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  • 1.
    Fryknäs, Mårten
    et al.
    Uppsala University, Sweden.
    Zhang, Xiaonan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    Bremberg, Ulf
    Beactica, Sweden.
    Senkowski, Wojciech
    Uppsala University, Sweden.
    Hägg Olofsson, Maria
    Karolinska Institute, Sweden.
    Brandt, Peter
    Uppsala University, Sweden.
    Persson, Ingmar
    Swedish University of Agriculture Science, Sweden.
    D´arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Gullbo, Joachim
    Uppsala University, Sweden.
    Nygren, Peter
    Uppsala University, Sweden.
    Kunz Schughart, Leoni
    Technical University of Dresden, Germany.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden.
    Larsson, Rolf
    Uppsala University, Sweden.
    Iron chelators target both proliferating and quiescent cancer cells2016Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikel-id 38343Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Poorly vascularized areas of solid tumors contain quiescent cell populations that are resistant to cell cycle-active cancer drugs. The compound VLX600 was recently identified to target quiescent tumor cells and to inhibit mitochondrial respiration. We here performed gene expression analysis in order to characterize the cellular response to VLX600. The compound-specific signature of VLX600 revealed a striking similarity to signatures generated by compounds known to chelate iron. Validation experiments including addition of ferrous and ferric iron in excess, EXAFS measurements, and structure activity relationship analyses showed that VLX600 chelates iron and supported the hypothesis that the biological effects of this compound is due to iron chelation. Compounds that chelate iron possess anti-cancer activity, an effect largely attributed to inhibition of ribonucleotide reductase in proliferating cells. Here we show that iron chelators decrease mitochondrial energy production, an effect poorly tolerated by metabolically stressed tumor cells. These pleiotropic features make iron chelators an attractive option for the treatment of solid tumors containing heterogeneous populations of proliferating and quiescent cells.

  • 2.
    Hillert, Ellin-Kristina
    et al.
    Karolinska Inst, Sweden.
    Brnjic, Slavica
    Karolinska Inst, Sweden.
    Zhang, Xiaonan
    Karolinska Inst, Sweden.
    Mazurkiewicz, Magdalena
    Karolinska Inst, Sweden.
    Saei, Amir Ata
    Karolinska Inst, Sweden.
    Mofers, Arjan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Selvaraj, Karthik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Zubarev, Roman
    Karolinska Inst, Sweden.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Inst, Sweden.
    D´arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Inst, Sweden.
    Proteasome inhibitor b-AP15 induces enhanced proteotoxicity by inhibiting cytoprotective aggresome formation2019Ingår i: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 448, s. 70-83Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Proteasome inhibitors have been shown to induce cell death in cancer cells by triggering an acute proteotoxic stress response characterized by accumulation of poly-ubiquitinated proteins, ER stress and the production of reactive oxygen species. The aggresome pathway has been described as an escape mechanism from proteotoxicity by sequestering toxic cellular aggregates. Here we show that b-AP15, a small-molecule inhibitor of proteasomal deubiquitinase activity, induces poly-ubiquitin accumulation in absence of aggresome formation. b-AP15 was found to affect organelle transport in treated cells, raising the possibility that microtubule-transport of toxic protein aggregates is inhibited, leading to enhanced cytotoxicity. In contrast to the antiproliferative effects of the clinically used proteasome inhibitor bortezomib, the effects of b-AP15 are not further enhanced by the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). Our results suggest an inhibitory effect of b-AP15 on the transport of misfolded proteins, resulting in a lack of aggresome formation, and a strong proteotoxic stress response.

