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p53 mdm2

Andreas Gollner, Dorothea Rudolph, Heribert Arnhof, Markus Bauer, Sophia Maria Blake, Guido Boehmelt, Xiao-Ling Cockcroft, Georg Dahmann, Peter Ettmayer, Thomas Gerstberger, Jale Karolyi-Oezguer, Dirk Kessler, Christiane Kofink, Juergen Ramharter, Jörg Rinnenthal, Alexander Savchenko, Renate Schnitzer, Harald Weinstabl, Ulrike Weyer-Czernilofsky, Tobias Wunberg, Darryl B McConnell
Scaffold modification based on Wang´s pioneering MDM2-p53 inhibitors led to novel, chemically stable spiro-oxindole compounds bearing a spiro[3H-indole-3,2´-pyrrolidin]-2(1H)-one scaffold that are not prone to epimerization as observed for the initial spiro[3H-indole-3,3´-pyrrolidin]-2(1H)-one scaffold. Further structure based optimization inspired by natural product architectures led to a complex fused ring system ideally suited to bind to the MDM2 protein and to interrupt its protein-protein interaction (PPI) with TP53...
October 24, 2016: Journal of Medicinal Chemistry
Svetlana Demyanenko, Anatoly Uzdensky
In ischemic stroke, cell damage propagates from infarct core to surrounding tissue. To reveal proteins involved in neurodegeneration and neuroprotection, we explored the protein profile in penumbra surrounding the photothrombotic infarct core induced in rat cerebral cortex by local laser irradiation after Bengal Rose administration. Using antibody microarrays, we studied changes in expression of 224 signaling proteins 1, 4, or 24 h after photothrombotic infarct compared with untreated contralateral cortex...
October 22, 2016: Molecular Neurobiology
Jianfeng Lu, Donna McEachern, Shunqiang Li, Matthew J Ellis, Shaomeng Wang
Endocrine therapy has been highly effective for the treatment of estrogen-receptor positive breast cancer, but endocrine resistance develops in a significant proportion of patients. In an effort to develop novel therapeutic strategies for the treatment of endocrine resistant breast cancer, we have evaluated a potent and specific MDM2-p53 interaction inhibitor, MI-77301, which has been advanced into clinical development, for its therapeutic potential and mechanism of action in vitro and in vivo in WHIM9 and WHIM18 patient-derived xenograft (PDX) models...
October 7, 2016: Molecular Cancer Therapeutics
Jiaxiong Lu, Shan Guan, Yanling Zhao, Yang Yu, Yongfeng Wang, Yonghua Shi, Xinfang Mao, Kristine L Yang, Wenjing Sun, Xin Xu, Joanna S Yi, Tianshu Yang, Jianhua Yang, Jed G Nuchtern
Neuroblastoma (NB), which accounts for about 15% of cancer-related mortality in children, is the most common childhood extracranial malignant tumor. In NB, somatic mutations of the tumor suppressor, p53, are exceedingly rare. Unlike in adult tumors, the majority of p53 downstream functions are still intact in NB cells with wild-type p53. Thus, restoring p53 function by blocking its interaction with p53 suppressors such as MDM2 is a viable therapeutic strategy for NB treatment. Herein, we show that MDM2 inhibitor SAR405838 is a potent therapeutic drug for NB...
October 13, 2016: Oncotarget
X W Yuan, X F Huang, Z X Chen, S G Liang, W M Liao
Objective: To investigate the effect of IFNα on doxorubicin-induced apoptosis in human osteosarcoma cells with its molecular mechanisms to provide evidences for improving the treatment of osteosarcoma. Methods: Osteosacoma U2OS and MG63 cells were treated with IFNα and Doxorubicin, alone or in combination, for 72 h . Cytotoxicity was determined with MTT. Apoptosis was evaluated through fluorescence-activated cell sorting, Hoechst33258 staining and DNA ladder assay. The expression of p53, Bax, Bcl-2, Mdm2, p21, caspase-3 and PARP was determined with Western blot...
