Skip to main content

Positioning of aminopeptidase inhibitors in next generation cancer therapy

Amino Acids volume 46, pages 793–808 (2014)Cite this article

Abstract

Aminopeptidases represent a class of (zinc) metalloenzymes that catalyze the cleavage of amino acids nearby the N-terminus of polypeptides, resulting in hydrolysis of peptide bonds. Aminopeptidases operate downstream of the ubiquitin–proteasome pathway and are implicated in the final step of intracellular protein degradation either by trimming proteasome-generated peptides for antigen presentation or full hydrolysis into free amino acids for recycling in renewed protein synthesis. This review focuses on the function and subcellular location of five key aminopeptidases (aminopeptidase N, leucine aminopeptidase, puromycin-sensitive aminopeptidase, leukotriene A4 hydrolase and endoplasmic reticulum aminopeptidase 1/2) and their association with different diseases, in particular cancer and their current position as target for therapeutic intervention by aminopeptidase inhibitors. Historically, bestatin was the first prototypical aminopeptidase inhibitor that entered the clinic 35 years ago and is still used for the treatment of lung cancer. More recently, new generation aminopeptidase inhibitors became available, including the aminopeptidase inhibitor prodrug tosedostat, which is currently tested in phase II clinical trials for acute myeloid leukemia. Beyond bestatin and tosedostat, medicinal chemistry has emerged with additional series of potential aminopeptidases inhibitors which are still in an early phase of (pre)clinical investigations. The expanded knowledge of the unique mechanism of action of aminopeptidases has revived interest in aminopeptidase inhibitors for drug combination regimens in anti-cancer treatment. In this context, this review will discuss relevant features and mechanisms of action of aminopeptidases and will also elaborate on factors contributing to aminopeptidase inhibitor efficacy and/or loss of efficacy due to drug resistance-related phenomena. Together, a growing body of data point to aminopeptidase inhibitors as attractive tools for combination chemotherapy, hence their implementation may be a step forward in a new era of personalized treatment of cancer patients.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  • Abe M, Matsuki H, Domae M, Kuwata H, Kudo I, Nakanishi Y, Hara N, Mitsuyama T, Furukawa T (1996) Lung cancer cell lines inhibit leukotriene B4 production by human polymorphonuclear leukocytes at the level of phospholipase A2. Am J Respir Cell Mol Biol 15:565–573

    PubMed  CAS  Google Scholar 

  • Aoyagi T, Tobe H, Kojima F, Hamada M (1978) Amastatin, an inhibitor of aminopeptidase A, produced by actinomycetes. J Antibiot 31:636–638

    PubMed  CAS  Google Scholar 

  • Beninga J, Rock KL, Goldberg A (1998) Interferon-gamma can stimulate post-proteasomal trimming of the N terminus of an antigenic peptide by inducing leucine aminopeptidase. J Biol Chem 273:18734–18742

    PubMed  CAS  Google Scholar 

  • Bhutani N, Venkatraman P, Goldberg A (2007) Puromycin-sensitive aminopeptidase is the major peptidase responsible for digesting polyglutamine sequences released by proteasomes during protein degradation. EMBO J 26:1385–1396. doi:10.1038/sj.emboj.7601592

    PubMed Central  PubMed  CAS  Google Scholar 

  • Birtley JR, Saridakis E, Stratikos E, Mavridis IM (2012) The crystal structure of human endoplasmic reticulum aminopeptidase 2 reveals the atomic basis for distinct roles in antigen processing. Biochemistry 51:286–295. doi:10.1021/bi201230p

    PubMed  CAS  Google Scholar 

  • Botbol V, Scornik O (1979) Degradation of abnormal proteins in intact mouse reticulocytes: accumulation of intermediates in the presence of bestatin. Proc Natl Acad Sci USA 76:703–710

    Google Scholar 

  • Botbol V, Scornik O (1991) Measurement of instant rates of protein degradation in the livers of intact mice by the accumulation of bestatin-induced peptides. J Biol Chem 266:2151–2157

