Destabilization of ROR1 enhances activity of Ibrutinib against chronic lymphocytic leukemia in vivo.


:Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an onco-embryonic antigen presented on chronic lymphocytic leukemia (CLL), but not on normal adult tissues, which promotes CLL-cell survival. Here, ROR1 was identified as a new client of Heat Shock Protein 90 (HSP90) via a mass spectrometry-based screen for ROR1-associated partners followed by co-immunoprecipitation (co-IP) analysis. A binding motif (ELHHPNIV) on ROR1 for HSP90 was revealed, which forms a αC-β4 loop and is necessary for HSP90-facilitated ROR1 stabilization. We also found that targeting HSP90 leads to ROR1 degradation in a ubiquitin-proteasome dependent pathway, by which pro-survival ROR1 signaling was attenuated in CLL. Based on our previous finding that a humanized monoclonal antibody against ROR1 increases the activity of Ibrutinib against CLL, which is currently undergoing evaluation in clinical trials for the treatment of B-cell lymphoid malignancies, we then provided evidence that treatment with HSP90 inhibitor (17-DMAG) enhances anti-CLL activity of Ibrutinib in vitro and in vivo, by down-modulating ROR1. iTRAQ-based quantitative proteomic analysis of other HSP90 oncogenic clients in addition to ROR1, followed by GO/KEGG enrichment analysis, showed that Bruton's Tyrosine Kinase (BTK), B-lymphoid Tyrosine Kinase (BLK), Lymphocyte-specific Protein Tyrosine Kinase (LCK), or LCK/YES-Related Novel Protein Tyrosine Kinase (LYN), as HSP90 clients, were significantly involved in 11 biological processes and 6 signaling pathways. However, immunoblotting validation confirmed that Ibrutinib treatment dramatically deprived HSP90 inhibitors, 17-DMAG, AUY922 or PU-H71, of inducing the degradation of BTK, BLK, LCK or LYN, but not ROR1. Collectively, our data suggested that depletion of ROR1 induced by targeting HSP90 might facilitate the enhancement of Ibrutinib activity against CLL.


Pharmacol Res


Pharmacological research


Liu Z,Liu J,Zhang T,Shi M,Chen X,Chen Y,Yu J




Has Abstract


2020-01-01 00:00:00












  • Effect of DL alpha-lipoic acid on tissue lipid peroxidation and antioxidant systems in normal and glycollate treated rats.

    abstract::The cytoprotective activity of alpha-lipoic acid against free radical toxicity, manifested during experimental hyperoxaluria, has been investigated. Glycollate was used as the inducer of oxalate hyperoxaluria in rats. The increase in lipid peroxidation and superoxide dismutase (SOD) activity, associated with a decreas...

    journal_title:Pharmacological research

    pub_type: 杂志文章


    authors: Sumathi R,Jayanthi S,Kalpanadevi V,Varalakshmi P

    更新日期:1993-05-01 00:00:00

  • Impact of SLC22A1 and CYP3A5 genotypes on imatinib response in chronic myeloid leukemia: A systematic review and meta-analysis.

    abstract::Contrasting results have been reported on the role of rs628031 and rs683369 polymorphisms of SLC22A1 and rs776746 of CYP3A5 on imatinib treatment response in patients with chronic myeloid leukemia (CML). In the present study, we conducted a systematic review and meta-analysis of published studies to estimate the impac...

    journal_title:Pharmacological research

    pub_type: 杂志文章,meta分析


    authors: Cargnin S,Ravegnini G,Soverini S,Angelini S,Terrazzino S

    更新日期:2018-05-01 00:00:00

  • Pharmacokinetics of doxycycline after administration as a single intravenous bolus and intramuscular doses to non-lactating Egyptian goats.

    abstract::The pharmacokinetics of doxycycline hydrochloride (DoxHcl) at a dose of 5 mg kg-1 BW was studied after an intravenous (i.v.) bolus and intramuscular (i.m.) injections in non lactating goats. A microbiological assay employing Bacillus subtilis as the test organism was used to measure its concentrations in serum and uri...

    journal_title:Pharmacological research

    pub_type: 杂志文章


    authors: Abd El-Aty AM,Goudah A,Zhou HH

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  • Strengths, weaknesses and future challenges of biosimilars' development. An opinion on how to improve the knowledge and use of biosimilars in clinical practice.

    abstract::Biosimilars started receiving the marketing authorization by European Medicine Agency since 2006. The development of biosimilars follows a well-defined step-wise approach, the so-called comparability exercise, which aims to compare non-clinical (mainly quality features and biological activity) and clinical (efficacy a...

    journal_title:Pharmacological research

    pub_type: 杂志文章,评审


    authors: Scavone C,Rafaniello C,Berrino L,Rossi F,Capuano A

    更新日期:2017-12-01 00:00:00

  • Isobolographic analysis of the antinociceptive interactions of clonidine with nonsteroidal anti-inflammatory drugs.

