DOCSLIB.ORG

Elesclomol Restores Mitochondrial Function in Genetic Models of Copper Deficiency

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Elesclomol Restores Mitochondrial Function in Genetic Models of Copper Deficiency Elesclomol restores mitochondrial function in genetic models of copper deficiency Shivatheja Somaa, Andrew J. Latimerb, Haarin Chunc, Alison C. Vicarya, Shrishiv A. Timbaliaa, Aren Bouletd, Jennifer J. Rahne, Sherine S. L. Chane, Scot C. Learyd, Byung-Eun Kimc, Jonathan D. Gitlinb, and Vishal M. Gohila,1 aDepartment of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843; bEugene Bell Center for Regenerative Biology and Tissue Engineering, Marine Biological Laboratory, Woods Hole, MA 02543; cDepartment of Animal and Avian Sciences, University of Maryland, College Park, MD 20742; dDepartment of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; and eDepartment of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425 Edited by Amy C. Rosenzweig, Northwestern University, Evanston, IL, and approved July 3, 2018 (received for review April 11, 2018) Copper is an essential cofactor of cytochrome c oxidase (CcO), the other proteins, Coa6 and Cox19, have also been shown to be part of terminal enzyme of the mitochondrial respiratory chain. Inherited this copper delivery pathway in the IMS (10–13). loss-of-function mutations in several genes encoding proteins re- In humans, inherited partial loss-of-function mutations in quired for copper delivery to CcO result in diminished CcO activity SCO1, SCO2, and COA6 result in a CcO deficiency and are as- and severe pathologic conditions in affected infants. Copper sup- sociated with hepatopathy, metabolic acidosis, cardiomyopathy, plementation restores CcO function in patient cells with mutations and neurological defects in affected patients (14–16). Copper in two of these genes, COA6 and SCO2, suggesting a potential supplementation rescues CcO deficiency in myoblasts from pa- therapeutic approach. However, direct copper supplementation tients with mutations in SCO2 (17) and restores CcO activity in has not been therapeutically effective in human patients, under- COA6-deficient yeast and human patient cell lines (16, 18), scoring the need to identify highly efficient copper transporting suggesting that efficient delivery of copper to mitochondria could pharmacological agents. By using a candidate-based approach, we restore CcO activity by bypassing SCO2 and COA6 functions. In an identified an investigational anticancer drug, elesclomol (ES), that attempt to translate these observations in a clinical setting, s.c. in- COA6 rescues respiratory defects of -deficient yeast cells by in- jections of copper histidine were administered to a patient with an creasing mitochondrial copper content and restoring CcO activity. SCO2 mutation. Although copper supplementation improved the ES also rescues respiratory defects in other yeast mutants of cop- patient’s hypertrophic cardiomyopathy, it did not improve other per metabolism, suggesting a broader applicability. Low nanomo- clinical outcomes or survival (19). Thus, a more effective mecha- lar concentrations of ES reinstate copper-containing subunits of nism for restoration of copper homeostasis will be required for CcO in a zebrafish model of copper deficiency and in a series of human therapeutic agents. The present study employed yeast copper-deficient mammalian cells, including those derived from a coa6Δ cells to identify compounds that can efficiently transport patient with SCO2 mutations. These findings reveal that ES can restore intracellular copper homeostasis by mimicking the function copper across biological membranes and restore mitochondrial of missing transporters and chaperones of copper, and may have respiratory chain function over a broad range of concentrations. potential in treating human disorders of copper metabolism. This approach identified elesclomol (ES), which was shown to copper | mitochondria | elesclomol | cytochrome c oxidase Significance opper is an essential micronutrient required for the assembly Inherited pathogenic mutations in genes required for copper Cand activity of cytochrome c oxidase (CcO), the terminal delivery to cytochrome c oxidase (CcO) perturb mitochondrial enzyme of the mitochondrial respiratory chain that catalyzes the energy metabolism and result in fatal