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https://www.readbyqxmd.com/read/29762656/prevention-of-prostate-cancer-by-natural-product-mdm2-inhibitor-gs25-in-vitro-and-in-vivo-activities-and-molecular-mechanisms
#1
Wei Wang, Jiang-Jiang Qin, Xin Li, Guanyu Tao, Qiang Wang, Xuming Wu, Jianwei Zhou, Xiaolin Zi, Ruiwen Zhang
Prostate cancer remains a major health problem in the US and worldwide. There is an urgent need to develop novel approaches to preventing primary and metastatic prostate cancer. We have identified 25-OCH3-protopanaxadiol (GS25), the most active ginsenoside that has been identified so far; it has potent activity against human cancers, including prostate cancer. However, it has not been proven if GS25 could be a safe and effective agent for cancer prevention. In the present study, we used the TRAMP model and clearly demonstrated that GS25 inhibited prostate tumorigenesis and metastasis with minimal host toxicity...
May 12, 2018: Carcinogenesis
https://www.readbyqxmd.com/read/29678833/dual-targeting-of-mdmx-and-mdm2-has-antileukemic-activity
#2
(no author information available yet)
A p53-stapled peptide, ALRN-6924, blocks binding to MDMX and MDM2 to activate p53.
April 20, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29643228/dual-inhibition-of-mdmx-and-mdm2-as-a-therapeutic-strategy-in-leukemia
#3
Luis A Carvajal, Daniela Ben Neriah, Adrien Senecal, Lumie Benard, Victor Thiruthuvanathan, Tatyana Yatsenko, Swathi-Rao Narayanagari, Justin C Wheat, Tihomira I Todorova, Kelly Mitchell, Charles Kenworthy, Vincent Guerlavais, D Allen Annis, Boris Bartholdy, Britta Will, Jesus D Anampa, Ioannis Mantzaris, Manuel Aivado, Robert H Singer, Robert A Coleman, Amit Verma, Ulrich Steidl
The tumor suppressor p53 is often inactivated via its interaction with endogenous inhibitors mouse double minute 4 homolog (MDM4 or MDMX) or mouse double minute 2 homolog (MDM2), which are frequently overexpressed in patients with acute myeloid leukemia (AML) and other cancers. Pharmacological disruption of both of these interactions has long been sought after as an attractive strategy to fully restore p53-dependent tumor suppressor activity in cancers with wild-type p53. Selective targeting of this pathway has thus far been limited to MDM2-only small-molecule inhibitors, which lack affinity for MDMX...
April 11, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29593251/targeting-mdmx-and-pkc%C3%AE-to-improve-current-uveal-melanoma-therapeutic-strategies
#4
R C Heijkants, M Nieveen, K C 't Hart, A F A S Teunisse, A G Jochemsen
Uveal melanoma (UM) is the most frequent ocular cancer in adults, accounting for ~5% of the total melanoma incidence. Although the primary tumor is well treatable, patients frequently develop metastases for which no curative therapy exists. Highly activated protein kinase C (PKC) is a common feature of UM and has shown potential as therapeutic intervention for UM patients. Unfortunately, PKC inhibition as single treatment appears to have only limited clinical benefit. Combining PKC inhibition with activation of p53, which is rarely mutated in UM, by MDM2 inhibitors has shown promising results in vitro and in vivo...
March 29, 2018: Oncogenesis
https://www.readbyqxmd.com/read/29581299/mdmx-acidic-domain-inhibits-p53-dna-binding-in-vivo-and-regulates-tumorigenesis
#5
Qingling Huang, Lihong Chen, Leixiang Yang, Xiaoling Xie, Lin Gan, John L Cleveland, Jiandong Chen
The MDM2 homolog MDMX oncoprotein is indispensable for inhibition of p53 during normal embryonic development and malignant transformation, yet how MDMX harnesses p53 functions is unclear. In addition to a canonical N-terminal p53-binding domain, recent work suggests the central acidic domain of MDMX regulates p53 interaction through intramolecular mimicry and engages in second-site interaction with the p53 core domain in vitro. To test the physiological relevance of these interactions, we generated an MDMX knockin mouse having substitutions in a conserved WW motif necessary for these functions (W201S/W202G)...
