A thiol-bound drug reservoir enhances APR-246-induced mutant p53 tumor cell death.

Abstract:

:The tumor suppressor gene TP53 is the most frequently mutated gene in cancer. The compound APR-246 (PRIMA-1Met/Eprenetapopt) is converted to methylene quinuclidinone (MQ) that targets mutant p53 protein and perturbs cellular antioxidant balance. APR-246 is currently tested in a phase III clinical trial in myelodysplastic syndrome (MDS). By in vitro, ex vivo, and in vivo models, we show that combined treatment with APR-246 and inhibitors of efflux pump MRP1/ABCC1 results in synergistic tumor cell death, which is more pronounced in TP53 mutant cells. This is associated with altered cellular thiol status and increased intracellular glutathione-conjugated MQ (GS-MQ). Due to the reversibility of MQ conjugation, GS-MQ forms an intracellular drug reservoir that increases availability of MQ for targeting mutant p53. Our study shows that redox homeostasis is a critical determinant of the response to mutant p53-targeted cancer therapy.

journal_name

EMBO Mol Med

journal_title

EMBO molecular medicine

authors

Ceder S,Eriksson SE,Cheteh EH,Dawar S,Corrales Benitez M,Bykov VJN,Fujihara KM,Grandin M,Li X,Ramm S,Behrenbruch C,Simpson KJ,Hollande F,Abrahmsen L,Clemons NJ,Wiman KG

doi

10.15252/emmm.201910852

subject

Has Abstract

pub_date

2020-12-14 00:00:00

pages

e10852

eissn

1757-4676

issn

1757-4684

pub_type

杂志文章
  • Dietary magnesium supplementation improves lifespan in a mouse model of progeria.

    abstract::Aging is associated with redox imbalance according to the redox theory of aging. Consistently, a mouse model of premature aging (LmnaG609G/+ ) showed an increased level of mitochondrial reactive oxygen species (ROS) and a reduced basal antioxidant capacity, including loss of the NADPH-coupled glutathione redox system....

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.202012423

    authors: Villa-Bellosta R

    更新日期:2020-10-07 00:00:00

  • Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors.

    abstract::Mitochondrial metabolism and the generation of reactive oxygen species (ROS) contribute to the acquisition of DNA mutations and genomic instability in cancer. How genomic instability influences the metabolic capacity of cancer cells is nevertheless poorly understood. Here, we show that homologous recombination-defecti...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201911217

    authors: Lahiguera Á,Hyroššová P,Figueras A,Garzón D,Moreno R,Soto-Cerrato V,McNeish I,Serra V,Lazaro C,Barretina P,Brunet J,Menéndez J,Matias-Guiu X,Vidal A,Villanueva A,Taylor-Harding B,Tanaka H,Orsulic S,Junza A,Yanes O,

    更新日期:2020-06-08 00:00:00

  • A transcriptional network underlies susceptibility to kidney disease progression.

    abstract::The molecular networks that control the progression of chronic kidney diseases (CKD) are poorly defined. We have recently shown that the susceptibility to development of renal lesions after nephron reduction is controlled by a locus on mouse chromosome 6 and requires epidermal growth factor receptor (EGFR) activation....

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.1002/emmm.201101127

    authors: Laouari D,Burtin M,Phelep A,Bienaime F,Noel LH,Lee DC,Legendre C,Friedlander G,Pontoglio M,Terzi F

    更新日期:2012-08-01 00:00:00

  • Hacking cell differentiation: transcriptional rerouting in reprogramming, lineage infidelity and metaplasia.

    abstract::Initiating neoplastic cell transformation events are of paramount importance for the comprehension of regeneration and vanguard oncogenic processes but are difficult to characterize and frequently clinically overlooked. In epithelia, pre-neoplastic transformation stages are often distinguished by the appearance of phe...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章,评审

    doi:10.1002/emmm.201302834

    authors: Regalo G,Leutz A

    更新日期:2013-08-01 00:00:00

  • Metronomic chemotherapy offsets HIFα induction upon maximum-tolerated dose in metastatic cancers.

