Discovering proteasomal deubiquitinating enzyme inhibitors for cancer therapy: lessons from rational design, nature and old drug reposition

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

• 1 Hershko A, Heller H, Elias S, Ciechanover A. Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown. J. Biol. Chem. 258(13), 8206–8214 (1983).
  Medline CASGoogle Scholar
• 2 Groll M, Heinemeyer W, Jager S et al. The catalytic sites of 20S proteasomes and their role in subunit maturation: a mutational and crystallographic study. Proc. Natl Acad. Sci. USA 96(20), 10976–10983 (1999).
  Medline CASGoogle Scholar
• 3 Nguyen LK, Kolch W, Kholodenko BN. When ubiquitination meets phosphorylation: a systems biology perspective of EGFR/MAPK signalling. Cell Commun. Signal. 11, 52 (2013).
  Medline CASGoogle Scholar
• 4 Voges D, Zwickl P, Baumeister W. The 26S proteasome: a molecular machine designed for controlled proteolysis. Annu. Rev. Biochem. 68, 1015–1068 (1999).
  Medline CASGoogle Scholar
• 5 Arendt CS, Hochstrasser M. Eukaryotic 20S proteasome catalytic subunit propeptides prevent active site inactivation by N-terminal acetylation and promote particle assembly. EMBO J. 18(13), 3575–3585 (1999).
  Medline CASGoogle Scholar
• 6 Lee MJ, Lee BH, Hanna J, King RW, Finley D. Trimming of ubiquitin chains by proteasome-associated deubiquitinating enzymes. Mol. Cell Proteomics 10(5), R110 003871 (2011).
  Google Scholar
• 7 Amerik AY, Hochstrasser M. Mechanism and function of deubiquitinating enzymes. Biochim. Biophys. Acta 1695(1–3), 189–207 (2004).
  Medline CASGoogle Scholar
• 8 Wei R, Liu X, Yu W et al. Deubiquitinases in cancer. Oncotarget 6(15), 12872–12889 (2015).
  MedlineGoogle Scholar
• 9 Liao Y, Liu N, Hua X et al. Proteasome-associated deubiquitinase ubiquitin-specific protease 14 regulates prostate cancer proliferation by deubiquitinating and stabilizing androgen receptor. Cell Death Dis. 8(2), e2585 (2017).
  Medline CASGoogle Scholar
• 10 Nijman SM, Luna-Vargas MP, Velds A et al. A genomic and functional inventory of deubiquitinating enzymes. Cell 123(5), 773–786 (2005).
  Medline CASGoogle Scholar
• 11 Yao T, Cohen RE. A cryptic protease couples deubiquitination and degradation by the proteasome. Nature 419(6905), 403–407 (2002).
  Medline CASGoogle Scholar
• 12 Leggett DS, Hanna J, Borodovsky A et al. Multiple associated proteins regulate proteasome structure and function. Mol. Cell 10(3), 495–507 (2002).
  Medline CASGoogle Scholar
• 13 Verma R, Chen S, Feldman R et al. Proteasomal proteomics: identification of nucleotide-sensitive proteasome-interacting proteins by mass spectrometric analysis of affinity-purified proteasomes. Mol. Biol. Cell 11(10), 3425–3439 (2000).
  Medline CASGoogle Scholar
• 14 Peth A, Besche HC, Goldberg AL. Ubiquitinated proteins activate the proteasome by binding to Usp14/Ubp6, which causes 20S gate opening. Mol. Cell 36(5), 794–804 (2009).
  Medline CASGoogle Scholar
• 15 Yao T, Song L, Xu W et al. Proteasome recruitment and activation of the Uch37 deubiquitinating enzyme by Adrm1. Nat. Cell Biol. 8(9), 994–1002 (2006).
  Medline CASGoogle Scholar
• 16 Hamazaki J, Iemura S, Natsume T, Yashiroda H, Tanaka K, Murata S. A novel proteasome interacting protein recruits the deubiquitinating enzyme UCH37 to 26S proteasomes. EMBO J. 25(19), 4524–4536 (2006).
  Medline CASGoogle Scholar
• 17 Shi Y, Chen X, Elsasser S et al. Rpn1 provides adjacent receptor sites for substrate binding and deubiquitination by the proteasome. Science 351(6275), pii: aad9421 (2016).
  Google Scholar
• 18 Chernova TA, Allen KD, Wesoloski LM, Shanks JR, Chernoff YO, Wilkinson KD. Pleiotropic effects of Ubp6 loss on drug sensitivities and yeast prion are due to depletion of the free ubiquitin pool. J. Biol. Chem. 278(52), 52102–52115 (2003).