March 26, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29571049/lanthanide-doped-nanoparticles-conjugated-with-an-anti-cd33-antibody-and-a-p53-activating-peptide-for-acute-myeloid-leukemia-therapy
#6
Fan Niu, Jin Yan, Bohan Ma, Shichao Li, Yongping Shao, Pengcheng He, Wanggang Zhang, Wangxiao He, Peter X Ma, Wuyuan Lu
Roughly one third of all human cancers are attributable to the functional inhibition of the tumor suppressor protein p53 by its two negative regulators MDM2 and MDMX, making dual-specificity peptide antagonists of MDM2 and MDMX highly attractive drug candidates for anticancer therapy. Two pharmacological barriers, however, remain a major obstacle to the development of peptide therapeutics: susceptibility to proteolytic degradation in vivo and inability to traverse the cell membrane. Here we report the design of a fluorescent lanthanide oxyfluoride nanoparticle (LONp)-based multifunctional peptide drug delivery system for potential treatment of acute myeloid leukemia (AML) that commonly harbors wild type p53, high levels of MDM2 and/or MDMX, and an overexpressed cell surface receptor, CD33...
March 14, 2018: Biomaterials
https://www.readbyqxmd.com/read/29552226/the-co-treatment-of-metformin-with-flavone-synergistically-induces-apoptosis-through-inhibition-of-pi3k-akt-pathway-in-breast-cancer-cells
#7
Zhaodi Zheng, Wenzhen Zhu, Bingwu Yang, Rongfei Chai, Tingting Liu, Fenglin Li, Guanghui Ren, Shuhua Ji, Shan Liu, Guorong Li
Metformin, a widely used antidiabetic drug, exhibits anticancer effects which are mediated by the phosphatidylinositol 3-kinase (PI3K)/serine/threonine kinase (AKT) signaling pathway. However, its use in anticancer therapy combined with other natural products remains unclear. Flavone as the core structure of flavonoids has been demonstrated to induce cell apoptosis without causing serious side effect. Murine double minute X (MDMX) inhibits tumor suppressor gene p53 whose function is associated with the PI3K/AKT pathway...
April 2018: Oncology Letters
https://www.readbyqxmd.com/read/29540569/an-ezh2-mediated-epigenetic-mechanism-behind-p53-dependent-tissue-sensitivity-to-dna-damage
#8
Gamze Kuser-Abali, Lu Gong, Jiawei Yan, Qingqing Liu, Weiqi Zeng, Amanda Williamson, Chuan Bian Lim, Mary Ellen Molloy, John B Little, Lei Huang, Zhi-Min Yuan
Renewable tissues exhibit heightened sensitivity to DNA damage, which is thought to result from a high level of p53. However, cell proliferation in renewable tissues requires p53 down-regulation, creating an apparent discrepancy between the p53 level and elevated sensitivity to DNA damage. Using a combination of genetic mouse models and pharmacologic inhibitors, we demonstrate that it is p53-regulated MDM2 that functions together with MDMX to regulate DNA damage sensitivity by targeting EZH2 (enhancer of zeste homolog 2) for ubiquitination/degradation...
March 27, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29523541/peli1-modulates-the-subcellular-localization-and-activity-of-mdmx
#9
Dawei Li, Omid Tavana, Shao-Cong Sun, Wei Gu
Mdm2 and Mdmx, both major repressors of p53 in human cancers, are predominantly localized to the nucleus and cytoplasm, respectively. The mechanism by which subcellular localization of Mdmx is regulated remains unclear. In this study, we identify the E3 ligase Peli1 as a major binding partner and regulator of Mdmx in human cells. Peli1 bound Mdmx in vitro and in vivo and promoted high levels of ubiquitination of Mdmx. Peli1-mediated ubiquitination was degradation-independent, promoting cytoplasmic localization of Mdmx which in turn resulted in p53 activation...
March 9, 2018: Cancer Research
https://www.readbyqxmd.com/read/29484110/inhibition-of-mdmx-mdm4-in-vivo-induces-anti-obesity-effects
#10
Ning Kon, Donglai Wang, Tongyuan Li, Le Jiang, Li Qiang, Wei Gu
Although cell-cycle arrest, senescence and apoptosis remain as major canonical activities of p53 in tumor suppression, the emerging role of p53 in metabolism has been a topic of great interest. Nevertheless, it is not completely understood how p53-mediated metabolic activities are regulated in vivo and whether this part of the activities has an independent role beyond tumor suppression. Mdmx (also called Mdm4), like Mdm2, acts as a major suppressor of p53 but the embryonic lethality of mdmx-null mice creates difficulties to evaluate its physiological significance in metabolism...