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    journal_title:Pharmacological research

    pub_type: 杂志文章


    authors: Miranda HF,Pinardi G

    更新日期:2004-09-01 00:00:00

  • Influence of 3-PPP, a sigma receptor ligand, on the anticonvulsive action of conventional antiepileptic drugs.

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    journal_title:Pharmacological research

    pub_type: 杂志文章


    authors: Borowicz KK,Kleinrok Z,Czuczwar SJ

    更新日期:1999-12-01 00:00:00

  • Co-administration of raltegravir reduces daily darunavir exposure in HIV-1 infected patients.

    abstract::The potential drug-to-drug interaction between darunavir and raltegravir in the setting of HIV infection is a highly debated issue still unresolved. In the present study we have evaluated the pharmacokinetics of darunavir and ritonavir in 53 HIV-1 infected patients with or without concomitant raltegravir administratio...

    journal_title:Pharmacological research

    pub_type: 临床试验,杂志文章


    authors: Cattaneo D,Gervasoni C,Cozzi V,Baldelli S,Fucile S,Meraviglia P,Landonio S,Boreggio G,Rizzardini G,Clementi E

    更新日期:2012-02-01 00:00:00

  • Toxicogenomic and bioinformatics platforms to identify key molecular mechanisms of a curcumin-analogue DM-1 toxicity in melanoma cells.

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    journal_title:Pharmacological research

    pub_type: 杂志文章


    authors: Oliveira ÉA,Lima DS,Cardozo LE,Souza GF,de Souza N,Alves-Fernandes DK,Faião-Flores F,Quincoces JAP,Barros SBM,Nakaya HI,Monteiro G,Maria-Engler SS

    更新日期:2017-11-01 00:00:00

  • Poly(ADP-ribosyl)ation and stroke.

    abstract::Over the past decade, poly(ADP-ribosyl)ation has emerged as a crucial event in the pathogenesis of ischemic stroke. A large body of evidence unambiguously demonstrates that activity of poly(ADP-ribose) polymerase-1 (PARP-1) significantly increases during brain ischemia, and that inhibition of this enzymatic activity a...

    journal_title:Pharmacological research

    pub_type: 杂志文章,评审


    authors: Chiarugi A

    更新日期:2005-07-01 00:00:00

  • Effects of heparin-binding protein (CAP37/azurocidin) in a porcine model of Actinobacillus pleuropneumoniae-induced pneumonia.

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    journal_title:Pharmacological research

    pub_type: 杂志文章


    authors: Lauritzen B,Lykkesfeldt J,Djurup R,Flodgaard H,Svendsen O

    更新日期:2005-06-01 00:00:00

  • Involvement of the GABAA receptor α subunit in the mode of action of etifoxine.

    abstract::Etifoxine (EFX) is a non-benzodiazepine psychoactive drug which exhibits anxiolytic effects through a dual mechanism, by directly binding to GABAA receptors (GABAARs) and to the mitochondrial 18-kDa translocator protein, resulting in the potentiation of the GABAergic function. The β subunit subtype plays a key role in...

    journal_title:Pharmacological research

    pub_type: 杂志文章


    authors: Mattei C,Taly A,Soualah Z,Saulais O,Henrion D,Guérineau NC,Verleye M,Legros C

    更新日期:2019-07-01 00:00:00

  • Hydralazine improves ischemia-induced neovasculogenesis via xanthine-oxidase inhibition in chronic renal insufficiency.

    abstract::Oxidative stress is related to the progression of renal diseases and modulation of oxidative stress can lead to a reduction in vascular events in patients with chronic renal insufficiency (CRI). Indoxyl sulfate (IS) and xanthine oxidase (XO) are related to impaired neovasculogenesis in CRI. Hydralazine is suggested fo...

    journal_title:Pharmacological research

    pub_type: 杂志文章


    authors: Chang TT,Chen JW

    更新日期:2020-01-01 00:00:00

  • Paradoxical sleep deprivation in rats causes a selective reduction in the expression of type-2 metabotropic glutamate receptors in the hippocampus.