    abstract::Conventional maximum-tolerated dose (MTD) chemotherapy relies on periodic, massive cancer cell ablation events followed by treatment-free intermissions, stereotypically resulting in resistance, relapse, and mortality. Furthermore, MTD chemotherapy can promote metastatic dissemination via activation of a transcriptiona...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201911416

    authors: Schito L,Rey S,Xu P,Man S,Cruz-Muñoz W,Kerbel RS

    更新日期:2020-09-07 00:00:00

  • Somatically mutated ABL1 is an actionable and essential NSCLC survival gene.

    abstract::The lack of actionable mutations in patients with non-small cell lung cancer (NSCLC) presents a significant hurdle in the design of targeted therapies for this disease. Here, we identify somatically mutated ABL1 as a genetic dependency that is required to maintain NSCLC cell survival. We demonstrate that NSCLC cells w...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201505456

    authors: Testoni E,Stephenson NL,Torres-Ayuso P,Marusiak AA,Trotter EW,Hudson A,Hodgkinson CL,Morrow CJ,Dive C,Brognard J

    更新日期:2016-02-01 00:00:00

  • Antagonism of interferon signaling by fibroblast growth factors promotes viral replication.

    abstract::Fibroblast growth factors (FGFs) play key roles in the pathogenesis of different human diseases, but the cross-talk between FGFs and other cytokines remains largely unexplored. We identified an unexpected antagonistic effect of FGFs on the interferon (IFN) signaling pathway. Genetic or pharmacological inhibition of FG...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201911793

    authors: Maddaluno L,Urwyler C,Rauschendorfer T,Meyer M,Stefanova D,Spörri R,Wietecha M,Ferrarese L,Stoycheva D,Bender D,Li N,Strittmatter G,Nasirujjaman K,Beer HD,Staeheli P,Hildt E,Oxenius A,Werner S

    更新日期:2020-09-07 00:00:00

  • A versatile drug delivery system targeting senescent cells.

    abstract::Senescent cells accumulate in multiple aging-associated diseases, and eliminating these cells has recently emerged as a promising therapeutic approach. Here, we take advantage of the high lysosomal β-galactosidase activity of senescent cells to design a drug delivery system based on the encapsulation of drugs with gal...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201809355

    authors: Muñoz-Espín D,Rovira M,Galiana I,Giménez C,Lozano-Torres B,Paez-Ribes M,Llanos S,Chaib S,Muñoz-Martín M,Ucero AC,Garaulet G,Mulero F,Dann SG,VanArsdale T,Shields DJ,Bernardos A,Murguía JR,Martínez-Máñez R,Serrano M

    更新日期:2018-09-01 00:00:00

  • Adeno-associated virus-vectored influenza vaccine elicits neutralizing and Fcγ receptor-activating antibodies.

    abstract::The current seasonal inactivated influenza vaccine protects only against a narrow range of virus strains as it triggers a dominant antibody response toward the hypervariable hemagglutinin (HA) head region. The discovery of rare broadly protective antibodies against conserved regions in influenza virus proteins has pro...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201910938

    authors: Demminger DE,Walz L,Dietert K,Hoffmann H,Planz O,Gruber AD,von Messling V,Wolff T

    更新日期:2020-05-08 00:00:00

  • Decoding the evolution of a breast cancer genome.

    abstract::Shah et al have recently reported the first successful sequencing of the entire genome of a solid tumour (Shah et al, 2009). Philippe Bedard and Christos Sotiriou analyse their findings as well as the challenges of applying the study of cancer genomes to clinical cancer care. ...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.1002/emmm.200900054

    authors: Bedard PL,Sotiriou C

    更新日期:2010-01-01 00:00:00

  • Identification of the HSPB4/TLR2/NF-κB axis in macrophage as a therapeutic target for sterile inflammation of the cornea.