mitochondrial disease. A reduction of molecular oxygen and drives mitochondrial energy prior attempt to treat human patients with these mutations by direct copper supplementation was not successful, possibly production (1, 2). CcO is a highly conserved, multimeric inner because of inefficient copper delivery to the mitochondria. We mitochondrial membrane protein complex that has two copper- performed a targeted search to identify compounds that can containing subunits, Cox1 and Cox2, which together form its efficiently transport copper across biological membranes and catalytic core (2). Copper delivery to mitochondria and its in- identified elesclomol (ES), an investigational anticancer drug, sertion into these copper-containing subunits is an intricate as the most efficient copper delivery agent. ES rescues CcO process that requires multiple metallochaperones and ancillary function in yeast, zebrafish, and mammalian models of copper BIOCHEMISTRY proteins (3). Failure to deliver copper to Cox1 and Cox2 disrupts deficiency by increasing cellular and mitochondrial copper con- CcO assembly and results in a respiratory deficiency. tent. Thus, our study offers a possibility of repurposing this anti- Cytosolic copper is delivered to the mitochondrial matrix via cancer drug for the treatment of disorders of copper metabolism. the recently identified yeast protein Pic2 (4), where it is stored in a ligand-bound form (5). This mitochondrial matrix copper pool Author contributions: S.S. and V.M.G. designed research; S.S., A.J.L., H.C., A.C.V., S.A.T., A.B., and J.J.R. performed research; A.J.L., H.C., A.B., J.J.R., S.S.L.C., S.C.L., B.-E.K., and is the main source of copper ions that are inserted into the CcO J.D.G. contributed new reagents/analytic tools; S.S., A.J.L., H.C., A.C.V., S.A.T., J.J.R., subunits in the mitochondrial intermembrane space (IMS) (6). Mo- S.S.L.C., S.C.L., B.-E.K., J.D.G., and V.M.G. analyzed data; and S.S., S.C.L., J.D.G., and bilization of copper from the mitochondrial matrix to the IMS for its V.M.G. wrote the paper. delivery to copper sites in CcO subunits requires a number of evo- Conflict of interest statement: S.S. and V.M.G. are listed as inventors on a provisional patent application filed by Texas A&M University. lutionarily conserved proteins (3). The precise molecular functions of This article is a PNAS Direct Submission. these proteins have remained unsolved, except for the metal- This open access article is distributed under Creative Commons Attribution-NonCommercial- lochaperones Cox17, Sco1, Sco2, and Cox11, which have been shown NoDerivatives License 4.0 (CC BY-NC-ND). to transfer copper to CcO subunits in a bucket-brigade fashion (3). 1To whom correspondence should be addressed. Email: [email protected]. Specifically, Cox17 receives copper from the mitochondrial matrix This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. and transfers it to Cox11 and Sco1/Sco2 (7), which then metallate 1073/pnas.1806296115/-/DCSupplemental. copper sites on Cox1 and Cox2, respectively (8, 9). Recently, two Published online July 23, 2018. www.pnas.org/cgi/doi/10.1073/pnas.1806296115 PNAS | August 7, 2018 | vol. 115 | no. 32 | 8161–8166 Downloaded by guest on October 1, 2021 reestablish subcellular copper homeostasis in copper-deficient cells supplemented with ES (Fig. 1G). ES supplementation also cells, highlighting its therapeutic potential for human diseases of moderately increased total cellular copper levels (Fig. 1H). To copper metabolism. further corroborate that ES increases mitochondrial copper levels by actively transporting extracellular copper into the cells, Results we decreased copper availability in the extracellular compart- A Targeted Search for Copper-Binding Agents Identifies ES as the ment by cotreatment with ES and a known copper chelator, Most Potent Pharmacological Agent in Rescuing Respiratory Defects bathocuproine disulfonate (BCS). As expected, BCS treatment of Yeast coa6Δ Cells. We tested a number of copper-binding resulted in reduced respiratory growth of WT cells, which was pharmacological agents (20) for their ability to rescue respiratory rescued by cotreatment with ES, suggesting that ES is also able deficient growth of coa6Δ cells. Among all of the compounds to overcome pharmacological copper deficiency by outcompeting tested, ES was unique in that it rescued