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    journal_title:Pharmacological research

    pub_type: 杂志文章


    authors: Panaccione I,Iacovelli L,di Nuzzo L,Nardecchia F,Mauro G,Janiri D,De Blasi A,Sani G,Nicoletti F,Orlando R

    更新日期:2017-03-01 00:00:00

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    journal_title:Pharmacological research

    pub_type: 杂志文章


    authors: Brouillette RL,Besserer-Offroy É,Mona CE,Chartier M,Lavenus S,Sousbie M,Belleville K,Longpré JM,Marsault É,Grandbois M,Sarret P

    更新日期:2020-05-01 00:00:00

  • Advances into Understanding the Vital Role of the Mitochondrial Citrate Carrier (CIC) in Metabolic Diseases.

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    journal_title:Pharmacological research

    pub_type: 杂志文章,评审


    authors: Peng R,Zhang M,Wang H,Lin J,Wang H,Wang F,Liu L,Zhao Q,Liu J

    更新日期:2020-11-01 00:00:00

  • Ultramicronized palmitoylethanolamide (PEA-um(®)) in the treatment of idiopathic pulmonary fibrosis.

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    journal_title:Pharmacological research

    pub_type: 杂志文章


    authors: Di Paola R,Impellizzeri D,Fusco R,Cordaro M,Siracusa R,Crupi R,Esposito E,Cuzzocrea S

    更新日期:2016-09-01 00:00:00

  • Calumenin and fibulin-1 on tumor metastasis: Implications for pharmacology.

    abstract::Tumor metastasis is a key cause of cancer mortality, and inhibiting migration of cancer cells is one of the major directions of anti-metastatic drug development. Calumenin and fibulin-1 are two extracellular proteins that synergistically inhibit cell migration and tumor metastasis, and could potentially be served as t...

    journal_title:Pharmacological research

    pub_type: 杂志文章,评审


    authors: Zheng P,Wang Q,Teng J,Chen J

    更新日期:2015-09-01 00:00:00

  • Mechanisms involved in the relaxant action of testosterone in the renal artery from male normoglycemic and diabetic rabbits.

    abstract::Kidney disease is a frequent complication in diabetes, and significant differences have been reported between male and female patients. Our working hypothesis was that diabetes might modify the vascular actions of testosterone in isolated rabbit renal arteries and the mechanisms involved in these actions. Testosterone...

    journal_title:Pharmacological research

    pub_type: 杂志文章


    authors: Marrachelli VG,Miranda FJ,Centeno JM,Burguete MC,Castelló-Ruiz M,Jover-Mengual T,Pérez AM,Salom JB,Torregrosa G,Alborch E

    更新日期:2010-02-01 00:00:00

  • Nutraceuticals: An emerging therapeutic approach against the pathogenesis of Alzheimer's disease.

    abstract::Alzheimer's disease (AD) is regarded as a progressive and devastating neurodegenerative disorder. In aged individuals, it is the most prevalent cause of dementia and is characterized by gradual loss of cognitive functions. In the last decade, numerous research works were undertaken to investigate the pathogenesis of A...

    journal_title:Pharmacological research

    pub_type: 杂志文章,评审


    authors: Sadhukhan P,Saha S,Dutta S,Mahalanobish S,Sil PC

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  • Protection from apoptotic cell death by cilostazol, phosphodiesterase type III inhibitor, via cAMP-dependent protein kinase activation.

    abstract::This study aimed to elucidate whether the effect of cilostazol to suppress apoptotic cell death is directly coupled to cAMP-dependent protein kinase activation in human umbilical vein endothelial cells (HUVECs). After exposure of HUVECs to LPS (1 microgml(-1)) for 18 h, the endothelial cells irregularly aggregated wit...

    journal_title:Pharmacological research

    pub_type: 杂志文章


    authors: Kim MJ,Lee JH,Park SY,Hong KW,Kim CD,Kim KY,Lee WS

    更新日期:2006-10-01 00:00:00

  • Genotoxicity and carcinogenicity studies of analgesics, anti-inflammatory drugs and antipyretics.