  Medline CASGoogle Scholar
• 19 Shabek N, Herman-Bachinsky Y, Ciechanover A. Ubiquitin degradation with its substrate, or as a monomer in a ubiquitination-independent mode, provides clues to proteasome regulation. Proc. Natl Acad. Sci. USA 106(29), 11907–11912 (2009).
  Medline CASGoogle Scholar
• 20 Kuo CL, Goldberg AL. Ubiquitinated proteins promote the association of proteasomes with the deubiquitinating enzyme Usp14 and the ubiquitin ligase Ube3c. Proc. Natl Acad. Sci. USA 114(17), e3404–e3413 (2017).
  Medline CASGoogle Scholar
• 21 Mazumdar T, Gorgun FM, Sha Y et al. Regulation of NF-kappaB activity and inducible nitric oxide synthase by regulatory particle non-ATPase subunit 13 (Rpn13). Proc. Natl Acad. Sci. USA 107(31), 13854–13859 (2010).
  Medline CASGoogle Scholar
• 22 Ventii KH, Wilkinson KD. Protein partners of deubiquitinating enzymes. Biochem. J. 414(2), 161–175 (2008).
  Medline CASGoogle Scholar
• 23 Qiu XB, Ouyang SY, Li CJ, Miao S, Wang L, Goldberg AL. hRpn13/ADRM1/GP110 is a novel proteasome subunit that binds the deubiquitinating enzyme, UCH37. EMBO J. 25(24), 5742–5753 (2006).
  Medline CASGoogle Scholar
• 24 Muratani M, Tansey WP. How the ubiquitin-proteasome system controls transcription. Nat. Rev. Mol. Cell Biol. 4(3), 192–201 (2003).
  Medline CASGoogle Scholar
• 25 Jin J, Cai Y, Yao T et al. A mammalian chromatin remodeling complex with similarities to the yeast INO80 complex. J. Biol. Chem. 280(50), 41207–41212 (2005).
  Medline CASGoogle Scholar
• 26 Verma R, Aravind L, Oania R et al. Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome. Science 298(5593), 611–615 (2002).
  Medline CASGoogle Scholar
• 27 Lam YA, Xu W, Demartino GN, Cohen RE. Editing of ubiquitin conjugates by an isopeptidase in the 26S proteasome. Nature 385(6618), 737–740 (1997).
  Medline CASGoogle Scholar
• 28 Chauhan D, Bianchi G, Anderson KC. Targeting the UPS as therapy in multiple myeloma. BMC Biochem. 9(Suppl. 1), S1 (2008).
  MedlineGoogle Scholar
• 29 Song Y, Li S, Ray A et al. Blockade of deubiquitylating enzyme Rpn11 triggers apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Oncogene 36(40), 5631–5638 (2017).
  Medline CASGoogle Scholar
• 30 Liu H, Buus R, Clague MJ, Urbe S. Regulation of ErbB2 receptor status by the proteasomal DUB POH1. PLoS ONE 4(5), e5544 (2009).
  MedlineGoogle Scholar
• 31 Chen Z, Niu X, Li Z et al. Effect of ubiquitin carboxy-terminal hydrolase 37 on apoptotic in A549 cells. Cell Biochem. Funct. 29(2), 142–148 (2011).
  MedlineGoogle Scholar
• 32 Shinji S, Naito Z, Ishiwata S et al. Ubiquitin-specific protease 14 expression in colorectal cancer is associated with liver and lymph node metastases. Oncol. Rep. 15(3), 539–543 (2006).
  Medline CASGoogle Scholar
• 33 Mines MA, Goodwin JS, Limbird LE, Cui FF, Fan GH. Deubiquitination of CXCR4 by USP14 is critical for both CXCL12-induced CXCR4 degradation and chemotaxis but not ERK ativation. J. Biol. Chem. 284(9), 5742–5752 (2009).
  Medline CASGoogle Scholar
• 34 D'Arcy P, Wang X, Linder S. Deubiquitinase inhibition as a cancer therapeutic strategy. Pharmacol. Ther. 147, 32–54 (2015).
  MedlineGoogle Scholar
• 35 Hussain S, Zhang Y, Galardy PJ. DUBs and cancer: the role of deubiquitinating enzymes as oncogenes, non-oncogenes and tumor suppressors. Cell Cycle 8(11), 1688–1697 (2009).
  Medline CASGoogle Scholar
• 36 Wang Y, Wang J, Zhong J et al. Ubiquitin-specific protease 14 (USP14) regulates cellular proliferation and apoptosis in epithelial ovarian cancer. Med. Oncol. 32(1), 379 (2015).
  Medline CASGoogle Scholar
• 37 Richardson PG, Anderson KC. Bortezomib: a novel therapy approved for multiple myeloma. Clin. Adv. Hematol. Oncol. 1(10), 596–600 (2003).