    abstract::Sterile inflammation underlies many diseases of the cornea including serious chemical burns and the common dry eye syndrome. In search for therapeutic targets for corneal inflammation, we defined the kinetics of neutrophil infiltration in a model of sterile injury to the cornea and identified molecular and cellular me...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.1002/emmm.201200221

    authors: Oh JY,Choi H,Lee RH,Roddy GW,Ylöstalo JH,Wawrousek E,Prockop DJ

    更新日期:2012-05-01 00:00:00

  • Chimeric Pneumoviridae fusion proteins as immunogens to induce cross-neutralizing antibody responses.

    abstract::Human respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV), two members of the Pneumoviridae family, account for the majority of severe lower respiratory tract infections worldwide in very young children. They are also a frequent cause of morbidity and mortality in the elderly and immunocompromised adul...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201708078

    authors: Olmedillas E,Cano O,Martínez I,Luque D,Terrón MC,McLellan JS,Melero JA,Más V

    更新日期:2018-02-01 00:00:00

  • Balancing the fat: lipid droplets and human disease.

    abstract::Lipid droplets (LDs) are dynamic, cytosolic lipid-storage organelles found in nearly all cell types. Too many or too few LDs during excess or deficient fat storage lead to many different human diseases. Recent insights into LD biology and LD protein functions shed new light on mechanisms underlying those metabolic pat...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章,评审

    doi:10.1002/emmm.201100671

    authors: Krahmer N,Farese RV Jr,Walther TC

    更新日期:2013-07-01 00:00:00

  • Neutrophils suppress tumor-infiltrating T cells in colon cancer via matrix metalloproteinase-mediated activation of TGFβ.

    abstract::High T-cell infiltration in colorectal cancer (CRC) correlates with a favorable disease outcome and immunotherapy response. This, however, is only observed in a small subset of CRC patients. A better understanding of the factors influencing tumor T-cell responses in CRC could inspire novel therapeutic approaches to ac...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201910681

    authors: Germann M,Zangger N,Sauvain MO,Sempoux C,Bowler AD,Wirapati P,Kandalaft LE,Delorenzi M,Tejpar S,Coukos G,Radtke F

    更新日期:2020-01-09 00:00:00

  • Treating lysosomal storage diseases with pharmacological chaperones: from concept to clinics.

    abstract::Lysosomal storage diseases (LSDs) are a group of genetic disorders due to defects in any aspect of lysosomal biology. During the past two decades, different approaches have been introduced for the treatment of these conditions. Among them, enzyme replacement therapy (ERT) represented a major advance and is used succes...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章,评审

    doi:10.1002/emmm.200900036

    authors: Parenti G

    更新日期:2009-08-01 00:00:00

  • Google's Project Nightingale highlights the necessity of data science ethics review.

    abstract::On November 14 last year, the British Guardian published an account from an anonymous whistleblower at Google, accusing the company of misconduct in regard to handling sensitive health data. The whistleblower works for Project Nightingale, an attempt by Google to get into the lucrative US healthcare market, by storing...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.202012053

    authors: Schneble CO,Elger BS,Shaw DM

    更新日期:2020-03-06 00:00:00

  • A brain microvasculature endothelial cell-specific viral vector with the potential to treat neurovascular and neurological diseases.

    abstract::Gene therapy critically relies on vectors that combine high transduction efficiency with a high degree of target specificity and that can be administered through a safe intravenous route. The lack of suitable vectors, especially for gene therapy of brain disorders, represents a major obstacle. Therefore, we applied an...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201506078

    authors: Körbelin J,Dogbevia G,Michelfelder S,Ridder DA,Hunger A,Wenzel J,Seismann H,Lampe M,Bannach J,Pasparakis M,Kleinschmidt JA,Schwaninger M,Trepel M

    更新日期:2016-06-01 00:00:00

  • Reprogramming-derived gene cocktail increases cardiomyocyte proliferation for heart regeneration.