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    journal_title:Pharmacological research

    pub_type: 杂志文章,评审


    authors: Brambilla G,Martelli A

    更新日期:2009-07-01 00:00:00

  • Biochemical changes on the cardioprotective effect of nicorandil and amlodipine during experimental myocardial infarction in rats.

    abstract::The synergistic protective effect of nicorandil (KATP channel opener) and amlodipine (calcium channel blocker) on mitochondrial respiration and mitochondrial lipid contents were examined on isoproterenol-induced myocardial infarction in rats. The rats given isoproterenol (150 mg kg(-1) daily, i.p.) for 2 days showed s...

    journal_title:Pharmacological research

    pub_type: 杂志文章


    authors: Sathish V,Ebenezar KK,Devaki T

    更新日期:2003-12-01 00:00:00

  • The development of medicines for children. Part of a series on Pediatric Pharmacology, guest edited by Gianvincenzo Zuccotti, Emilio Clementi, and Massimo Molteni.

    abstract::The lack of availability of appropriate medicines for children is an extensive and well known problem. As a consequence off label or unlicensed administration of medicinal products in every day paediatric practice is frequent. A variety of obstacles hinder the development of paediatric indications for drugs primarily ...

    journal_title:Pharmacological research

    pub_type: 社论,评审


    authors: Rocchi F,Tomasi P

    更新日期:2011-09-01 00:00:00

  • Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy.

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    journal_title:Pharmacological research

    pub_type: 杂志文章,评审


    authors: Abdel-Wahab AF,Mahmoud W,Al-Harizy RM

    更新日期:2019-12-01 00:00:00

  • Cholinergic responses of seminal vesicles isolated from rats exposed perinatally to hydrocortisone.

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    journal_title:Pharmacological research

    pub_type: 杂志文章


    authors: Pereira OC,Yasuhara F,Arena AC

    更新日期:2003-07-01 00:00:00

  • Immune system in renal injury and repair: burning the candle from both ends?

    abstract::This brief overview is focused on the inherent duality of immune responses: on the one hand they may induce inflammation and precipitate injury, on the other, a number of examples of participation in organ and tissue repair are growing. These processes will be reviewed from the nephrological stand-point. Specifically,...

    journal_title:Pharmacological research

    pub_type: 杂志文章,评审


    authors: Goligorsky MS

    更新日期:2008-08-01 00:00:00

  • Conjugated linoleic acid: implications for human health.

    abstract::Conjugated linoleic acid (CLA) is being sold as a panacea that has the capability of reducing or eliminating cancer, preventing heart disease, improving immune function, and altering body composition to treat obesity or build lean body mass. Unfortunately, there has been very little published human research on CLA. Th...

    journal_title:Pharmacological research

    pub_type: 杂志文章,评审


    authors: Whigham LD,Cook ME,Atkinson RL

    更新日期:2000-12-01 00:00:00

  • Influence of mianserin on some central effects of ethanol.

    abstract::The interaction of mianserin with ethanol in central nervous system (CNS) was investigated. Mianserin was administered at a single dose of 5 or 20 mgkg(-1) i.p. or as daily injections in a dose of 2.5 mgkg(-1) given for 14 days. The influence of mianserin on acute ethanol toxicity (LD(50)), on ED(50) of ethanol in rot...

    journal_title:Pharmacological research

    pub_type: 杂志文章


    authors: Pietrzak B,Kubik-Bogucka E

    更新日期:2002-07-01 00:00:00

  • FeTPPS protects against global cerebral ischemic-reperfusion injury in gerbils.

    abstract::Neuronal damage following cerebral ischemia is mediated by various mechanisms, among which nitrosative stress plays an important role. Peroxynitrite, a powerful oxidant, contributes heavily to the neuronal damage in cerebral ischemic-reperfusion (IR) injury. In the present study, we have investigated the neuroprotecti...

    journal_title:Pharmacological research

    pub_type: 杂志文章


    authors: Sharma SS,Dhar A,Kaundal RK

    更新日期:2007-04-01 00:00:00

  • Biosimilars in rheumatology.

    abstract::Biotechnologicals are an invaluable resource in the treatment of patients with inflammatory rheumatic diseases (IRD) non-responsive or intolerant to conventional therapies. However, they are the main driver for increase in direct costs and represent a significant economic burden to healthcare systems worldwide. Since ...

    journal_title:Pharmacological research

    pub_type: 杂志文章,评审


    authors: Araújo FC,Gonçalves J,Fonseca JE

    更新日期:2019-11-01 00:00:00