  MedlineGoogle Scholar
• 38 O'Connor OA, Wright J, Moskowitz C et al. Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma. J. Clin. Oncol. 23(4), 676–684 (2005).
  MedlineGoogle Scholar
• 39 Laubach JP, Mitsiades CS, Roccaro AM, Ghobrial IM, Anderson KC, Richardson PG. Clinical challenges associated with bortezomib therapy in multiple myeloma and Waldenstroms macroglobulinemia. Leuk. Lymphoma 50(5), 694–702 (2009).
  Medline CASGoogle Scholar
• 40 Oerlemans R, Franke NE, Assaraf YG et al. Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood 112(6), 2489–2499 (2008).
  Medline CASGoogle Scholar
• 41 Franke NE, Niewerth D, Assaraf YG et al. Impaired bortezomib binding to mutant beta5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells. Leukemia 26(4), 757–768 (2012).
  Medline CASGoogle Scholar
• 42 Ruckrich T, Kraus M, Gogel J et al. Characterization of the ubiquitin-proteasome system in bortezomib-adapted cells. Leukemia 23(6), 1098–1105 (2009).
  Medline CASGoogle Scholar
• 43 Nawrocki ST, Carew JS, Dunner K Jr et al. Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells. Cancer Res. 65(24), 11510–11519 (2005).
  Medline CASGoogle Scholar
• 44 Hagenbuchner J, Ausserlechner MJ, Porto V et al. The anti-apoptotic protein BCL2L1/Bcl-xL is neutralized by pro-apoptotic PMAIP1/Noxa in neuroblastoma, thereby determining bortezomib sensitivity independent of prosurvival MCL1 expression. J. Biol. Chem. 285(10), 6904–6912 (2010).
  Medline CASGoogle Scholar
• 45 Premkumar DR, Jane EP, DiDomenico JD, Vukmer NA, Agostino NR, Pollack IF. ABT-737 synergizes with bortezomib to induce apoptosis, mediated by Bid cleavage, Bax activation, and mitochondrial dysfunction in an Akt-dependent context in malignant human glioma cell lines. J. Pharmacol. Exp. Ther. 341(3), 859–872 (2012).
  Medline CASGoogle Scholar
• 46 San Miguel JF, Schlag R, Khuageva NK et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N. Engl. J. Med. 359(9), 906–917 (2008).
  Medline CASGoogle Scholar
• 47 Gourzones-Dmitriev C, Kassambara A, Sahota S et al. DNA repair pathways in human multiple myeloma: role in oncogenesis and potential targets for treatment. Cell Cycle 12(17), 2760–2773 (2013).
  Medline CASGoogle Scholar
• 48 Kuhn DJ, Chen Q, Voorhees PM et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood 110(9), 3281–3290 (2007).
  Medline CASGoogle Scholar
• 49 Chauhan D, Singh AV, Aujay M et al. A novel orally active proteasome inhibitor ONX 0912 triggers in vitro and in vivo cytotoxicity in multiple myeloma. Blood 116(23), 4906–4915 (2010).
  Medline CASGoogle Scholar
• 50 Piva R, Ruggeri B, Williams M et al. CEP-18770: a novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib. Blood 111(5), 2765–2775 (2008).
  Medline CASGoogle Scholar
• 51 Sanchez E, Li M, Steinberg JA et al. The proteasome inhibitor CEP-18770 enhances the anti-myeloma activity of bortezomib and melphalan. Br. J. Haematol. 148(4), 569–581 (2010).
  Medline CASGoogle Scholar
• 52 Nakai K, Satoh M, Hirano M et al. Clinical evaluation of ECG R-R interval variation in normal person and patients with coronary artery diseases. Rinsho. Byori. 34(3), 339–342 (1986).
  Medline CASGoogle Scholar
• 53 Thomas S, Quinn BA, Das SK et al. Targeting the Bcl-2 family for cancer therapy. Expert Opin. Ther. Targets 17(1), 61–75 (2013).
  Medline CASGoogle Scholar
• 54 Borodovsky A, Kessler BM, Casagrande R, Overkleeft HS, Wilkinson KD, Ploegh HL. A novel active site-directed probe specific for deubiquitylating enzymes reveals proteasome association of USP14. EMBO J. 20(18), 5187–5196 (2001).
  Medline CASGoogle Scholar
• 55 Rivard C, Bazzaro M. Measurement of deubiquitinating enzyme activity via a suicidal HA-Ub-VS probe. Methods Mol. Biol. 1249, 193–200 (2015). •• Describes methods to measuring deubiquitinating enzyme (DUB) activity. These methods are widely used to further characterize DUB processes and evaluate potential inhibition. Many in the field use this technique to evaluate potential DUB inhibitors.
  Medline CASGoogle Scholar
• 56 Lee BH, Lee MJ, Park S et al. Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature 467(7312), 179–184 (2010).