October 11, 2016: Zhonghua Yi Xue za Zhi [Chinese medical journal]
Irsan E Kooi, Saskia E van Mil, David MacPherson, Berber M Mol, Annette C Moll, Hanne Meijers-Heijboer, Gertjan J L Kaspers, Jacqueline Cloos, Hein Te Riele, Josephine C Dorsman
Several murine retinoblastoma models have been generated by deleting the genes encoding for retinoblastoma susceptibility protein pRb and one of its family members p107 or p130. In Rb(-/-) p107(-/-) retinoblastomas, somatic copy number alterations (SCNAs) like Mdm2 amplification or Cdkn2a deletion targeting the p53-pathway occur, which is uncommon for human retinoblastoma. In our study, we determined SCNAs in retinoblastomas developing in Rb(-/-) p130(-/-) mice and compared this to murine Rb(-/-) p107(-/-) tumors and human tumors...
October 17, 2016: Genes, Chromosomes & Cancer
Lin Yang, Yanqing Liu, Mei Wang, Yayun Qian, Xiaoyun Dong, Hao Gu, Haibo Wang, Shiyu Guo, Tadashi Hisamitsu
Constitutive photomorphogenesis 9 signalosome (CSN) consists of a total of eight subunits (CSN1-CSN8) in mammalian cells. CSN6 may promote carcinogenesis by positively regulating v‑myc avian myelocytomatosis viral oncogene homolog (Myc) and MDM2 proto‑oncogene stability, and is regarded as a potential target for cancer therapy. Quercetin has a substantial anticancer effect on various human cancer cells. The present study investigated the effects of quercetin on HT-29 human colorectal cancer cell viability, apoptosis and cell cycle arrest using an MTT assay, flow cytometry, transmission electron microscopy and western blotting...
October 10, 2016: Molecular Medicine Reports
D-L Qi, D Cobrinik
Retinoblastomas can arise from cone photoreceptor precursors in response to the loss of pRB function. Cone precursor-specific circuitry cooperates with pRB loss to initiate this process and subsequently contributes to the malignancy. Intrinsic high-level MDM2 expression is a key component of the cone precursor circuitry and is thought to inactivate p53-mediated tumor surveillance, which could otherwise be induced in response to pRB loss. However, the MDM2-related MDM4 has also been proposed to abrogate p53-mediated tumor surveillance in the absence of detectable MDM2 in retinoblastoma cells, bringing into question the importance of high-level MDM2 versus MDM4 expression...
October 17, 2016: Oncogene
Prabhu Thirusangu, V Vigneshwaran, T Prashanth, B R Vijay Avin, Vikas H Malojirao, H Rakesh, Shaukath Ara Khanum, Riaz Mahmood, B T Prabhakar
Hypoxia is a feature of all solid tumours, contributing to tumour progression. Activation of HIF-1α plays a critical role in promoting tumour angiogenesis and metastasis. Since its expression is positively correlated with poor prognosis for cancer patients, HIF-1α is one of the most convincing anticancer targets. BP-1T is a novel antiproliferative agent with promising antiangiogenic effects. In the present study, the molecular mechanism underlying cytotoxic/antiangiogenic effects of BP-1T on tumour/non-tumour angiogenesis was evaluated...
October 14, 2016: Angiogenesis
Hsiang-Tsui Wang, Tzu-Ying Chen, Ching-Wen Weng, Chun-Hsiang Yang, Moon-Shong Tang
Acrolein (Acr) is a potent cytotoxic and DNA damaging agent which is ubiquitous in the environment and abundant in tobacco smoke. Acr is also an active cytotoxic metabolite of the anti-cancer drugs cyclophosphamide and ifosfamide. The mechanisms via which Acr exerts its anti-cancer activity and cytotoxicity are not clear. In this study, we found that Acr induces cytotoxicity and cell death in human cancer cells with different activities of p53. Acr preferentially binds nucleolar ribosomal DNA (rDNA) to form Acr-deoxyguanosine adducts, and induces oxidative damage to both rDNA and ribosomal RNA (rRNA)...