  • 3.
    Mazurkiewicz, Magdalena
    et al.
    Karolinska Institute, Sweden.
    Hillert, Ellin-Kristina
    Karolinska Institute, Sweden.
    Wang, Xin
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Pellegrini, Paola
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Hägg Olofsson, Maria
    Karolinska Institute, Sweden.
    Selvaraj, Karthik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    D´arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    Acute lymphoblastic leukemia cells are sensitive to disturbances in protein homeostasis induced by proteasome deubiquitinase inhibition2017Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 13, s. 21115-21127Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The non-genotoxic nature of proteasome inhibition makes it an attractive therapeutic option for the treatment of pediatric malignancies. We recently described the small molecule VLX1570 as an inhibitor of proteasome deubiquitinase (DUB) activity that induces proteotoxic stress and apoptosis in cancer cells. Here we show that acute lymphoblastic leukemia (ALL) cells are highly sensitive to treatment with VLX1570, resulting in the accumulation of polyubiquitinated proteasome substrates and loss of cell viability. VLX1570 treatment increased the levels of a number of proteins, including the chaperone HSP70B , the oxidative stress marker heme oxygenase-1 (HO-1) and the cell cycle regulator p21(Cip1). Unexpectedly, polybiquitin accumulation was found to be uncoupled from ER stress in ALL cells. Thus, increased phosphorylation of eIF2a occurred only at supra-pharmacological VLX1570 concentrations and did not correlate with polybiquitin accumulation. Total cellular protein synthesis was found to decrease in the absence of eIF2a phosphorylation. Furthermore, ISRIB (Integrated Stress Response inhibitor) did not overcome the inhibition of protein synthesis. We finally show that VLX1570 can be combined with L-asparaginase for additive or synergistic antiproliferative effects on ALL cells. We conclude that ALL cells are highly sensitive to the proteasome DUB inhibitor VLX1570 suggesting a novel therapeutic option for this disease.

  • 4.
    Mofers, Arjan
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Pellegrini, Paola
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    D´arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Proteasome-associated deubiquitinases and cancer2017Ingår i: Cancer Metastasis Review, ISSN 0167-7659, E-ISSN 1573-7233, Vol. 36, nr 4, s. 635-653Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Maintenance of protein homeostasis is a crucial process for the normal functioning of the cell. The regulated degradation of proteins is primarily facilitated by the ubiquitin proteasome system (UPS), a system of selective tagging of proteins with ubiquitin followed by proteasome-mediated proteolysis. The UPS is highly dynamic consisting of both ubiquitination and deubiquitination steps that modulate protein stabilization and degradation. Deregulation of protein stability is a common feature in the development and progression of numerous cancer types. Simultaneously, the elevated protein synthesis rate of cancer cells and consequential accumulation of misfolded proteins drives UPS addiction, thus sensitizing them to UPS inhibitors. This sensitivity along with the potential of stabilizing pro-apoptotic signaling pathways makes the proteasome an attractive clinical target for the development of novel therapies. Targeting of the catalytic 20S subunit of the proteasome is already a clinically validated strategy in multiple myeloma and other cancers. Spurred on by this success, promising novel inhibitors of the UPS have entered development, targeting the 20S as well as regulatory 19S subunit and inhibitors of deubiquitinating and ubiquitin ligase enzymes. In this review, we outline the manner in which deregulation of the UPS can cause cancer to develop, current clinical application of proteasome inhibitors, and the (pre-)clinical development of novel inhibitors of the UPS.

  • 5.
    Pellegrini, Paola
    et al.
    Karolinska Inst, Sweden.
    Serviss, Jason T.
    Karolinska Inst, Sweden.
    Lundback, Thomas
    Chem Biol Consortium Sweden, Sweden; AstraZeneca, Sweden.
    Bancaro, Nicolo
    Karolinska Inst, Sweden.
    Mazurkiewicz, Magdalena
    Karolinska Inst, Sweden.
    Kolosenko, Iryna
    Karolinska Inst, Sweden.
    Yu, Di
    Karolinska Inst, Sweden.
    Haraldsson, Martin
    Chem Biol Consortium Sweden, Sweden.
    D´arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    De Milito, Angelo
    Karolinska Inst, Sweden.
    A drug screening assay on cancer cells chronically adapted to acidosis2018Ingår i: Cancer Cell International, ISSN 1475-2867, E-ISSN 1475-2867, Vol. 18, artikel-id 147Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Drug screening for the identification of compounds with anticancer activity is commonly performed using cell lines cultured under normal oxygen pressure and physiological pH. However, solid tumors are characterized by a microenvironment with limited access to nutrients, reduced oxygen supply and acidosis. Tumor hypoxia and acidosis have been identified as important drivers of malignant progression and contribute to multicellular resistance to different forms of therapy. Tumor acidosis represents an important mechanism mediating drug resistance thus the identification of drugs active on acid-adapted cells may improve the efficacy of cancer therapy. Methods: Here, we characterized human colon carcinoma cells (HCT116) chronically adapted to grow at pH 6.8 and used them to screen the Prestwick drug library for cytotoxic compounds. Analysis of gene expression profiles in parental and low pH-adapted cells showed several differences relating to cell cycle, metabolism and autophagy. Results: The screen led to the identification of several compounds which were further selected for their preferential cytotoxicity towards acid-adapted cells. Amongst 11 confirmed hits, we primarily focused our investigation on the benzoporphyrin derivative Verteporfin (VP). VP significantly reduced viability in low pH-adapted HCT116 cells as compared to parental HCT116 cells and normal immortalized epithelial cells. The cytotoxic activity of VP was enhanced by light activation and acidic pH culture conditions, likely via increased acid-dependent drug uptake. VP displayed the unique property to cause light-dependent cross-linking of proteins and resulted in accumulation of polyubiquitinated proteins without inducing inhibition of the proteasome. Conclusions: Our study provides an example and a tool to identify anticancer drugs targeting acid-adapted cancer cells.