    PubMed  CAS  Google Scholar 

  • Bozza PT, Magalhães KG, Weller PF (2009) Leukocyte lipid bodies––biogenesis and functions in inflammation. Biochim Biophys Acta 1791:540–551. doi:10.1016/j.bbalip.2009.01.005

    PubMed Central  PubMed  CAS  Google Scholar 

  • Chen X, Li N, Wang S, Wu N, Hong J, Jiao X, Krasna MJ, Beer DG, Yang CS (2003) Leukotriene A4 hydrolase in rat and human esophageal adenocarcinomas and inhibitory effects of bestatin. J Natl Cancer Inst 95:1053–1061

    PubMed  CAS  Google Scholar 

  • Cifaldi L, Romania P, Lorenzi S, Locatelli F, Fruci D (2012) Role of endoplasmic reticulum aminopeptidases in health and disease: from infection to cancer. Int J Mol Sci 13:8338–8352. doi:10.3390/ijms13078338

    PubMed Central  PubMed  CAS  Google Scholar 

  • Constam DB, Tobler AR, Rensing-ehl A, Kemler I, Hersh LB, Fontana A (1995) Puromycin-sensitive aminopeptidase. Sequence analysis, expression, and functional characterization. J Biol Chem 270:26931–26939

    PubMed  CAS  Google Scholar 

  • De Oliveira E, Wang K, Kong H (2011) Effect of the leukotriene A4 hydrolase aminopeptidase augmentor 4-methoxydiphenylmethane in a pre-clinical model of pulmonary emphysema. Bioorg Med Chem Lett 21:6746–6750. doi:10.1016/j.bmcl.2011.09.048.Effect

    PubMed Central  PubMed  Google Scholar 

  • Dong X, An B, Salvucci Kierstead L, Storkus WJ, Amoscato AA, Salter RD (2000) Modification of the amino terminus of a class II epitope confers resistance to degradation by CD13 on dendritic cells and enhances presentation to T cells. J Immunol 164:129–135

    PubMed  CAS  Google Scholar 

  • Emmerich NP, Nussbaum AK, Stevanovic S, Priemer M, Toes RE, Rammensee HG, Schild H (2000) The human 26 S and 20 S proteasomes generate overlapping but different sets of peptide fragments from a model protein substrate. J Biol Chem 275:21140–21148. doi:10.1074/jbc.M000740200

    PubMed  CAS  Google Scholar 

  • Fan X, Ross DD, Arakawa H, Ganapathy V, Tamai I, Nakanishi T (2010) Impact of system L amino acid transporter 1 (LAT1) on proliferation of human ovarian cancer cells: a possible target for combination therapy with anti-proliferative aminopeptidase inhibitors. Biochem Pharmacol 80:811–818. doi:10.1016/j.bcp.2010.05.021

    PubMed  CAS  Google Scholar 

  • Feng J, Jin K, Zhu H, Zhang X, Zhang L, Liu J, Xu W (2012) A novel aminopeptidase N inhibitor developed by virtual screening approach. Bioorg Med Chem Lett 22:5863–5869. doi:10.1016/j.bmcl.2012.07.086

    PubMed  CAS  Google Scholar 

  • Fitzpatrick F, Lepley R, Orning L, Duffin K (1994) Suicide inactivation of leukotriene A4 hydrolase/aminopeptidase. Ann N Y Acad Sci 744:31–38

    PubMed  CAS  Google Scholar 

  • Fruci D, Ferracuti S (2006) Expression of endoplasmic reticulum aminopeptidases in EBV-B cell lines from healthy donors and leukemia/lymphoma, carcinoma, and melanoma cell lines. J Immunol 176:4869–4879

    PubMed  CAS  Google Scholar 

  • Fruci D, Giacomini P, Nicotra MR, Forloni M, Fraioli R, Saveanu L, Van Endert P, Natali PG (2008) Altered expression of endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 in transformed non-lymphoid human tissues. J Cell Physiol 216:742–749. doi:10.1002/jcp.21454