October 12, 2016: Oncotarget
Wen-Bin Ou, Minmin Lu, Grant Eilers, Hailong Li, Jiongyan Ding, Xuli Meng, Yuehong Wu, Quan He, Qing Sheng, Hai-Meng Zhou, Jonathan A Fletcher
BACKGROUND: Improved mesothelioma patient survival will require development of novel and more effective pharmacological interventions. TP53 genomic mutations are uncommon in mesothelioma, and recent data indicate that p53 remains functional, and therefore is a potential therapeutic target in these cancers. In addition, the tumour suppressor NF2 is inactivated by genomic mechanisms in more than 80% of mesothelioma, causing upregulation of FAK activity. Because FAK is a negative regulator of p53, NF2 regulation of FAK-p53-MDM2 signalling loops were evaluated...
October 13, 2016: British Journal of Cancer
Yvonne Voges, Martin Michaelis, Florian Rothweiler, Torsten Schaller, Constanze Schneider, Katharina Politt, Marco Mernberger, Andrea Nist, Thorsten Stiewe, Mark N Wass, Franz Rödel, Jindrich Cinatl
Resistance formation after initial therapy response (acquired resistance) is common in high-risk neuroblastoma patients. YM155 is a drug candidate that was introduced as a survivin suppressant. This mechanism was later challenged, and DNA damage induction and Mcl-1 depletion were suggested instead. Here we investigated the efficacy and mechanism of action of YM155 in neuroblastoma cells with acquired drug resistance. The efficacy of YM155 was determined in neuroblastoma cell lines and their sublines with acquired resistance to clinically relevant drugs...
October 13, 2016: Cell Death & Disease
Emma Danelius, Mariell Pettersson, Matilda Bred, Jaeki Min, M Brett Waddell, R Kiplin Guy, Morten Grøtli, Mate Erdelyi
Protein-protein interactions that have large, flat and featureless binding sites are difficult drug targets. In the development of their modulators conventional drug discovery strategies are often unsuccessful. Gaining a detailed understanding of the binding mode of protein-protein interaction inhibitors is therefore of vast importance for their future pharmaceutical use. The MDM2/p53 protein pair is a highly promising target for cancer treatment. Disruption of the protein complex using p53 α-helix mimetics has been shown to be a successful strategy to control p53 activity...
October 12, 2016: Organic & Biomolecular Chemistry
Leiming Li, Yan Li, Jiansong Zhao, Shuli Fan, Liguo Wang, Xu Li
Osteosarcoma (OS) is the most common primary bone tumor, but molecular mechanisms of the disease have not been well understood, and treatment of metastatic OS remains a challenge. Rapid ribosomal RNA synthesis in cancer is transcribed by RNA polymerase I, which results in unbridled cell growth. The recent discovery of CX-5461, a selective RNA polymerase I inhibitor, exerted its inhibitory effect of ribosomal RNA synthesis and antiproliferative potency. Here, we demonstrate that CX-5461 induces G2 arrest in the cell cycle and expression of microtubule-associated protein 1 light chain 3 II isoform in OS cell lines...
2016: OncoTargets and Therapy
Stephen Bohlman, James J Manfredi
In this issue of Cancer Cell, Gu et al. characterize small molecules that inhibit the interaction of Mdm2 with the mRNA that encodes the anti-apoptotic XIAP, simultaneously decreasing expression of both proteins. This represents a novel approach that has relevance in tumor cells independent of p53 status.
October 10, 2016: Cancer Cell
Yiwen Bu, Guoshuai Cai, Yi Shen, Chenfei Huang, Xi Zeng, Yu Cao, Chuan Cai, Yuhong Wang, Dan Huang, Duan-Fang Liao, Deliang Cao
Inactivation of p53 occurs frequently in various cancers. RITA is a promising anticancer small molecule that dissociates p53-MDM2 interaction, reactivates p53 and induces exclusive apoptosis in cancer cells, but acquired RITA resistance remains a major drawback. This study found that the site-differential phosphorylation of nuclear factor-κB (NF-κB) RelA/p65 creates a barcode for RITA chemosensitivity in cancer cells. In naïve MCF7 and HCT116 cells where RITA triggered vast apoptosis, phosphorylation of RelA/p65 increased at Ser536, but decreased at Ser276 and Ser468; oppositely, in RITA-resistant cells, RelA/p65 phosphorylation decreased at Ser536, but increased at Ser276 and Ser468...