  • 6.
    Selvaraj, Karthik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Mofers, Arjan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Pellegrini, Paola
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Salomonsson, Johannes
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Ahlner, Alexandra
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Morad, Vivian
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Hillert, Ellin-Kristina
    Karolinska Inst, Sweden.
    Espinosa, Belen
    Karolinska Inst, Sweden.
    Arner, Elias S. J.
    Karolinska Inst, Sweden.
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi.
    Malmstrom, Jonas
    Recipharm AB, Sweden.
    Turkina, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    D´arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Walters, Michael A.
    Univ Minnesota, MN 55455 USA.
    Sunnerhagen, Maria
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Inst, Sweden.
    Cytotoxic unsaturated electrophilic compounds commonly target the ubiquitin proteasome system2019Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, artikel-id 9841Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A large number of natural products have been advocated as anticancer agents. Many of these compounds contain functional groups characterized by chemical reactivity. It is not clear whether distinct mechanisms of action can be attributed to such compounds. We used a chemical library screening approach to demonstrate that a substantial fraction (similar to 20%) of cytotoxic synthetic compounds containing Michael acceptor groups inhibit proteasome substrate processing and induce a cellular response characteristic of proteasome inhibition. Biochemical and structural analyses showed binding to and inhibition of proteasome-associated cysteine deubiquitinases, in particular ubiquitin specific peptidase 14 (USP14). The results suggested that compounds bind to a crevice close to the USP14 active site with modest affinity, followed by covalent binding. A subset of compounds was identified where cell death induction was closely associated with proteasome inhibition and that showed significant antineoplastic activity in a zebrafish embryo model. These findings suggest that proteasome inhibition is a relatively common mode of action by cytotoxic compounds containing Michael acceptor groups and help to explain previous reports on the antineoplastic effects of natural products containing such functional groups.

  • 7.
    Selvaraju, Karthik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Medicinska fakulteten.
    Mazurkiewicz, Magdalena
    Karolinska Institute, Sweden.
    Wang, Xin
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Gullbo, Joachim
    Uppsala University, Sweden.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    D´arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Inhibition of proteasome deubiquitinase activity: a strategy to overcome resistance to conventional proteasome inhibitors?2015Ingår i: Drug resistance updates, ISSN 1368-7646, E-ISSN 1532-2084, Vol. 21-22, s. 20-29Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Although more traditionally associated with degradation and maintenance of protein homeostasis, the ubiquitin-proteasome system (UPS) has emerged as a critical component in the regulation of cancer cell growth and survival. The development of inhibitors that block the proteolytic activities of the proteasome have highlighted its suitability as a bona fide anti-cancer drug target. However, key determinants including the development of drug resistance and dose-limiting toxicity call for the identification of alternative components of the UPS for novel drug targeting. Recently the deubiquitinases (DUBS), a diverse family of enzymes that catalyze ubiquitin removal, have attracted significant interest as targets for the development of next generation UPS inhibitors. In particular, pharmacological inhibition of the proteasomal cysteine DUBs (i.e., USP14 and UCHL5) has been shown to be particularly cytotoxic to cancer cells and inhibit tumour growth in several in vivo models. In the current review we focus on the modes of action of proteasome DUB inhibitors and discus the potential of DUB inhibitors to circumvent acquired drug resistance and provide a therapeutic option for the treatment of cancer. (C) 2015 Elsevier Ltd. All rights reserved.