    PubMed  CAS  Google Scholar 

  • Gao J-J, Gao Z-H, Zhao C-R, Yuan Y, Cui S-X, Zhang X-F, Cheng Y-N, Xu W-F, Tang W, Qu X-J (2011) LYP, a novel bestatin derivative, inhibits cell growth and suppresses APN/CD13 activity in human ovarian carcinoma cells more potently than bestatin. Invest New Drugs 29:574–582. doi:10.1007/s10637-010-9391-9

    PubMed  CAS  Google Scholar 

  • Garg LN, Yadav SP, Lal H (1994) Serum leucine aminopeptidase in head and neck cancer. J Laryngol Otol 108:660–662

    PubMed  CAS  Google Scholar 

  • Glickman MH, Ciechanover A (2002) The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 82:373–428. doi:10.1152/physrev.00027.2001

    PubMed  CAS  Google Scholar 

  • Goberdhan D (2010) Intracellular amino acid sensing and mTORC1-regulated growth: new ways to block an old target? Curr Opin Investig Drugs 11:1360–1367

    PubMed Central  PubMed  CAS  Google Scholar 

  • Goldberg AL (2003) Protein degradation and protection against misfolded or damaged proteins. Nature 426:895–899. doi:10.1038/nature02263

    PubMed  CAS  Google Scholar 

  • Gottesman MM, Fojo T, Bates SE (2002) Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2:48–58. doi:10.1038/nrc706

    PubMed  CAS  Google Scholar 

  • Groettrup M, Soza A, Kuckelkorn U, Kloetzel P (1996) Peptide antigen production by the proteasome: complexity provides efficiency. Immunol Today 17:429–435

    PubMed  CAS  Google Scholar 

  • Grujić M, Renko M (2002) Aminopeptidase inhibitors bestatin and actinonin inhibit cell proliferation of myeloma cells predominantly by intracellular interactions. Cancer Lett 182:113–119

    PubMed  Google Scholar 

  • Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12:9–22. doi:10.1016/j.ccr.2007.05.008

    PubMed  CAS  Google Scholar 

  • Haeggström JZ (2004) Leukotriene A4 hydrolase/aminopeptidase, the gatekeeper of chemotactic leukotriene B4 biosynthesis. J Biol Chem 279:50639–50642. doi:10.1074/jbc.R400027200

    PubMed  Google Scholar 

  • Haeggström JZ, Nordlund P, Thunnissen MMGM (2002) Functional properties and molecular architecture of leukotriene A4 hydrolase, a pivotal catalyst of chemotactic leukotriene formation. Sci World J 2:1734–1749. doi:10.1100/tsw.2002.810

    Google Scholar 

  • Hallberg L, Michaëlsson K (2003) Adipocyte-derived leucine aminopeptidase genotype and response to antihypertensive therapy. BMC cardiovasc Disord 6:7–12

    Google Scholar 

  • Hashida H, Takabayashi A, Kanai M, Adachi M, Kondo K, Kohno N, Yamaoka Y, Miyake M (2002) Aminopeptidase N is involved in cell motility and angiogenesis: its clinical significance in human colon cancer. Gastroenterology 122:376–386. doi:10.1053/gast.2002.31095

    PubMed  CAS  Google Scholar 

  • Hattori A, Tsujimoto M (2004) Processing of antigenic peptides by aminopeptidases. Biol Pharm Bull 27:777–780

    PubMed  CAS  Google Scholar 

  • Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18:1926–1945. doi:10.1101/gad.1212704

    PubMed  CAS  Google Scholar 

  • Hershko A (2005) The ubiquitin system for protein degradation and some of its roles in the control of the cell division cycle. Cell Death Differ 12:1191–1197. doi:10.1038/sj.cdd.4401702

    PubMed  CAS  Google Scholar 

  • Hershko A, Ciechanover A (1992) The ubiquitin system for protein degradation. Annu Rev Biochem 61:761–807. doi:10.1146/annurev.bi.61.070192.003553

    PubMed  CAS  Google Scholar 

  • Hershko A, Ciechanover A (1998) The ubiquitin system. Annu Rev Biochem 67:425–479. doi:10.1146/annurev.biochem.67.1.425