respiratory growth at low BCS (SI Appendix,Fig.S4A). Moreover, ES-mediated rescue of nanomolar concentrations without exhibiting overt toxicity over coa6Δ was diminished in the presence of BCS (SI Appendix,Fig. a broad range of concentrations (SI Appendix, Fig. S1). ES res- S4B). To determine whether ES is able to bypass a mitochondrial cued the respiratory growth of coa6Δ cells with an ED50 of copper transporter, Pic2, we performed ES supplementation in 0.8 nM (SI Appendix, Fig. S2). ES-mediated growth rescue of pic2Δ and coa6Δpic2Δ cells. Although, under the conditions tested, coa6Δ cells was also observed on solid growth medium contain- we did not observe a respiratory growth defect of pic2Δ cells, ES did ing a nonfermentable carbon source (Fig. 1A). Consistent with rescue coa6Δpic2Δ cells, suggesting that this compound can deliver the rescue of respiratory growth, ES supplementation restored copper to the mitochondria independent
Load more

Recommended publications
  • Thesis Was Carried out at the K
    Experimental modeling and novel therapeutic strategies in melanoma brain metastasis Terje Sundstrøm Dissertation for the degree of philosophiae doctor (PhD) University of Bergen, Norway 2015 Dissertation date: June 9th 2015 LIST OF ABBREVIATIONS 3D 3-dimensional 5-ALA 5-aminolevulinic acid AAAS American Association for the Advancement of Science ACT Adoptive cell transfer ADC Apparent diffusion coefficient AJCC American Joint Committee on Cancer AKT Protein kinase B ALK Anaplastic lymphoma kinase APC Antigen-presenting cell APOE Apolipoprotein-E ATP Adenosine triphosphate B7-H3 B7 homolog 3 BBB Blood-brain barrier BCL2A1 Bcl-2-related protein A1 bFGF Basic fibroblast growth factor BLI Bioluminescence imaging BRAF Serine/threonine-protein kinase B-raf BRMS1 Breast cancer metastasis-suppressor 1 BTB Blood-tumor barrier CI (Mitochondrial) Complex I CC22 Chemokine (C-C motif) ligand 22 CD44v6 CD44 splicing variant 6 CDK4 Cyclin-dependent kinase 4 CDKN2A p16INK4A inhibitor of CDK4 cMAP Connectivity Map CNS Central nervous system COT Serine/threonine kinase Cot CRAF RAF proto-oncogene serine/threonine-protein kinase CT Computed tomography CTLA4 Cytotoxic T-lymphocyte-associated protein 4 CXCR4 C-X-C chemokine receptor type 4 2 Da Dalton (unit) DNA Deoxyribonucleic acid DWI Diffusion weighted imaging ECM Extracranial metastases EDNRB Endothelin receptor B EFSA European Foods Safety Authority EGFR Epidermal growth factor receptor ER Estrogen receptor ERBB2 Receptor tyrosine-protein kinase erbB-2 ERK Extracellular signal-regulated kinase ET3 Endothelin-3
    [Show full text]
  • Systematic Drug Screening Identifies Tractable Targeted Combination Therapies in Triple-Negative Breast Cancer
    Author Manuscript Published OnlineFirst on November 21, 2016; DOI: 10.1158/0008-5472.CAN-16-1901 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Systematic drug screening identifies tractable targeted combination therapies in triple-negative breast cancer Vikram B Wali1,3, Casey G Langdon2, Matthew A Held2, James T Platt1, Gauri A Patwardhan1, Anton Safonov1, Bilge Aktas1, Lajos Pusztai1,3, David F Stern2,3,Christos Hatzis1,3 1 Department of Internal Medicine, Section of Medical Oncology, Yale School of Medicine, Yale University, New Haven, Connecticut, USA 2 Department of Pathology, Yale School of Medicine, Yale University, New Haven, Connecticut, USA 3 Yale Cancer Center, New Haven Connecticut, USA Corresponding authors: Christos Hatzis, Ph.D. or Vikram B Wali, Ph.D. Section of Medical Oncology Yale School of Medicine Yale University 333 Cedar Street PO Box 208032 New Haven, CT 06520 [email protected] [email protected] Running Title: Novel Combination Therapies in Triple Negative Breast Cancer CONFLICTS OF INTEREST Authors have no conflict of interest to disclose. 1 Downloaded from cancerres.aacrjournals.org on October 6, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 21, 2016; DOI: 10.1158/0008-5472.CAN-16-1901 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT Triple-negative breast cancer (TNBC) remains an aggressive disease without effective targeted therapies. In this study, we addressed this challenge by testing 128 FDA-approved or investigational drugs as either single agents or in 768 pairwise drug combinations in TNBC cell lines to identify synergistic combinations tractable to clinical translation.