  • 8.
    Shukla, Neerav
    et al.
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Somwar, Romel
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Smith, Roger S.
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Ambati, Sri
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Munoz, Stanley
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Merchant, Melinda
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    D´arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Wang, Xin
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Kobos, Rachel
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Antczak, Christophe
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Bhinder, Bhavneet
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Shum, David
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Radu, Constantin
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Yang, Guangbin
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Taylor, Barry S.
    Mem Sloan Kettering Cancer Centre, NY 10021 USA; Mem Sloan Kettering Cancer Centre, NY 10021 USA; Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Ng, Charlotte K. Y.
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Weigelt, Britta
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Khodos, Inna
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    de Stanchina, Elisa
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Reis-Filho, Jorge S.
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Ouerfelli, Ouathek
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden.
    Djaballah, Hakim
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Ladanyi, Marc
    Mem Sloan Kettering Cancer Centre, NY 10021 USA; Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Proteasome Addiction Defined in Ewing Sarcoma Is Effectively Targeted by a Novel Class of 19S Proteasome Inhibitors2016Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 76, nr 15, s. 4525-4534Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ewing sarcoma is a primitive round cell sarcoma with a peak incidence in adolescence that is driven by a chimeric oncogene created from the fusion of the EWSR1 gene with a member of the ETS family of genes. Patients with metastatic and recurrent disease have dismal outcomes and need better therapeutic options. We screened a library of 309,989 chemical compounds for growth inhibition of Ewing sarcoma cells to provide the basis for the development of novel therapies and to discover vulnerable pathways that might broaden our understanding of the pathobiology of this aggressive sarcoma. This screening campaign identified a class of benzyl-4-piperidone compounds that selectively inhibit the growth of Ewing sarcoma cell lines by inducing apoptosis. These agents disrupt 19S proteasome function through inhibition of the deubiquitinating enzymes USP14 and UCHL5. Functional genomic data from a genome-wide shRNA screen in Ewing sarcoma cells also identified the proteasome as a node of vulnerability in Ewing sarcoma cells, providing orthologous confirmation of the chemical screen findings. Furthermore, shRNA-mediated silencing of USP14 or UCHL5 in Ewing sarcoma cells produced significant growth inhibition. Finally, treatment of a xenograft mouse model of Ewing sarcoma with VLX1570, a benzyl-4-piperidone compound derivative currently in clinical trials for relapsed multiple myeloma, significantly inhibited in vivo tumor growth. Overall, our results offer a preclinical proof of concept for the use of 19S proteasome inhibitors as a novel therapeutic strategy for Ewing sarcoma. (C) 2016 AACR.

  • 9.
    Wang, Xin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    D´arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Caulfield, Thomas R.
    Mayo Clin, FL 32224 USA.
    Paulus, Aneel
    Mayo Clin, FL 32224 USA.
    Chitta, Kasyapa
    Mayo Clin, FL 32224 USA.
    Mohanty, Chitralekha
    Karolinska Institute, Sweden.
    Gullbo, Joachim
    Uppsala University, Sweden.
    Chanan-Khan, Asher
    Mayo Clin, FL 32224 USA.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    Synthesis and Evaluation of Derivatives of the Proteasome Deubiquitinase Inhibitor b-AP152015Ingår i: Chemical Biology and Drug Design, ISSN 1747-0277, E-ISSN 1747-0285, Vol. 86, nr 5, s. 1036-1048Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The ubiquitin-proteasome system (UPS) is increasingly recognized as a therapeutic target for the development of anticancer therapies. The success of the 20S proteasome core particle (20S CP) inhibitor bortezomib in the clinical management of multiple myeloma has raised the possibility of identifying other UPS components for therapeutic intervention. We previously identified the small molecule b-AP15 as an inhibitor of 19S proteasome deubiquitinase (DUB) activity. Building upon our previous data, we performed a structure-activity relationship (SAR) study on b-AP15 and identified VLX1570 as an analog with promising properties, including enhanced potency and improved solubility in aqueous solution. In silico modeling was consistent with interaction of VLX1570 with key cysteine residues located at the active sites of the proteasome DUBs USP14 and UCHL5. VLX1570 was found to inhibit proteasome deubiquitinase activity in vitro in a manner consistent with competitive inhibition. Furthermore, using active-site-directed probes, VLX1570 also inhibited proteasome DUB activity in exposed cells. Importantly, VLX1570 did not show inhibitory activity on a panel of recombinant non-proteasome DUBs, on recombinant kinases, or on caspase-3 activity, suggesting that VLX1570 is not an overtly reactive general enzyme inhibitor. Taken together, our data shows the chemical and biological properties of VLX1570 as an optimized proteasome DUB inhibitor.