  Medline CASGoogle Scholar
• 57 Boselli M, Lee BH, Robert J et al. An inhibitor of the proteasomal deubiquitinating enzyme USP14 induces tau elimination in cultured neurons. J. Biol. Chem. 292(47), 19209–19225 (2017).
  Medline CASGoogle Scholar
• 58 D'Arcy P, Brnjic S, Olofsson MH et al. Inhibition of proteasome deubiquitinating activity as a new cancer therapy. Nat. Med. 17(12), 1636–1640 (2011).
  MedlineGoogle Scholar
• 59 Tian Z, D'Arcy P, Wang X et al. A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance. Blood 123(5), 706–716 (2014).
  Medline CASGoogle Scholar
• 60 Wang X, D'Arcy P, Caulfield TR et al. Synthesis and evaluation of derivatives of the proteasome deubiquitinase inhibitor b-AP15. Chem. Biol. Drug Des. 86(5), 1036–1048 (2015).
  Medline CASGoogle Scholar
• 61 Paulus A, Akhtar S, Caulfield TR et al. Coinhibition of the deubiquitinating enzymes, USP14 and UCHL5, with VLX1570 is lethal to ibrutinib- or bortezomib-resistant Waldenstrom macroglobulinemia tumor cells. Blood Cancer J. 6(11), e492 (2016).
  Medline CASGoogle Scholar
• 62 Linder S, Larsson R. Method for inhibition of deubiquitinating activity. WO/2013/058691 (2013).
  Google Scholar
• 63 Issaenko OA, Amerik AY. Chalcone-based small-molecule inhibitors attenuate malignant phenotype via targeting deubiquitinating enzymes. Cell Cycle 11(9), 1804–1817 (2012).
  Medline CASGoogle Scholar
• 64 Coughlin K, Anchoori R, Iizuka Y et al. Small-molecule RA-9 inhibits proteasome-associated DUBs and ovarian cancer in vitro and in vivo via exacerbating unfolded protein responses. Clin. Cancer Res. 20(12), 3174–3186 (2014).
  Medline CASGoogle Scholar
• 65 Brandt WW, Dwyer FP, Gyarfas ED. Chelate complexes of 1,10-phenanthroline and related compounds. Chem. Rev. 54(6), 959–1017 (1954).
  CASGoogle Scholar
• 66 Guterman A, Glickman MH. Complementary roles for Rpn11 and Ubp6 in deubiquitination and proteolysis by the proteasome. J. Biol. Chem. 279(3), 1729–1738 (2004).
  Medline CASGoogle Scholar
• 67 Li J, Yakushi T, Parlati F et al. Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11. Nat. Chem. Biol. 13(5), 486–493 (2017). •• As RPN11's specificity has been difficult to achieve, Li et al. studied capzimin an analog to 8-thioquioline. While capzimin is a zinc chelator, it can potentially interact with the catalytic active site of RPN11 to increase specificity. This reference highlights the difficulty of developing a potent RPN11 inhibitor that is specific and nontoxic, thus stressing the importance of RPN11 inhibition.
  Medline CASGoogle Scholar
• 68 Kapuria V, Peterson LF, Fang D, Bornmann WG, Talpaz M, Donato NJ. Deubiquitinase inhibition by small-molecule WP1130 triggers aggresome formation and tumor cell apoptosis. Cancer Res. 70(22), 9265–9276 (2010).
  Medline CASGoogle Scholar
• 69 Sun H, Kapuria V, Peterson LF et al. Bcr-Abl ubiquitination and USP9X inhibition block kinase signaling and promote CML cell apoptosis. Blood 117(11), 3151–3162 (2011).
  Medline CASGoogle Scholar
• 70 Peterson LF, Sun H, Liu Y et al. Targeting deubiquitinase activity with a novel small-molecule inhibitor as therapy for B-cell malignancies. Blood 125(23), 3588–3597 (2015).
  Medline CASGoogle Scholar
• 71 Chauhan D, Tian Z, Nicholson B et al. A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Cancer Cell 22(3), 345–358 (2012).
  Medline CASGoogle Scholar
• 72 Crankshaw MW, Grant GA. Modification of cysteine. Curr. Protoc. Protein Sci. 3(1), 15.1.1–15.1.18 (1996).
  Google Scholar
• 73 Hjerpe R, Aillet F, Lopitz-Otsoa F, Lang V, England P, Rodriguez MS. Efficient protection and isolation of ubiquitylated proteins using tandem ubiquitin-binding entities. EMBO Rep. 10(11), 1250–1258 (2009).
  Medline CASGoogle Scholar
• 74 Surh YJ. Cancer chemoprevention with dietary phytochemicals. Nat. Rev. Cancer 3(10), 768–780 (2003).
