of Tankyrase I...
November 22, 2017: Molecular Diversity
https://www.readbyqxmd.com/read/29155568/discovery-of-a-novel-series-of-tankyrase-inhibitors-by-a-hybridization-approach
#10
Upendra Rao Anumala, Jo Waaler, Yves Nkizinkiko, Alexander Ignatev, Katina Lazarow, Peter Lindemann, Petter Angell Olsen, Sudarshan Murthy, Ezeogo Obaji, Alexander G Majouga, Sergey V Leonov, Jens Peter von Kries, Lari Lehtiö, Stefan Krauss, Marc Nazaré
A structure-guided hybridization approach using two privileged substructures gave instant access to a new series of tankyrase inhibitors. The identified inhibitor 16 displays high target affinity on tankyrase 1 and 2 with a biochemical and cellular IC50 values of 29 nM, 6.3 nM and 19 nM, respectively, and high selectivity towards other Poly(ADP-ribose) polymerase enzymes. The identified inhibitor shows a favorable in-vitro ADME profile as well as good oral bioavailability in mice, rats and dogs. Critical for the approach was the utilization of an appropriate linker between 1,2,4-triazole and benzimidazolone moieties, whereby a cyclobutyl linker displayed superior affinity compared to a cyclohexane and phenyl linker...
November 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29126913/iwr-1-a-tankyrase-inhibitor-attenuates-wnt-%C3%AE-catenin-signaling-in-cancer-stem-like-cells-and-inhibits-in%C3%A2-vivo-the-growth-of-a-subcutaneous-human-osteosarcoma-xenograft
#11
Sara R Martins-Neves, Daniela I Paiva-Oliveira, Carlos Fontes-Ribeiro, Judith V M G Bovée, Anne-Marie Cleton-Jansen, Célia M F Gomes
Wnt/β-catenin or canonical Wnt signaling pathway regulates the self-renewal of cancer stem-like cells (CSCs) and is involved in tumor progression and chemotherapy resistance. Previously, we reported that this pathway is activated in a subset of osteosarcoma CSCs and that doxorubicin induced stemness properties in differentiated cells through Wnt/β-catenin activation. Here, we investigated whether pharmacological Wnt/β-catenin inhibition, using a tankyrase inhibitor (IWR-1), might constitute a strategy to target CSCs and improve chemotherapy efficacy in osteosarcoma...
November 8, 2017: Cancer Letters
https://www.readbyqxmd.com/read/29107427/targeting-wnt-driven-cancers-discovery-of-novel-tankyrase-inhibitors
#12
REVIEW
Martina Ferri, Paride Liscio, Andrea Carotti, Stefania Asciutti, Roccaldo Sardella, Antonio Macchiarulo, Emidio Camaioni
Recent years have seen substantially heightened interest in the discovery of tankyrase inhibitors (TNKSi) as new promising anticancer agents. In this framework, the aim of this review article is focused on the description of potent TNKSi also endowed with disruptor activity toward the Wnt/β-catenin signaling pathway. Beginning with an overview of the most characterized TNKSi deriving from several drug design approaches and classifying them on the basis of the molecular interactions with the target, we discuss only those ones acting against Wnt cancer cell lines...
October 7, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29055830/pharmacological-inhibition-of-tankyrase-induces-bone-loss-in-mice-by-increasing-osteoclastogenesis
#13
Shunichi Fujita, Tomoyuki Mukai, Takafumi Mito, Shoko Kodama, Akiko Nagasu, Mizuho Kittaka, Teruki Sone, Yasuyoshi Ueki, Yoshitaka Morita
Tankyrase is a poly (ADP-ribose) polymerase that leads to ubiquitination and degradation of target proteins. Since tankyrase inhibitors suppress the degradation of AXIN protein, a negative regulator of the canonical Wnt pathway, they effectively act as Wnt inhibitors. Small molecule tankyrase inhibitors are being investigated as drug candidates for cancer and fibrotic diseases, in which the Wnt pathways are aberrantly activated. Tankyrase is also reported to degrade the adaptor protein SH3BP2 (SH3 domain-binding protein 2)...
October 18, 2017: Bone
https://www.readbyqxmd.com/read/29048660/canonical-and-non-canonical-wnt-signaling-in-cancer-stem-cells-and-their-niches-cellular-heterogeneity-omics-reprogramming-targeted-therapy-and-tumor-plasticity-review
#14
Masaru Katoh
Cancer stem cells (CSCs), which have the potential for self-renewal, differentiation and de-differentiation, undergo epigenetic, epithelial-mesenchymal, immunological and metabolic reprogramming to adapt to the tumor microenvironment and survive host defense or therapeutic insults. Intra-tumor heterogeneity and cancer-cell plasticity give rise to therapeutic resistance and recurrence through clonal replacement and reactivation of dormant CSCs, respectively. WNT signaling cascades cross-talk with the FGF, Notch, Hedgehog and TGFβ/BMP signaling cascades and regulate expression of functional CSC markers, such as CD44, CD133 (PROM1), EPCAM and LGR5 (GPR49)...