  • 10.
    Wang, Xin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Mazurkiewicz, Magdalena
    Karolinska Institute, Sweden.
    Hillert, Ellin-Kristina
    Karolinska Institute, Sweden.
    Hägg Olofsson, Maria
    Karolinska Institute, Sweden.
    Pierrou, Stefan
    ESP Life Science Consulting AB, Sweden.
    Hillertz, Per
    Biosynchro West AB, Sweden.
    Gullbo, Joachim
    Uppsala University, Sweden.
    Selvaraju, Karthik
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning.
    Paulus, Aneel
    Mayo Clin, FL 32224 USA.
    Akhtar, Sharoon
    Mayo Clin, FL 32224 USA.
    Bossler, Felicitas
    DKFZ, Germany.
    Chanan Khan, Asher
    Mayo Clin, FL 32224 USA; Mayo Clin, FL 32224 USA.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden.
    D´arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells2016Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, s. 1-14, artikel-id 26979Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Inhibition of deubiquitinase (DUB) activity is a promising strategy for cancer therapy. VLX1570 is an inhibitor of proteasome DUB activity currently in clinical trials for relapsed multiple myeloma. Here we show that VLX1570 binds to and inhibits the activity of ubiquitin-specific protease-14 (USP14) in vitro, with comparatively weaker inhibitory activity towards UCHL5 (ubiquitin-C-terminal hydrolase-5). Exposure of multiple myeloma cells to VLX1570 resulted in thermostabilization of USP14 at therapeutically relevant concentrations. Transient knockdown of USP14 or UCHL5 expression by electroporation of siRNA reduced the viability of multiple myeloma cells. Treatment of multiple myeloma cells with VLX1570 induced the accumulation of proteasome-bound high molecular weight polyubiquitin conjugates and an apoptotic response. Sensitivity to VLX1570 was moderately affected by altered drug uptake, but was unaffected by overexpression of BCL2-family proteins or inhibitors of caspase activity. Finally, treatment with VLX1570 was found to lead to extended survival in xenograft models of multiple myeloma. Our findings demonstrate promising antiproliferative activity of VLX1570 in multiple myeloma, primarily associated with inhibition of USP14 activity.

  • 11.
    Zhang, Xiaonan
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
    De Milito, Angelo
    Department of Oncology-Pathology, Karolinska Institute, SE-171 76 Stockholm, Sweden.
    Demiroglu-Zergeroglu, Asuman
    Department of Molecular Biology and Genetics, Gebze Technical University, 41400, Gebze, Kocaeli, Turkey.
    Gullbo, Joachim
    Department of Immunology, Genetics and Pathology, Section of Oncology, Uppsala University, Uppsala, Sweden.
    D’Arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
    Eradicating Quiescent Tumor Cells by Targeting Mitochondrial Bioenergetics2016Ingår i: Trends in Cancer, ISSN 2405-8033, Vol. 2, nr 11, s. 7s. 657-663Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Solid tumors contain slowly proliferating cells that show limited sensitivity to conventional cell cycle-active chemotherapeutic drugs. Tumor cells that are not exposed to therapeutically relevant drug concentrations and/or are insensitive to drugs survive treatment and repopulate tumors between treatment cycles. Cancer cells residing in hypoxic and nutritionally compromised environments are expected to have limited metabolic plasticity and to be susceptible to the manipulation of energy supply pathways. Drug screening campaigns using glucose-depleted tumor cells and 3D tumor cell cultures have resulted in the identification of inhibitors of mitochondrial energy production.