  Medline CASGoogle Scholar
• 75 Singh RP, Agarwal R. Mechanisms of action of novel agents for prostate cancer chemoprevention. Endocr. Relat. Cancer 13(3), 751–778 (2006).
  Medline CASGoogle Scholar
• 76 Conaway CC, Yang YM, Chung FL. Isothiocyanates as cancer chemopreventive agents: their biological activities and metabolism in rodents and humans. Curr. Drug Metab. 3(3), 233–255 (2002).
  Medline CASGoogle Scholar
• 77 Singh SV, Singh K. Cancer chemoprevention with dietary isothiocyanates mature for clinical translational research. Carcinogenesis 33(10), 1833–1842 (2012).
  Medline CASGoogle Scholar
• 78 Cheung KL, Kong AN. Molecular targets of dietary phenethyl isothiocyanate and sulforaphane for cancer chemoprevention. AAPS J. 12(1), 87–97 (2010).
  Medline CASGoogle Scholar
• 79 Mi L, Di Pasqua AJ, Chung FL. Proteins as binding targets of isothiocyanates in cancer prevention. Carcinogenesis 32(10), 1405–1413 (2011).
  Medline CASGoogle Scholar
• 80 Gupta P, Kim B, Kim SH, Srivastava SK. Molecular targets of isothiocyanates in cancer: recent advances. Mol. Nutr. Food Res. 58(8), 1685–1707 (2014).
  Medline CASGoogle Scholar
• 81 Bommareddy A, Hahm ER, Xiao D et al. Atg5 regulates phenethyl isothiocyanate-induced autophagic and apoptotic cell death in human prostate cancer cells. Cancer Res. 69(8), 3704–3712 (2009).
  Medline CASGoogle Scholar
• 82 Xiao D, Singh SV. p66Shc is indispensable for phenethyl isothiocyanate-induced apoptosis in human prostate cancer cells. Cancer Res. 70(8), 3150–3158 (2010).
  Medline CASGoogle Scholar
• 83 Gupta P, Wright SE, Kim SH, Srivastava SK. Phenethyl isothiocyanate: a comprehensive review of anti-cancer mechanisms. Biochim. Biophys. Acta 1846(2), 405–424 (2014).
  Medline CASGoogle Scholar
• 84 Wang LG, Chiao JW. Prostate cancer chemopreventive activity of phenethyl isothiocyanate through epigenetic regulation (review). Int. J. Oncol. 37(3), 533–539 (2010).
  MedlineGoogle Scholar
• 85 Moon YJ, Brazeau DA, Morris ME. Dietary phenethyl isothiocyanate alters gene expression in human breast cancer cells. Evid. Based Complement. Alternat. Med. 2011, pii: 462525 (2011).
  Google Scholar
• 86 Wu X, Kassie F, Mersch-Sundermann V. Induction of apoptosis in tumor cells by naturally occurring sulfur-containing compounds. Mutat. Res. 589(2), 81–102 (2005).
  Medline CASGoogle Scholar
• 87 Zhang Y, Tang L, Gonzalez V. Selected isothiocyanates rapidly induce growth inhibition of cancer cells. Mol. Cancer Ther. 2(10), 1045–1052 (2003).
  Medline CASGoogle Scholar
• 88 Popovic D, Vucic D, Dikic I. Ubiquitination in disease pathogenesis and treatment. Nat. Med. 20(11), 1242–1253 (2014).
  Medline CASGoogle Scholar
• 89 Gao N, Budhraja A, Cheng S et al. Phenethyl isothiocyanate exhibits antileukemic activity in vitro and in vivo by inactivation of Akt and activation of JNK pathways. Cell Death Dis. 2, e140 (2011).
  Medline CASGoogle Scholar
• 90 Zhou T, Li G, Cao B et al. Downregulation of Mcl-1 through inhibition of translation contributes to benzyl isothiocyanate-induced cell cycle arrest and apoptosis in human leukemia cells. Cell Death Dis. 4, e515 (2013).
  Medline CASGoogle Scholar
• 91 Zhang H, Trachootham D, Lu W et al. Effective killing of Gleevec-resistant CML cells with T315I mutation by a natural compound PEITC through redox-mediated mechanism. Leukemia 22(6), 1191–1199 (2008).
  Medline CASGoogle Scholar
• 92 Lawson AP, Long MJC, Coffey RT et al. Naturally occurring isothiocyanates exert anticancer effects by inhibiting deubiquitinating enzymes. Cancer Res. 75(23), 5130–5142 (2015). • While work was done identifying isothiocyanates as inhibitors of the ubiquitin proteasome system, Lawson et al. were one of the first to discover that isothiocyanates were DUB-specific inhibitors. Their investigation into isothiocyanates linked DUB inhibition and potential chemotherapeutics with compounds such as benzyl isothiocyanate and phenthyl isothiocyanate.