    abstract::Although remnant cardiomyocytes (CMs) possess a certain degree of proliferative ability, efficiency is too low for cardiac regeneration after injury. In this study, we identified a distinct stage within the initiation phase of CM reprogramming before the MET process, and microarray analysis revealed the strong up-regu...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201606558

    authors: Cheng YY,Yan YT,Lundy DJ,Lo AH,Wang YP,Ruan SC,Lin PJ,Hsieh PC

    更新日期:2017-02-01 00:00:00

  • Dissecting human antibody responses: useful, basic and surprising findings.

    abstract::Human memory B cells and plasma cells represent a rich source of antibodies that have been selected in response to human pathogens. In the last decade, different methods have been developed to interrogate the human memory repertoire and isolate monoclonal antibodies. I will discuss how a target-agnostic approach based...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201808879

    authors: Lanzavecchia A

    更新日期:2018-03-01 00:00:00

  • MYC and the unfolded protein response in cancer: synthetic lethal partners in crime?

    abstract::The transcription factors of the MYC family play pivotal roles in the initiation and progression of human cancers. High oncogenic level of MYC invades low-affinity sites and enhancer sequences, which subsequently alters the transcriptome, causes metabolic imbalance, and induces stress response. The endoplasmic reticul...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章,评审

    doi:10.15252/emmm.201911845

    authors: Zhang T,Li N,Sun C,Jin Y,Sheng X

    更新日期:2020-05-08 00:00:00

  • Intellectual disability and nutrition-related health.

    abstract::Intellectual disability (ID) is a condition that affects approximately 1% of the population (Maulik et al, 2011). The numbers may differ across nations, owing to different systems and diagnosis entries or lack of such, but usually range between 0.6 and 3% (Stromme & Valvatne, 1998). Persons with ID are a heterogeneous...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.202012899

    authors: Kolset SO

    更新日期:2020-10-07 00:00:00

  • Modification of γ-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease.

    abstract::Inherited familial Alzheimer's disease (AD) is characterized by small increases in the ratio of Aβ42 versus Aβ40 peptide which is thought to drive the amyloid plaque formation in the brain of these patients. Little is known however whether ageing, the major risk factor for sporadic AD, affects amyloid beta-peptide (Aβ...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.1002/emmm.201200243

    authors: Guix FX,Wahle T,Vennekens K,Snellinx A,Chávez-Gutiérrez L,Ill-Raga G,Ramos-Fernandez E,Guardia-Laguarta C,Lleó A,Arimon M,Berezovska O,Muñoz FJ,Dotti CG,De Strooper B

    更新日期:2012-07-01 00:00:00

  • Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice.

    abstract::The combinations of genetic alterations that cooperate with von Hippel-Lindau (VHL) mutation to cause clear cell renal cell carcinoma (ccRCC) remain poorly understood. We show that the TP53 tumour suppressor gene is mutated in approximately 9% of human ccRCCs. Combined deletion of Vhl and Trp53 in primary mouse embryo...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.1002/emmm.201202231

    authors: Albers J,Rajski M,Schönenberger D,Harlander S,Schraml P,von Teichman A,Georgiev S,Wild PJ,Moch H,Krek W,Frew IJ

    更新日期:2013-06-01 00:00:00

  • FGF21 gene therapy as treatment for obesity and insulin resistance.

    abstract::Prevalence of type 2 diabetes (T2D) and obesity is increasing worldwide. Currently available therapies are not suited for all patients in the heterogeneous obese/T2D population, hence the need for novel treatments. Fibroblast growth factor 21 (FGF21) is considered a promising therapeutic agent for T2D/obesity. Native ...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201708791

    authors: Jimenez V,Jambrina C,Casana E,Sacristan V,Muñoz S,Darriba S,Rodó J,Mallol C,Garcia M,León X,Marcó S,Ribera A,Elias I,Casellas A,Grass I,Elias G,Ferré T,Motas S,Franckhauser S,Mulero F,Navarro M,Haurigot V,Rube