  • 12.
    Zhang, Xiaonan
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    de Milito, Angelo
    Karolinska Institute, Sweden.
    Hagg Olofsson, Maria
    Karolinska Institute, Sweden.
    Gullbo, Joachim
    Uppsala University, Sweden.
    D´arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    Targeting Mitochondrial Function to Treat Quiescent Tumor Cells in Solid Tumors2015Ingår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 16, nr 11, s. 27313-27326Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The disorganized nature of tumor vasculature results in the generation of microenvironments characterized by nutrient starvation, hypoxia and accumulation of acidic metabolites. Tumor cell populations in such areas are often slowly proliferating and thus refractory to chemotherapeutical drugs that are dependent on an active cell cycle. There is an urgent need for alternative therapeutic interventions that circumvent growth dependency. The screening of drug libraries using multicellular tumor spheroids (MCTS) or glucose-starved tumor cells has led to the identification of several compounds with promising therapeutic potential and that display activity on quiescent tumor cells. Interestingly, a common theme of these drug screens is the recurrent identification of agents that affect mitochondrial function. Such data suggest that, contrary to the classical Warburg view, tumor cells in nutritionally-compromised microenvironments are dependent on mitochondrial function for energy metabolism and survival. These findings suggest that mitochondria may represent an Achilles heel for the survival of slowly-proliferating tumor cells and suggest strategies for the development of therapy to target these cell populations.

  • 13.
    Zhang, Xiaonan
    et al.
    Karolinska Inst, Sweden.
    Espinosa, Bela
    Karolinska Inst, Sweden.
    Saei, Amir Ata
    Karolinska Inst, Sweden.
    D´arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Zubarev, Roman A.
    Karolinska Inst, Sweden.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Inst, Sweden.
    Oxidative Stress Induced by the Deubiquitinase Inhibitor b-AP15 Is Associated with Mitochondrial Impairment2019Ingår i: Oxidative Medicine and Cellular Longevity, ISSN 1942-0900, E-ISSN 1942-0994, artikel-id 1659468Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Inhibitors of the 20S proteasome such as bortezomib are cytotoxic to tumor cells and have been proven to be valuable for the clinical management of multiple myeloma. The therapeutic efficacy of bortezomib is, however, hampered by the emergence of acquired resistance. Available data suggest that blocking proteasome activity at the level of proteasome-associated deubiquitinases (DUBs) provides a mechanism to overcome resistance to bortezomib and also to other cancer therapies. The small molecule b-AP15 is an inhibitor of proteasome-associated DUB activity that induces both proteotoxic stress and increases in the levels of reactive oxygen species (ROS) in tumor cells. Antioxidants have been shown to decrease apoptosis induction by b-AP15 and we here addressed the question of the mechanism of redox perturbation by this compound. We show that oxidative stress induction by b-AP15 is abrogated in cells deprived of mitochondrial DNA (rho(0) cells). We also show associations between the level of proteotoxic stress, the degree of mitochondrial dysfunction, and the extent of induction of hemeoxygenase-1 (HO-1), a target of the redox-regulated Nrf-2 transcription factor. Decreased expression of COX5b (cytochrome c oxidase subunit 5b) and TOMM34 (translocase of outer mitochondrial membrane 34) was observed in b-AP15-treated cells. These findings suggest a mitochondrial origin of the increased levels of ROS observed in cells exposed to the DUB inhibitor b-AP15.

  • 14.
    Zhang, Xiaonan
    et al.
    Karolinska Institute, Sweden.
    Mofers, Arjan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Hydbring, Per
    Karolinska Institute, Sweden.
    Hagg Olofsson, Maria
    Karolinska Institute, Sweden.
    Guo, Jing
    Karolinska Institute, Sweden; Duke NUS National University of Singapore Medical Sch, Singapore.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    D´arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    MYC is downregulated by a mitochondrial checkpoint mechanism2017Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 52, s. 90225-90237Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The MYC proto-oncogene serves as a rheostat coupling mitogenic signaling with the activation of genes regulating growth, metabolism and mitochondrial biogenesis. Here we describe a novel link between mitochondria and MYC levels. Perturbation of mitochondrial function using a number of conventional and novel inhibitors resulted in the decreased expression of MYC mRNA. This decrease in MYC mRNA occurred concomitantly with an increase in the levels of tumor-suppressive miRNAs such as members of the let-7 family and miR-34a-5p. Knockdown of let-7 family or miR-34a-5p could partially restore MYC levels following mitochondria damage. We also identified let-7-dependent downregulation of the MYC mRNA chaperone, CRD-BP (coding region determinant-binding protein) as an additional control following mitochondria damage. Our data demonstrates the existence of a homeostasis mechanism whereby mitochondrial function controls MYC expression.