January 26, 2018: Oncotarget
https://www.readbyqxmd.com/read/29464071/activation-of-p53-and-destabilization-of-androgen-receptor-by-combinatorial-inhibition-of-mdm2-and-mdmx-in-prostate-cancer-cells
#11
Harman Chopra, Zara Khan, Jamie Contreras, Herui Wang, Abanob Sedrak, Yan Zhu
Castration-resistant prostate cancer (CRPC) frequently develops after initial standard radiation and androgen deprivation therapy, leaving patients with limited further treatment options. Androgen receptor (AR) is a transcription factor that plays a key role in the initiation and progression of prostate cancer. p53, a major tumor suppressor that is rarely mutated in early-stages of prostate cancer, is often deregulated during prostate cancer progression. Here, we report an unusual co-amplification of MDM2 and MDMX, two crucial negative regulators of p53, in CRPC datasets...
January 19, 2018: Oncotarget
https://www.readbyqxmd.com/read/29348869/role-of-the-n-terminal-lid-in-regulating-the-interaction-of-phosphorylated-mdmx-with-p53
#12
Jane Vin Chan, Dawn Xin Ping Koh, Yun Liu, Thomas L Joseph, David P Lane, Chandra S Verma, Yaw Sing Tan
Murine double minute 4 protein (MDMX) is crucial for the regulation of the tumor suppressor protein p53. Phosphorylation of the N-terminal domain of MDMX is thought to affect its binding with the transactivation domain of p53, thus playing a role in p53 regulation. In this study, the effects of MDMX phosphorylation on the binding of p53 were investigated using molecular dynamics simulations. It is shown that in addition to the previously proposed mechanism in which phosphorylated Y99 of MDMX inhibits p53 binding through steric clash with P27 of p53, the N-terminal lid of MDMX also appears to play an important role in regulating the phosphorylation-dependent interactions between MDMX and p53...
December 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29158845/in-tether-chiral-center-induced-helical-peptide-modulators-target-p53-mdm2-mdmx-and-inhibit-tumor-growth-in-stem-like-cancer-cell
#13
Kuan Hu, Feng Yin, Mengyin Yu, Chengjie Sun, Jingxu Li, Yujie Liang, Wenjun Li, Mingsheng Xie, Yuanzhi Lao, Wei Liang, Zi-Gang Li
Inhibition of the interaction between p53 and MDM2/MDMX has attracted significant attention in anticancer therapy development. We designed a series of in-tether chiral center-induced helical stabilized peptides, among which MeR/PhR effectively reactivated p53. The activation of p53 inhibits cell proliferation and induces apoptosis in both the MCF-7 normal tumor cell line and the PA-1 pluripotent cancer cell line with only minimal cellular toxicity towards normal cells or cancer cell lines with p53 mutations...
2017: Theranostics
https://www.readbyqxmd.com/read/29123033/inactivation-of-the-mdm2-ring-domain-enhances-p53-transcriptional-activity-in-mice
#14
Hui Tian, Nicole R Tackmann, Aiwen Jin, Junnian Zheng, Yanping Zhang
The MDM2 RING domain harbors E3 ubiquitin ligase activity critical for regulating the degradation of tumor suppressor p53, which controls many cellular pathways. The MDM2 RING domain also is required for an interaction with MDMX. Mice containing a substitution in the MDM2 RING domain, MDM2C462A , disrupting MDM2 E3 function and the MDMX interaction, die during early embryogenesis that can be rescued by p53 deletion. To investigate whether MDM2C462A , which retains p53 binding, has p53-suppressing activity, we generated Mdm2C462A/C462A ; p53ER /- mice, in which we replaced the endogenous p53 alleles with an inducible p53ER /- allele, and compared survival with that of similarly generated Mdm2 -/- ; p53ER /- mice...
December 29, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29023092/effect-of-the-flexible-regions-of-the-oncoprotein-mouse-double-minute-x-on-inhibitor-binding-affinity
#15
Lingyun Qin, Huili Liu, Rong Chen, Jingjing Zhou, Xiyao Cheng, Yao Chen, Yongqi Huang, Zhengding Su
The oncoprotein MdmX (mouse double minute X) is highly homologous to Mdm2 (mouse double minute 2) in terms of their amino acid sequences and three-dimensional conformations, but Mdm2 inhibitors exhibit very weak affinity for MdmX, providing an excellent model for exploring how protein conformation distinguishes and alters inhibitor binding. The intrinsic conformation flexibility of proteins plays pivotal roles in determining and predicting the binding properties and the design of inhibitors. Although the molecular dynamics simulation approach enables us to understand protein-ligand interactions, the mechanism underlying how a flexible binding pocket adapts an inhibitor has been less explored experimentally...