    [Show full text]
  • Mitochondrial Reprogramming in Tumor Progression and Therapy M
    Published OnlineFirst December 9, 2015; DOI: 10.1158/1078-0432.CCR-15-0460 Molecular Pathways Clinical Cancer Research Molecular Pathways: Mitochondrial Reprogramming in Tumor Progression and Therapy M. Cecilia Caino and Dario C. Altieri Abstract Small-molecule inhibitors of the phosphoinositide 3-kinase mitochondrial Hsp90s in preclinical development (gamitrinib) (PI3K), Akt, and mTOR pathway currently in the clinic produce a prevents adaptive mitochondrial reprogramming and shows paradoxical reactivation of the pathway they are intended to potent antitumor activity in vitro and in vivo. Other therapeutic suppress. Furthermore, fresh experimental evidence with PI3K strategies to target mitochondria for cancer therapy include antagonists in melanoma, glioblastoma, and prostate cancer small-molecule inhibitors of mutant isocitrate dehydrogenase shows that mitochondrial metabolism drives an elaborate process (IDH) IDH1 (AG-120) and IDH2 (AG-221), which opened new of tumor adaptation culminating with drug resistance and met- therapeutic prospects for patients with high-risk acute myelog- astatic competency. This is centered on reprogramming of mito- enous leukemia (AML). A second approach of mitochondrial chondrial functions to promote improved cell survival and to fuel therapeutics focuses on agents that elevate toxic ROS levels from the machinery of cell motility and invasion. Key players in these a leaky electron transport chain; nevertheless, the clinical expe- responses are molecular chaperones of the Hsp90 family com- rience with these compounds, including a quinone derivative, partmentalized in mitochondria, which suppress apoptosis via ARQ 501, and a copper chelator, elesclomol (STA-4783) is phosphorylation of the pore component, Cyclophilin D, and limited. In light of this evidence, we discuss how best to target enable the subcellular repositioning of active mitochondria to a resurgence of mitochondrial bioenergetics for cancer therapy.
    [Show full text]
  • Modifications to the Harmonized Tariff Schedule of the United States to Implement Changes to the Pharmaceutical Appendix
    United States International Trade Commission Modifications to the Harmonized Tariff Schedule of the United States to Implement Changes to the Pharmaceutical Appendix USITC Publication 4208 December 2010 U.S. International Trade Commission COMMISSIONERS Deanna Tanner Okun, Chairman Irving A. Williamson, Vice Chairman Charlotte R. Lane Daniel R. Pearson Shara L. Aranoff Dean A. Pinkert Address all communications to Secretary to the Commission United States International Trade Commission Washington, DC 20436 U.S. International Trade Commission Washington, DC 20436 www.usitc.gov Modifications to the Harmonized Tariff Schedule of the United States to Implement Changes to the Pharmaceutical Appendix Publication 4208 December 2010 (This page is intentionally blank) Pursuant to the letter of request from the United States Trade Representative of December 15, 2010, set forth at the end of this publication, and pursuant to section 1207(a) of the Omnibus Trade and Competitiveness Act, the United States International Trade Commission is publishing the following modifications to the Harmonized Tariff Schedule of the United States (HTS) to implement changes to the Pharmaceutical Appendix, effective on January 1, 2011. Table 1 International Nonproprietary Name (INN) products proposed for addition to the Pharmaceutical Appendix to the Harmonized Tariff Schedule INN CAS Number Abagovomab 792921-10-9 Aclidinium Bromide 320345-99-1 Aderbasib 791828-58-5 Adipiplon 840486-93-3 Adoprazine 222551-17-9 Afimoxifene 68392-35-8 Aflibercept 862111-32-8 Agatolimod
    [Show full text]
  • A Genetic Dissection of Mitochondrial Respiratory Chain Biogenesis
    A GENETIC DISSECTION OF MITOCHONDRIAL RESPIRATORY CHAIN BIOGENESIS An Undergraduate Research Scholars Thesis by AARON GRIFFIN, SARAH THERIAULT, SHRISHIV TIMBALIA Submitted to Honors and Undergraduate Research Texas A&M University in partial fulfillment of the requirements for the designation as an UNDERGRADUATE RESEARCH SCHOLAR Approved by Research Advisor: Dr. Vishal Gohil May 2014 Major: Biochemistry, Genetics Biochemistry Biochemistry TABLE OF CONTENTS Page ABSTRACT .....................................................................................................................................1 CHAPTER I INTRODUCTION ...............................................................................................................3 