October 6, 2016: Cancer Letters
Aditi Bhowmik, Sambuddha Das, Abhinandan Bhattacharjee, Biswadeep Choudhury, Momota Naiding, Sankar Kumar Ghosh, Yashmin Choudhury
We investigated the role of BRCA1, MDM2, and p53 in the pathogenesis of head and neck cancer (HNC) and evaluated their potential utility as blood-based predictive biomarkers of HNC. Immunostaining of tissue biopsies and whole blood lymphocytes (WBL) of 36 HNC patients were evaluated by immunohistochemistry (IHC) and immunocytochemistry (ICC), respectively. The staining intensities of BRCA1 and MDM2 in matched tissue and blood samples were significantly associated with cancer stage. Furthermore, the cellular levels of BRCA1, MDM2, and p53 were evaluated in peripheral blood lymphocytes (PBL) of 134 HNC patients and 126 controls by slot blotting...
October 6, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Ewa Surmiak, Aleksandra Twarda-Clapa, Krzysztof M Zak, Bogdan Musielak, Marcin D Tomala, Katarzyna Kubica, Przemysław Grudnik, Mariusz Madej, Mateusz Jabłoński, Jan Potempa, Justyna Kalinowska-Tłuścik, Grzegorz Dubin, Alexander Dömling, Tad A Holak
The p53 pathway is inactivated in almost all types of cancer by mutations in the p53 encoding gene or overexpression of the p53 negative regulators, Mdm2 and/or Mdmx. Restoration of the p53 function by inhibition of the p53-Mdm2/Mdmx interaction opens up a prospect for a non-genotoxic anticancer therapy. Here we present the syntheses, activities and crystal structures on two novel classes of Mdm2-p53 inhibitors that are based on the 3-pyrrolin-2-one and 2-furanone scaffolds. The structures of the complexes formed by these inhibitors and Mdm2 reveal the dimeric protein molecular organization that has not been observed in the small-molecule/Mdm2 complexes described until now...
October 6, 2016: ACS Chemical Biology
Salman Akhtar, M Kalim A Khan, Jamal M Arif
Exposure to exogenous and endogenous chemicals and subsequent cellular and molecular changes has been linked to enhanced cell proliferation and restricted apoptosis phenomenon. Though in the past decades numerous anticancer drugs inducing programmed cell death in cancer cells by targeting specific apoptotic markers have reached the market, they have been allied with unwanted side effects, ranging from mild to severe toxicity. With further understanding on the functional mechanism of p53 and MDM2 in apoptosis and in our continuous search for new and potent multi-target anticancer lead compounds, we have carried out molecular docking and inhibition studies of the selected aglycones along with selected anticancer leads, against the specific apoptotic and cell cycle markers using AutoDock Tools 4...
October 5, 2016: Interdisciplinary Sciences, Computational Life Sciences
Jian-Li Gao, Yan-Mei Shui, Wei Jiang, En-Yi Huang, Qi-Yang Shou, Xin Ji, Bai-Cheng He, Gui-Yuan Lv, Tong-Chuan He
Hypoxic in the tumor mass is leading to the myeloproliferative-like disease (leukemoid reaction) and anemia of body, which characterized by strong extensive extramedullary hematopoiesis (EMH) in spleen. As the key transcription factor of hypoxia, hypoxia-inducible factor-1 (HIF-1) activates the expression of genes essential for EMH processes including enhanced blood cell production and angiogenesis. We found ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid, inhibited growth of breast cancer both in vivo and in vitro...
September 30, 2016: Oncotarget
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