  Medline CASGoogle Scholar
• 93 Chen YJ, Ma YS, Fang Y, Wang Y, Fu D, Shen XZ. Power and promise of ubiquitin carboxyl-terminal hydrolase 37 as a target of cancer therapy. Asian-Pac. J. Cancer Prev. 14(4), 2173–2179 (2013).
  MedlineGoogle Scholar
• 94 Peddaboina C, Jupiter D, Fletcher S et al. The downregulation of Mcl-1 via USP9X inhibition sensitizes solid tumors to Bcl-xl inhibition. BMC Cancer 12, 541 (2012).
  Medline CASGoogle Scholar
• 95 Jimenez A, Tipper DJ, Davies J. Mode of action of thiolutin, an inhibitor of macromolecular synthesis in Saccharomyces cerevisiae. Antimicrob. Agents Chemother. 3(6), 729–738 (1973).
  Medline CASGoogle Scholar
• 96 Pelechano V, Perez-Ortin JE. The transcriptional inhibitor thiolutin blocks mRNA degradation in yeast. Yeast 25(2), 85–92 (2008).
  Medline CASGoogle Scholar
• 97 Lauinger L, Li J, Shostak A et al. Thiolutin is a zinc chelator that inhibits the Rpn11 and other JAMM metalloproteases. Nat. Chem. Biol. 13(7), 709–714 (2017).
  Medline CASGoogle Scholar
• 98 Agromayor M, Martin-Serrano J. Interaction of AMSH with ESCRT-III and deubiquitination of endosomal cargo. J. Biol. Chem. 281(32), 23083–23091 (2006).
  Medline CASGoogle Scholar
• 99 Duvoix A, Blasius R, Delhalle S et al. Chemopreventive and therapeutic effects of curcumin. Cancer Lett. 223(2), 181–190 (2005).
  Medline CASGoogle Scholar
• 100 Goel A, Kunnumakkara AB, Aggarwal BB. Curcumin as “Curecumin”: from kitchen to clinic. Biochem. Pharmacol. 75(4), 787–809 (2008).
  Medline CASGoogle Scholar
• 101 Aggarwal BB. Prostate cancer and curcumin: add spice to your life. Cancer Biol. Ther. 7(9), 1436–1440 (2008).
  Medline CASGoogle Scholar
• 102 Menon VP, Sudheer AR. Antioxidant and anti-inflammatory properties of curcumin. Adv. Exp. Med. Biol. 595, 105–125 (2007).
  MedlineGoogle Scholar
• 103 Sandur SK, Pandey MK, Sung B et al. Curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and turmerones differentially regulate anti-inflammatory and anti-proliferative responses through a ROS-independent mechanism. Carcinogenesis 28(8), 1765–1773 (2007).
  Medline CASGoogle Scholar
• 104 Balogun E, Hoque M, Gong P et al. Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem. J. 371(Pt 3), 887–895 (2003).
  Medline CASGoogle Scholar
• 105 Yoysungnoen P, Wirachwong P, Changtam C, Suksamrarn A, Patumraj S. Anti-cancer and anti-angiogenic effects of curcumin and tetrahydrocurcumin on implanted hepatocellular carcinoma in nude mice. World J. Gastroenterol. 14(13), 2003–2009 (2008).
  Medline CASGoogle Scholar
• 106 Teiten MH, Gaascht F, Eifes S, Dicato M, Diederich M. Chemopreventive potential of curcumin in prostate cancer. Genes Nutr. 5(1), 61–74 (2010).
  Medline CASGoogle Scholar
• 107 Arbiser JL, Klauber N, Rohan R et al. Curcumin is an in vivo inhibitor of angiogenesis. Mol. Med. 4(6), 376–383 (1998).
  Medline CASGoogle Scholar
• 108 Dorai T, Gehani N, Katz A. Therapeutic potential of curcumin in human prostate cancer-I. Curcumin induces apoptosis in both androgen-dependent and androgen-independent prostate cancer cells. Prostate Cancer Prostatic Dis. 3(2), 84–93 (2000).
  Medline CASGoogle Scholar
• 109 Schneider C, Gordon ON, Edwards RL, Luis PB. Degradation of curcumin: from mechanism to biological implications. J. Agric. Food Chem. 63(35), 7606–7614 (2015).
  Medline CASGoogle Scholar
• 110 Zhu J, Sanidad KZ, Sukamtoh E, Zhang G. Potential roles of chemical degradation in the biological activities of curcumin. Food Funct. 8(3), 907–914 (2017).
  Medline CASGoogle Scholar
• 111 Fuchs JR, Pandit B, Bhasin D et al. Structure–activity relationship studies of curcumin analogues. Bioorg. Med. Chem. Lett. 19(7), 2065–2069 (2009).