II MATERIALS AND METHODS .........................................................................................7 Yeast strains, plasmids, and culture conditions .......................................................7 Yeast growth measurements ..................................................................................10 Yeast oxygen consumption and mitochondrial isolation .......................................11 SDS-PAGE and Western blotting ..........................................................................11 Sporulation, tetrad dissection, and genotyping ......................................................12 High-throughput phenotypic analysis of yeast strains ...........................................15 III RESULTS ..........................................................................................................................16
    [Show full text]
  • Gene Regulatory Network Analysis with Drug Sensitivity Reveals Synergistic
    www.nature.com/scientificreports OPEN Gene regulatory network analysis with drug sensitivity reveals synergistic efects of combinatory chemotherapy in gastric cancer Jeong Hoon Lee1, Yu Rang Park 2, Minsun Jung 3 & Sun Gyo Lim 4* The combination of docetaxel, cisplatin, and fuorouracil (DCF) is highly synergistic in advanced gastric cancer. We aimed to explain these synergistic efects at the molecular level. Thus, we constructed a weighted correlation network using the diferentially expressed genes between Stage I and IV gastric cancer based on The Cancer Genome Atlas (TCGA), and three modules were derived. Next, we investigated the correlation between the eigengene of the expression of the gene network modules and the chemotherapeutic drug response to DCF from the Genomics of Drug Sensitivity in Cancer (GDSC) database. The three modules were associated with functions related to cell migration, angiogenesis, and the immune response. The eigengenes of the three modules had a high correlation with DCF (−0.41, −0.40, and −0.15). The eigengenes of the three modules tended to increase as the stage increased. Advanced gastric cancer was afected by the interaction the among modules with three functions, namely cell migration, angiogenesis, and the immune response, all of which are related to metastasis. The weighted correlation network analysis model proved the complementary efects of DCF at the molecular level and thus, could be used as a unique methodology to determine the optimal combination of chemotherapy drugs for patients with gastric cancer. Although its incidence is decreasing in some parts of the world, gastric cancer is still the fourth most common cancer worldwide1,2.
    [Show full text]
  • ROS and the DNA Damage Response in Cancer T Upadhyayula Sai Srinivasa,1, Bryce W.Q
    Redox Biology 25 (2019) 101084 Contents lists available at ScienceDirect Redox Biology journal homepage: www.elsevier.com/locate/redox ROS and the DNA damage response in cancer T Upadhyayula Sai Srinivasa,1, Bryce W.Q. Tana,1, Balamurugan A. Vellayappanb, ⁎ Anand D. Jeyasekharana,c, a Cancer Science Institute of Singapore, National University of Singapore, Singapore b Department of Radiation Oncology, National University Hospital, Singapore c Department of Haematology-Oncology, National University Hospital, Singapore ARTICLE INFO ABSTRACT Keywords: Reactive oxygen species (ROS) are a group of short-lived, highly reactive, oxygen-containing molecules that can Reactive Oxygen Species induce DNA damage and affect the DNA damage response (DDR). There is unequivocal pre-clinical and clinical ROS evidence that ROS influence the genotoxic stress caused by chemotherapeutics agents and ionizing radiation. DNA damage response Recent studies have provided mechanistic insight into how ROS can also influence the cellular response to DNA DDR damage caused by genotoxic therapy, especially in the context of Double Strand Breaks (DSBs). This has led to Chemotherapy the clinical evaluation of agents modulating ROS in combination with genotoxic therapy for cancer, with mixed Radiotherapy success so far. These studies point to context dependent outcomes with ROS modulator combinations with Chemotherapy and radiotherapy, indicating a need for additional pre-clinical research in the field. In this review, we discuss the current knowledge on the effect of ROS in the DNA damage response, and its clinical relevance. 1. Introduction to the DNA damage response and ROS collectively termed as the DNA damage response (DDR) is activated. This response includes DNA damage recognition, activation of check- 1.1.