  • 15.
    Zhang, Xiaonan
    et al.
    Karolinska Inst, Sweden.
    Pellegrini, Paola
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Saei, Amir Ata
    Karolinska Inst, Sweden.
    Hillert, Ellin-Kristina
    Karolinska Inst, Sweden.
    Mazurkiewicz, Magdalena
    Karolinska Inst, Sweden.
    Olofsson, Maria Hagg
    Karolinska Inst, Sweden.
    Zubarev, Roman A.
    Karolinska Inst, Sweden.
    D´arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Inst, Sweden.
    The deubiquitinase inhibitor b-AP15 induces strong proteotoxic stress and Check for mitochondrial damage2018Ingår i: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 156, s. 291-301Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Human cancers are characterized by intrinsic or acquired resistance to apoptosis and evasion of apoptosis has been proposed to contribute to treatment resistance. Bis-benzylidine piperidone compounds, containing alpha,beta-unsaturated carbonyl functionalities, have been extensively documented as being effective in killing apoptosis-resistant cells and to display promising antineoplastic activities in a number of tumor models. We here explored the phenotypic response of colon cancer cells to b-AP15, a bis-benzylidine piperidone previously shown to inhibit the proteasome deubiquitinases (DUBs) USP14 and UCHL5. Whereas similar overall mRNA and protein expression profiles were induced by b-AP15 and the clinically available proteasome inhibitor bortezomib, b-APIS induced stronger increases of chaperone expression. b-AP15 also induced a stronger accumulation of polyubiquitinated proteins in exposed cells. These proteins were found to partially colocalize with organelle structures, including mitochondria. Mitochondrial oxidative phosphorylation decreased in cells exposed to b-APIS, a phenomenon enhanced under conditions of severe proteotoxic stress caused by inhibition of the VCP/p97 ATPase and inhibition of protein translocation over the ER. We propose that mitochondrial damage caused by the association of misfolded proteins with mitochondrial membranes may contribute to the atypical cell death mode induced by b-AP15 and related compounds. The robust mode of cell death induction by this class of drugs holds promise for treatment of tumor cells characterized by apoptosis resistance.

  • 16.
    Zhang, Xiaonan
    et al.
    Karolinska Inst, Sweden.
    Selvaraj, Karthik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Saei, Amir Ata
    Karolinska Inst, Sweden.
    D´arcy, Padraig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Zubarev, Roman A.
    Karolinska Inst, Sweden.
    Arner, Elias S. J.
    Karolinska Inst, Sweden.
    Linder, Stig
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Inst, Sweden.
    Repurposing of auranofin: Thioredoxin reductase remains a primary target of the drug2019Ingår i: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 162, s. 46-54Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Auranofin is a gold (1)-containing compound used for the treatment of rheumatic arthritis. Auranofin has anticancer activity in animal models and is approved for clinical trials for lung and ovarian carcinomas. Both the cytosolic and mitochondrial forms of the selenoprotein thioredoxin reductase (TrxR) are well documented targets of auranofin. Auranofin was recently reported to also inhibit proteasome activity at the level of the proteasome-associated deubiquitinases (DUBs) UCHL5 and USP14. We here set out to re-examine the molecular mechanism underlying auranofin cytotoxicity towards cultured cancer cells. The effects of auranofin on the proteasome were examined in cells and in vitro, effects on DUB activity were assessed using different substrates. The cellular response to auranofin was compared to that of the 20S proteasome inhibitor bortezomib and the 19S DUB inhibitor b-AP15 using proteomics. Auranofin was found to inhibit mitochondrial activity and to an induce oxidative stress response at IC50 doses. At 2-3-fold higher doses, auranofin inhibits proteasome processing in cells. At such supra-pharmacological concentrations USP14 activity was inhibited. Analysis of protein expression profiles in drug-exposed tumor cells showed that auranofin induces a response distinct from that of the 20S proteasome inhibitor bortezomib and the DUB inhibitor b-AP15, both of which induced similar responses. Our results support the notion that the primary mechanism of action of auranofin is TrxR inhibition and suggest that proteasome DUB inhibition is an off-target effect. Whether proteasome inhibition will contribute to the antineoplastic effect of auranofin in treated patients is unclear but remains a possibility. (C) 2019 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.

    Publikationen är tillgänglig i fulltext från 2020-04-01 09:23
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