  Medline CASGoogle Scholar
• 112 Si X, Wang Y, Wong J, Zhang J, Mcmanus BM, Luo H. Dysregulation of the ubiquitin-proteasome system by curcumin suppresses coxsackievirus B3 replication. J. Virol. 81(7), 3142–3150 (2007).
  Medline CASGoogle Scholar
• 113 Zhou B, Zuo Y, Li B et al. Deubiquitinase inhibition of 19S regulatory particles by 4-arylidene curcumin analog AC17 causes NF-kappaB inhibition and p53 reactivation in human lung cancer cells. Mol. Cancer Ther. 12(8), 1381–1392 (2013).
  Medline CASGoogle Scholar
• 114 Suh JJ, Pettinati HM, Kampman KM, O'Brien CP. The status of disulfiram: a half of a century later. J. Clin. Psychopharmacol. 26(3), 290–302 (2006).
  Medline CASGoogle Scholar
• 115 Dufour P, Lang JM, Giron C et al. Sodium dithiocarb as adjuvant immunotherapy for high risk breast cancer: a randomized study. Biotherapy 6(1), 9–12 (1993).
  Medline CASGoogle Scholar
• 116 Cen D, Gonzalez RI, Buckmeier JA, Kahlon RS, Tohidian NB, Meyskens FL Jr. Disulfiram induces apoptosis in human melanoma cells: a redox-related process. Mol. Cancer Ther. 1(3), 197–204 (2002).
  Medline CASGoogle Scholar
• 117 Chen D, Cui QC, Yang H, Dou QP. Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. Cancer Res. 66(21), 10425–10433 (2006). •• This original report shows that disulfiram (DSF)–copper complex potently inhibits the 20S proteasomal activity in cultured breast cancer, but not normal, immortalized cells before apoptosis; breast cancer cells containing high copper were sensitive to DSF-induced proteasome inhibition and apoptosis; and DSF significantly inhibited the tumor growth, associated with in vivo proteasome inhibition and apoptosis induction, suggesting that proteasome inhibition can be achieved by targeting tumor cellular copper with the DSF, resulting in selective apoptosis induction within tumor cells.
  Medline CASGoogle Scholar
• 118 Lovborg H, Oberg F, Rickardson L, Gullbo J, Nygren P, Larsson R. Inhibition of proteasome activity, nuclear factor-KappaB translocation and cell survival by the antialcoholism drug disulfiram. Int. J. Cancer 118(6), 1577–1580 (2006).
  MedlineGoogle Scholar
• 119 Lin J, Haffner MC, Zhang Y et al. Disulfiram is a DNA demethylating agent and inhibits prostate cancer cell growth. Prostate 71(4), 333–343 (2011).
  Medline CASGoogle Scholar
• 120 Liu P, Brown S, Goktug T et al. Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells. Br. J. Cancer 107(9), 1488–1497 (2012).
  Medline CASGoogle Scholar
• 121 Yip NC, Fombon IS, Liu P et al. Disulfiram modulated ROS-MAPK and NFkappaB pathways and targeted breast cancer cells with cancer stem cell-like properties. Br. J. Cancer 104(10), 1564–1574 (2011).
  Medline CASGoogle Scholar
• 122 Wang W, Mcleod HL, Cassidy J. Disulfiram-mediated inhibition of NF-kappaB activity enhances cytotoxicity of 5-fluorouracil in human colorectal cancer cell lines. Int. J. Cancer 104(4), 504–511 (2003).
  Medline CASGoogle Scholar
• 123 Skrott Z, Mistrik M, Andersen KK et al. Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature 552(7684), 194–199 (2017).
  Medline CASGoogle Scholar
• 124 Kuo HW, Chen SF, Wu CC, Chen DR, Lee JH. Serum and tissue trace elements in patients with breast cancer in Taiwan. Biol. Trace Elem. Res. 89(1), 1–11 (2002).
  Medline CASGoogle Scholar
• 125 Habib FK, Dembinski TC, Stitch SR. The zinc and copper content of blood leucocytes and plasma from patients with benign and malignant prostates. Clin. Chim. Acta 104(3), 329–335 (1980).
  Medline CASGoogle Scholar
• 126 Brar SS, Grigg C, Wilson KS et al. Disulfiram inhibits activating transcription factor/cyclic AMP-responsive element binding protein and human melanoma growth in a metal-dependent manner in vitro, in mice and in a patient with metastatic disease. Mol. Cancer Ther. 3(9), 1049–1060 (2004).
  Medline CASGoogle Scholar
• 127 Cvek B, Milacic V, Taraba J, Dou QP. Ni(II), Cu(II), and Zn(II) diethyldithiocarbamate complexes show various activities against the proteasome in breast cancer cells. J. Med. Chem. 51(20), 6256–6258 (2008).