September 19, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/29043869/identifying-the-biomarker-potential-of-telomerase-activity-and-shelterin-complex-molecule-telomeric-repeat-binding-factor-2-terf2-in-multiple-myeloma
#15
Raman Kumar, Rehan Khan, Nidhi Gupta, Tulika Seth, Atul Sharma, Mani Kalaivani, Alpana Sharma
Telomere length (TL) is maintained by telomere capping protein complex called shelterin complex. We studied the possible involvement and biomarker potential of shelterin complex molecules in naive multiple myeloma (MM) patients and controls. TL, relative telomerase activity (RTA), real-time PCR and Western blotting were performed in bonemarrow sample of 70 study subjects (patients = 50; controls = 20). Significantly lowered mean TL, increased RTA and higher mRNA expression of shelterin molecules were observed in patients, while PIN2/TERF1 interacting telomerase inhibitor 1 (PINX1) showed lower mRNA expression...
October 18, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28986473/mouse-red-blood-cell-mediated-rare-xenobiotic-phosphorylation-of-a-drug-molecule-not-intended-to-be-a-kinase-substrate
#16
Chungang Gu, Shenghua Wen, Peter Doig, Eric Gangl, Xiaolan Zheng, Yanjun Wang, Jeffrey W Johannes
Phosphorylation of xenobiotics is rare, probably due to a strong evolutionary pressure against it. This rarity may have attracted more attention recently, owing to intentionally designed kinase-substrate analogs which depend on kinase-catalyzed activation to form phosphorylated active drugs. We report a rare phosphorylated metabolite observed unexpectedly in mouse plasma samples after an oral dose of a Tankyrase inhibitor that was not intended to be a kinase substrate, i.e. (S)-2-(4-(6-(3,4-dimethylpiperazin-1-yl)-4-methylpyridin-3-yl)phenyl)-8-(hydroxymethyl)quinazolin-4(3H)-one (AZ2381)...
October 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28910490/regulation-of-wnt-%C3%AE-catenin-signalling-by-tankyrase-dependent-poly-adp-ribosyl-ation-and-scaffolding
#17
REVIEW
Laura Mariotti, Katie Pollock, Sebastian Guettler
The Wnt/β-catenin signalling pathway is pivotal for stem cell function and the control of cellular differentiation, both during embryonic development and tissue homeostasis in adults. Its activity is carefully controlled through the concerted interactions of concentration-limited pathway components and a wide range of posttranslational modifications, including phosphorylation, ubiquitylation, sumoylation, poly(ADP-ribosyl)ation (PARylation) and acetylation. Regulation of Wnt/β-catenin signalling by PARylation was discovered relatively recently...
September 14, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28900081/-mir-218-promoted-the-apoptosis-of-human-ovarian-carcinoma-cells-via-suppression-of-the-wnt-%C3%AE-catenin-signaling-pathway
#18
Y Huang, S-H Liang, L-B Xiang, X-T Han, W Zhang, J Tang, X-H Wu, M-Q Zhang
MicroRNA-218 (miR-218) is a short, noncoding RNA, with multiple biological functions. In this study, we aimed to investigate the potential effects of miR-218 on the apoptosis of human ovarian carcinoma cells and the underlying mechanisms by which miR-218 exerted its actions. After over-expressing miR-218 in human ovarian carcinoma (OVCAR3) cells, cell viability was determined by MTT method, cell apoptosis was observed by flow cytometry (FCM), mRNA expression of miR-218, Bcl2, Bax was measured by RT-PCR and protein expression levels of Wnt, tankyrase and β-catenin were quantified by Western blots...
July 2017: Molekuliarnaia Biologiia
https://www.readbyqxmd.com/read/28877210/tankyrase-inhibitors-suppress-hepatocellular-carcinoma-cell-growth-via-modulating-the-hippo-cascade
#19
Jiaoyuan Jia, Yu Qiao, Maria G Pilo, Antonio Cigliano, Xianqiong Liu, Zixuan Shao, Diego F Calvisi, Xin Chen
Previous data indicate that Tankyrase inhibitors exert anti-growth functions in many cancer cell lines due to their ability to inactivate the YAP protooncogene. In the present manuscript, we investigated the effect of Tankyrase inhibitors on the growth of hepatocellular carcinoma (HCC) cell lines and the molecular mechanisms involved. For this purpose, we performed cell proliferation assay by colony-forming ability in seven human HCC cells subjected to XAV-939 and G007-LK Tankyrase inhibitors. Noticeably, the two Tankyrase inhibitors suppressed the HCC cell growth in a dose-dependent manner...
2017: PloS One
https://www.readbyqxmd.com/read/28731148/molecular-genetics-and-targeted-therapy-of-wnt-related-human-diseases-review
#20
Masuko Katoh, Masaru Katoh
Canonical WNT signaling through Frizzled and LRP5/6 receptors is transduced to the WNT/β-catenin and WNT/stabilization of proteins (STOP) signaling cascades to regulate cell fate and proliferation, whereas non-canonical WNT signaling through Frizzled or ROR receptors is transduced to the WNT/planar cell polarity (PCP), WNT/G protein-coupled receptor (GPCR) and WNT/receptor tyrosine kinase (RTK) signaling cascades to regulate cytoskeletal dynamics and directional cell movement. WNT/β-catenin signaling cascade crosstalks with RTK/SRK and GPCR-cAMP-PKA signaling cascades to regulate β-catenin phosphorylation and β-catenin-dependent transcription...
September 2017: International Journal of Molecular Medicine
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