    [Show full text]
  • New Perspective in Diagnostics of Mitochondrial Disorders
    Pronicka et al. J Transl Med (2016) 14:174 DOI 10.1186/s12967-016-0930-9 Journal of Translational Medicine RESEARCH Open Access New perspective in diagnostics of mitochondrial disorders: two years’ experience with whole‑exome sequencing at a national paediatric centre Ewa Pronicka1,2*, Dorota Piekutowska‑Abramczuk1†, Elżbieta Ciara1†, Joanna Trubicka1†, Dariusz Rokicki2, Agnieszka Karkucińska‑Więckowska3, Magdalena Pajdowska4, Elżbieta Jurkiewicz5, Paulina Halat1, Joanna Kosińska6, Agnieszka Pollak7, Małgorzata Rydzanicz6, Piotr Stawinski7, Maciej Pronicki3, Małgorzata Krajewska‑Walasek1 and Rafał Płoski6* Abstract Background: Whole-exome sequencing (WES) has led to an exponential increase in identification of causative vari‑ ants in mitochondrial disorders (MD). Methods: We performed WES in 113 MD suspected patients from Polish paediatric reference centre, in whom routine testing failed to identify a molecular defect. WES was performed using TruSeqExome enrichment, followed by variant prioritization, validation by Sanger sequencing, and segregation with the disease phenotype in the family. Results: Likely causative mutations were identified in 67 (59.3 %) patients; these included variants in mtDNA (6 patients) and nDNA: X-linked (9 patients), autosomal dominant (5 patients), and autosomal recessive (47 patients, 11 homozygotes). Novel variants accounted for 50.5 % (50/99) of all detected changes. In 47 patients, changes in 31 MD-related genes (ACAD9, ADCK3, AIFM1, CLPB, COX10, DLD, EARS2, FBXL4, MTATP6, MTFMT, MTND1, MTND3, MTND5, NAXE, NDUFS6, NDUFS7, NDUFV1, OPA1, PARS2, PC, PDHA1, POLG, RARS2, RRM2B, SCO2, SERAC1, SLC19A3, SLC25A12, TAZ, TMEM126B, VARS2) were identified. The ACAD9, CLPB, FBXL4, PDHA1 genes recurred more than twice suggesting higher general/ethnic prevalence. In 19 cases, variants in 18 non-MD related genes (ADAR, CACNA1A, CDKL5, CLN3, CPS1, DMD, DYSF, GBE1, GFAP, HSD17B4, MECP2, MYBPC3, PEX5, PGAP2, PIGN, PRF1, SBDS, SCN2A) were found.
    [Show full text]
  • Loss of COX4I1 Leads to Combined Respiratory Chain Deficiency And
    cells Article Loss of COX4I1 Leads to Combined Respiratory Chain Deficiency and Impaired Mitochondrial Protein Synthesis Kristýna Cunˇ átová 1,2, David Pajuelo Reguera 1 , Marek Vrbacký 1, Erika Fernández-Vizarra 3 , Shujing Ding 3, Ian M. Fearnley 3, Massimo Zeviani 3 , Josef Houštˇek 1 , Tomáš Mráˇcek 1,* and Petr Pecina 1,* 1 Laboratory of Bioenergetics, Institute of Physiology, Czech Academy of Sciences, 142 00 Prague, Czech Republic; [email protected] (K.C.);ˇ [email protected] (D.P.R.); [email protected] (M.V.); [email protected] (J.H.) 2 Department of Cell Biology, Faculty of Science, Charles University, 128 00 Prague, Czech Republic 3 MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK; [email protected] (E.F.-V.); [email protected] (S.D.); [email protected] (I.M.F.); [email protected] (M.Z.) * Correspondence: [email protected] (T.M.); [email protected] (P.P.) Abstract: The oxidative phosphorylation (OXPHOS) system localized in the inner mitochondrial membrane secures production of the majority of ATP in mammalian organisms. Individual OXPHOS complexes form supramolecular assemblies termed supercomplexes. The complexes are linked not only by their function but also by interdependency of individual complex biogenesis or maintenance. For instance, cytochrome c oxidase (cIV) or cytochrome bc1 complex (cIII) deficiencies affect the level of fully assembled NADH dehydrogenase (cI) in monomeric as well as supercomplex forms. It was hypothesized that cI is affected at the level of enzyme assembly as well as at the level of cI stability and maintenance.