    更新日期:2018-08-01 00:00:00

  • Oral administration of pyrophosphate inhibits connective tissue calcification.

    abstract::Various disorders including pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI), which are caused by inactivating mutations in ABCC6 and ENPP1, respectively, present with extensive tissue calcification due to reduced plasma pyrophosphate (PPi). However, it has always been assumed th...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201707532

    authors: Dedinszki D,Szeri F,Kozák E,Pomozi V,Tőkési N,Mezei TR,Merczel K,Letavernier E,Tang E,Le Saux O,Arányi T,van de Wetering K,Váradi A

    更新日期:2017-11-01 00:00:00

  • The role of interleukin-6 in monitoring severe case of coronavirus disease 2019.

    abstract::Progression to severe disease is a difficult problem in treating coronavirus disease 2019 (COVID-19). The purpose of this study is to explore changes in markers of severe disease in COVID-19 patients. Sixty-nine severe COVID-19 patients were included. Patients with severe disease showed significant lymphocytopenia. El...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.202012421

    authors: Liu T,Zhang J,Yang Y,Ma H,Li Z,Zhang J,Cheng J,Zhang X,Zhao Y,Xia Z,Zhang L,Wu G,Yi J

    更新日期:2020-07-07 00:00:00

  • Amyloid precursor protein controls cholesterol turnover needed for neuronal activity.

    abstract::Perturbation of lipid metabolism favours progression of Alzheimer disease, in which processing of Amyloid Precursor Protein (APP) has important implications. APP cleavage is tightly regulated by cholesterol and APP fragments regulate lipid homeostasis. Here, we investigated whether up or down regulation of full-length...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.1002/emmm.201202215

    authors: Pierrot N,Tyteca D,D'auria L,Dewachter I,Gailly P,Hendrickx A,Tasiaux B,Haylani LE,Muls N,N'kuli F,Laquerrière A,Demoulin JB,Campion D,Brion JP,Courtoy PJ,Kienlen-Campard P,Octave JN

    更新日期:2013-04-01 00:00:00

  • Pathogens under scrutiny in the south of France.

    abstract::The first EMBO workshop on Emerging Themes in Infection Biology was held last June in the South of France. It gathered scientists working on various pathogens from viruses and bacteria to larger eukaryotic fungi and parasites. Topics included not only the crosstalk between pathogens and their hosts but also the tools ...

    journal_title:EMBO molecular medicine

    pub_type:

    doi:10.1002/emmm.201000087

    authors: Caldeira S,Dumenil G

    更新日期:2010-09-01 00:00:00

  • iPhemap: an atlas of phenotype to genotype relationships of human iPSC models of neurological diseases.

    abstract::Disease modeling with induced pluripotent stem cells (iPSCs) is creating an abundance of phenotypic information that has become difficult to follow and interpret. Here, we report a systematic analysis of research practices and reporting bias in neurological disease models from 93 published articles. We find heterogene...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201708191

    authors: Hollingsworth EW,Vaughn JE,Orack JC,Skinner C,Khouri J,Lizarraga SB,Hester ME,Watanabe F,Kosik KS,Imitola J

    更新日期:2017-12-01 00:00:00

  • Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients.

    abstract::Familial Mediterranean fever (FMF) is the most frequent hereditary systemic autoinflammatory syndrome. FMF is usually caused by biallelic mutations in the MEFV gene, encoding Pyrin. Conclusive genetic evidence lacks for about 30% of patients diagnosed with clinical FMF. Pyrin is an inflammasome sensor maintained inact...

    journal_title:EMBO molecular medicine

    pub_type: 杂志文章

    doi:10.15252/emmm.201910547

    authors: Magnotti F,Lefeuvre L,Benezech S,Malsot T,Waeckel L,Martin A,Kerever S,Chirita D,Desjonqueres M,Duquesne A,Gerfaud-Valentin M,Laurent A,Sève P,Popoff MR,Walzer T,Belot A,Jamilloux Y,Henry T

    更新日期:2019-11-07 00:00:00