  Medline CASGoogle Scholar
• 128 Cvek B, Dvorak Z. Targeting of nuclear factor-kappaB and proteasome by dithiocarbamate complexes with metals. Curr. Pharm. Des. 13(30), 3155–3167 (2007).
  Medline CASGoogle Scholar
• 129 Guthery E, Seal LA, Anderson EL. Zinc pyrithione in alcohol-based products for skin antisepsis: persistence of antimicrobial effects. Am. J. Infect. Control. 33(1), 15–22 (2005).
  MedlineGoogle Scholar
• 130 Lamore SD, Wondrak GT. Zinc pyrithione impairs zinc homeostasis and upregulates stress response gene expression in reconstructed human epidermis. Biometals 24(5), 875–890 (2011).
  Medline CASGoogle Scholar
• 131 Zhao C, Chen X, Yang C et al. Repurposing an antidandruff agent to treating cancer: zinc pyrithione inhibits tumor growth via targeting proteasome-associated deubiquitinases. Oncotarget 8, 13942–13956 (2017).
  MedlineGoogle Scholar
• 132 Zhao C, Chen X, Zang D et al. Platinum-containing compound platinum pyrithione is stronger and safer than cisplatin in cancer therapy. Biochem. Pharmacol. 116, 22–38 (2016).
  MedlineGoogle Scholar
• 133 Liu N, Liu C, Li X et al. A novel proteasome inhibitor suppresses tumor growth via targeting both 19S proteasome deubiquitinases and 20S proteolytic peptidases. Sci. Rep. 4, 5240 (2014).
  Medline CASGoogle Scholar
• 134 Zhao C, Chen X, Zang D et al. A novel nickel complex works as a proteasomal deubiquitinase inhibitor for cancer therapy. Oncogene 35(45), 5916–5927 (2016).
  Medline CASGoogle Scholar
• 135 Lan X, Zhao C, Chen X et al. Nickel pyrithione induces apoptosis in chronic myeloid leukemia cells resistant to imatinib via both Bcr/Abl-dependent and Bcr/Abl-independent mechanisms. J. Hematol. Oncol. 9(1), 129 (2016).
  MedlineGoogle Scholar
• 136 Milacic V, Dou QP. The tumor proteasome as a novel target for gold(III) complexes: implications for breast cancer therapy. Coord. Chem. Rev. 253(11–12), 1649–1660 (2009).
  Medline CASGoogle Scholar
• 137 Zhang JJ, Ng KM, Lok CN, Sun RW, Che CM. Deubiquitinases as potential anti-cancer targets for gold(III) complexes. Chem. Commun. (Camb.) 49(45), 5153–5155 (2013).
  Medline CASGoogle Scholar
• 138 Milacic V, Chen D, Ronconi L, Landis-Piwowar KR, Fregona D, Dou QP. A novel anticancer gold(III) dithiocarbamate compound inhibits the activity of a purified 20S proteasome and 26S proteasome in human breast cancer cell cultures and xenografts. Cancer Res. 66(21), 10478–10486 (2006).
  Medline CASGoogle Scholar
• 139 Liu N, Li X, Huang H et al. Clinically used antirheumatic agent auranofin is a proteasomal deubiquitinase inhibitor and inhibits tumor growth. Oncotarget 5(14), 5453–5471 (2014).
  Medline CASGoogle Scholar
• 140 Deininger MW, Vieira S, Mendiola R, Schultheis B, Goldman JM, Melo JV. BCR-ABL tyrosine kinase activity regulates the expression of multiple genes implicated in the pathogenesis of chronic myeloid leukemia. Cancer Res. 60(7), 2049–2055 (2000).
  Medline CASGoogle Scholar
• 141 Lan X, Zhao C, Chen X et al. Platinum pyrithione induces apoptosis in chronic myeloid leukemia cells resistant to imatinib via DUB inhibition-dependent caspase activation and Bcr-Abl downregulation. Cell Death Dis. 8(7), e2913 (2017).
  Medline CASGoogle Scholar
• 142 Chen X, Shi X, Zhao C et al. Anti-rheumatic agent auranofin induced apoptosis in chronic myeloid leukemia cells resistant to imatinib through both Bcr/Abl-dependent and -independent mechanisms. Oncotarget 5(19), 9118–9132 (2014).
  MedlineGoogle Scholar
• 143 Huang H, Liao Y, Liu N et al. Two clinical drugs deubiquitinase inhibitor auranofin and aldehyde dehydrogenase inhibitor disulfiram trigger synergistic anti-tumor effects in vitro and in vivo. Oncotarget 7(3), 2796–2808 (2016).
  MedlineGoogle Scholar