November 7, 2017: Biochemistry
https://www.readbyqxmd.com/read/28973015/a-small-molecule-drug-promoting-mirna-processing-induces-alternative-splicing-of-mdmx-transcript-and-rescues-p53-activity-in-human-cancer-cells-overexpressing-mdmx-protein
#16
Georgios Valianatos, Barbora Valcikova, Katerina Growkova, Amandine Verlande, Jitka Mlcochova, Lenka Radova, Monika Stetkova, Michaela Vyhnakova, Ondrej Slaby, Stjepan Uldrijan
MdmX overexpression contributes to the development of cancer by inhibiting tumor suppressor p53. A switch in the alternative splicing of MdmX transcript, leading to the inclusion of exon 6, has been identified as the primary mechanism responsible for increased MdmX protein levels in human cancers, including melanoma. However, there are no approved drugs, which could translate these new findings into clinical applications. We analyzed the anti-melanoma activity of enoxacin, a fluoroquinolone antibiotic inhibiting the growth of some human cancers in vitro and in vivo by promoting miRNA maturation...
2017: PloS One
https://www.readbyqxmd.com/read/28927521/when-the-guardian-sleeps-reactivation-of-the-p53-pathway-in-cancer
#17
REVIEW
Olaf Merkel, Ninon Taylor, Nicole Prutsch, Philipp B Staber, Richard Moriggl, Suzanne D Turner, Lukas Kenner
The p53 tumor suppressor is inactivated in most cancers, thus suggesting that loss of p53 is a prerequisite for tumor growth. Therefore, its reintroduction through different means bears great clinical potential. After a brief introduction to current knowledge of p53 and its regulation by the ubiquitin-ligases MDM2/MDMX and post-translational modifications, we will discuss small molecules that are able to reactivate specific, frequently observed mutant forms of p53 and their applicability for clinical purposes...
July 2017: Mutation Research
https://www.readbyqxmd.com/read/28916339/d-amino-acid-mutation-of-pmi-as-potent-dual-peptide-inhibitors-of-p53-mdm2-mdmx-interactions
#18
Xiang Li, Chao Liu, Si Chen, Honggang Hu, Jiacan Su, Yan Zou
According to the previously reported potent dual l-peptide PMI of p53-MDM2/MDMX interactions, a series of d-amino acid mutational PMI analogues, PMI-1-4, with enhanced proteolytic resistence and in vitro tumor cell inhibitory activities were reported, of which Liposome-PMI-1 showed a stronger inhibitory activity against the U87 cell lines than Nutlin-3. This d-amino acid mutation strategy may give a hand for enhancing the potential of peptide drugs.
October 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28673313/mdm2-x-inhibitors-under-clinical-evaluation-perspectives-for-the-management-of-hematological-malignancies-and-pediatric-cancer
#19
REVIEW
Veronica Tisato, Rebecca Voltan, Arianna Gonelli, Paola Secchiero, Giorgio Zauli
The two murine double minute (MDM) family members MDM2 and MDMX are at the center of an intense clinical assessment as molecular target for the management of cancer. Indeed, the two proteins act as regulators of P53, a well-known key controller of the cell cycle regulation and cell proliferation that, when altered, plays a direct role on cancer development and progression. Several evidence demonstrated that functional aberrations of P53 in tumors are in most cases the consequence of alterations on the MDM2 and MDMX regulatory proteins, in particular in patients with hematological malignancies where TP53 shows a relatively low frequency of mutation while MDM2 and MDMX are frequently found amplified/overexpressed...
July 3, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28581721/a-fusion-protein-of-the-p53-transaction-domain-and-the-p53-binding-domain-of-the-oncoprotein-mdmx-as-an-efficient-system-for-high-throughput-screening-of-mdmx-inhibitors
#20
Rong Chen, Jingjing Zhou, Lingyun Qin, Yao Chen, Yongqi Huang, Huili Liu, Zhengding Su
In nearly half of cancers, the anticancer activity of p53 protein is often impaired by the overexpressed oncoprotein Mdm2 and its homologue, MdmX, demanding efficient therapeutics to disrupt the aberrant p53-MdmX/Mdm2 interactions to restore the p53 activity. While many potent Mdm2-specific inhibitors have already undergone clinical investigations, searching for MdmX-specific inhibitors has become very attractive, requiring a more efficient screening strategy for evaluating potential scaffolds or leads. In this work, considering that the intrinsic fluorescence residue Trp23 in the p53 transaction domain (p53p) plays an important role in determining the p53-MdmX/Mdm2 interactions, we constructed a fusion protein to utilize this intrinsic fluorescence signal to monitor high-throughput screening of a compound library...
June 27, 2017: Biochemistry
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