    [Show full text]
  • Clinical Trial Outcomes for Cancer Drug Combinations Can Be Predicted
    Clinical trial outcomes for cancer drug combinations can be predicted using cancer cell line monotherapy screens and a model of independent drug action Alexander Ling and R. Stephanie Huang Experimental and Clinical Pharmacology, University of Minnesota MSI Research Exhibition, 2020 Introduction In vitro validation of IDACombo Clinical validation of IDACombo In many cancer settings, it is evident that combination drug therapies show We utilized three high-throughput cancer cell line drug combination screens to Figure 4. Trial selection Figure 5. Clinical trial validation results increased efficacy compared to monotherapies. However, it is infeasible to validate whether or not IDACombo’s predicted drug combination efficacies match pipeline for clinical show accurate efficacy predictions for trials experimentally evaluate the vast number of possible drug combinations when with measured drug combination efficacies. For each screen, IDACombo was validation. Flowchart in previously untreated patients but not for designing new therapies. To overcome this problem, many computational used to predict drug combination efficacies using the monotherapy data from the detailing how completed, trials in previously treated patients. methods have been developed to estimate drug combination efficacy prior to screen, and then these predictions were compared to the measured drug phase III cancer clinical trials IDACombo’s predicted powers for PFS/TTP experimental testing using existing pre-clinical datasets. These methods have combination efficacies also available in each screen (Figure 2). were selected for the clinical correctly classify 88.5% of clinical trials in which focused on estimating drug synergy and additivity, but they have so far shown trial validation analysis. patients had not received cancer drug treatment limited potential to be translated to independent pre-clinical datasets or to clinical NCI-ALMANAC7 Searches of ClinicalTrials.gov prior to trial entry (Figure 5A), with >85% drug development.1,2 A B C and PubMed.gov were sensitivity and specificity.
    [Show full text]
  • Formerly STA-4783) at AACR-NCI-EORTC International Conference
    Synta Presents New Data on Elesclomol (Formerly STA-4783) at AACR-NCI-EORTC International Conference October 25, 2007 LEXINGTON, Mass.--(BUSINESS WIRE)--Oct. 25, 2007--Synta Pharmaceuticals Corp., (NASDAQ: SNTA) announced it presented new preclinical data on elesclomol (formerly STA-4783) at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics sponsored by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI) and the European Organization for Research and Treatment of Cancer (EORTC), in San Francisco, CA. Data presented at the conference confirmed that the primary mechanism of action of elesclomol is through the induction of reactive oxygen species (ROS) and provided details of the sequence of events by which programmed cell death (apoptosis) is induced. The results presented at the conference also provided evidence that elesclomol enhances the efficacy of several leading first-line cancer agents including Rituxan(R), Gemzar(R), and Taxotere(R), with minimal additional toxicity. Finally, the results showed that elesclomol has single agent anti-tumor activity. "Oxidative stress induction by elesclomol represents a novel and promising anti-cancer strategy," said James Barsoum, Ph.D., Senior Vice President of Research at Synta Pharmaceuticals. "Cancer cells operate at a much higher level of oxidative stress than normal cells. By causing the level of ROS in cancer cells to exceed sustainable levels, elesclomol selectively induces apoptosis in cancer cells, with minimal effects on normal cells. The elevation of ROS also appears to sensitize cancer cells to killing by other agents acting through the mitochondrial apoptosis pathway." "Taken together, the encouraging results presented at the conference on mechanism and combination activity provide continuing evidence that oxidative stress induction has broad potential application across multiple tumor types and in combination with widely used anti-cancer agents," said Dr.
    [Show full text]
  • Regulation of the Oxidative Stress Response by Arid1a
    The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 12-2015 REGULATION OF THE OXIDATIVE STRESS RESPONSE BY ARID1A Suet Yan Kwan Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Oncology Commons Recommended Citation Kwan, Suet Yan, "REGULATION OF THE OXIDATIVE STRESS RESPONSE BY ARID1A" (2015). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 608. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/608 This Dissertation (PhD) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. REGULATION OF THE OXIDATIVE STRESS RESPONSE BY ARID1A By Suet Yan Kwan, BSc APPROVED: ______________________________ Kwong-Kwok Wong, Ph.D. Advisory Professor ______________________________ Russell Broaddus, M.D., Ph.D. ______________________________ Joya Chandra, Ph.D.
    [Show full text]