    PubMed  CAS  Google Scholar 

  • Holloway JW, Barton SJ, Holgate ST, Rose-Zerilli MJ, Sayers I (2008) The role of LTA4H and ALOX5AP polymorphism in asthma and allergy susceptibility. Allergy 63:1046–1053. doi:10.1111/j.1398-9995.2008.01667.x

    PubMed  CAS  Google Scholar 

  • Hui K-S (2007) Brain-specific aminopeptidase: from enkephalinase to protector against neurodegeneration. Neurochem Res 32:2062–2071. doi:10.1007/s11064-007-9356-3

    PubMed  CAS  Google Scholar 

  • Ichinose Y, Genka K, Koike T, Kato H, Watanabe Y, Mori T, Iioka S, Sakuma A, Ohta M (2003) Randomized double-blind placebo-controlled trial of bestatin in patients with resected stage I squamous-cell lung carcinoma. J Natl Cancer Inst 95:605–610

    PubMed  CAS  Google Scholar 

  • Inokuma S, Setoguchi K, Ohta T, Matsuzaki Y, Yoshida A (1999) Serum leucine aminopeptidase as an activity indicator in systemic lupus erythematosus: a study of 46 consecutive cases. Rheumatology 38:705–708

    PubMed  CAS  Google Scholar 

  • Ishii K, Usui S, Sugimura Y, Yoshida S, Hioki T, Tatematsu M, Yamamoto H, Hirano K (2001) Aminopeptidase N regulated by zinc in human prostate participates in tumor cell invasion. Int J Cancer 92:49–54

    PubMed  CAS  Google Scholar 

  • Jeong C-H, Bode AM, Pugliese A, Cho Y-Y, Kim H-G, Shim J-H, Jeon Y-J, Li H, Jiang H, Dong Z (2009) [6]-Gingerol suppresses colon cancer growth by targeting leukotriene A4 hydrolase. Cancer Res 69:5584–5591. doi:10.1158/0008-5472.CAN-09-0491

    PubMed  CAS  Google Scholar 

  • Kakuta H, Tanatani A, Nagasawa K, Hashimoto Y (2003) Specific nonpeptide inhibitors of puromycin-sensitive aminopeptidase with a 2,4(1H,3H)-quinazolinedione skeleton. Chem Pharm Bull 51:1273–1282

    PubMed  CAS  Google Scholar 

  • Kamphausen E, Kellert C, Abbas T, Akkad N, Tenzer S, Pawelec G, Schild H, Van Endert P, Seliger B (2010) Distinct molecular mechanisms leading to deficient expression of ER-resident aminopeptidases in melanoma. Cancer Immunol Immunother 59:1273–1284. doi:10.1007/s00262-010-0856-7

    PubMed  CAS  Google Scholar 

  • Kehlen A, Lendeckel U, Dralle H (2003) Biological significance of aminopeptidase N/CD13 in thyroid carcinomas. Cancer Res 63:8500–8506

    PubMed  CAS  Google Scholar 

  • Kim E, Kwak H, Ahn K (2009) Cytosolic aminopeptidases influence MHC class I-mediated antigen presentation in an allele-dependent manner. J Immunol 183:7379–7387. doi:10.4049/jimmunol.0901489

    PubMed  CAS  Google Scholar 

  • Kisselev A, Akopian T, Goldberg A (1998) Range of sizes of peptide products generated during degradation of different proteins by archaeal proteasomes. J Biol Chem 273:1982–1989

    PubMed  CAS  Google Scholar 

  • Kisselev A, Akopian T, Woo K, AL G (1999) The sizes of peptides generated from protein by mammalian 26 and 20 S proteasomes. J Biol Chem 274:3363–3371

    PubMed  CAS  Google Scholar 

  • Krige D, Needham LA, Bawden LJ, Flores N, Farmer H, Miles LEC, Stone E, Callaghan J, Chandler S, Clark VL, Kirwin-Jones P, Legris V, Owen J, Patel T, Wood S, Box G, Laber D, Odedra R, Wright A, Wood LM, Eccles SA, Bone EA, Ayscough A, Drummond AH (2008) CHR-2797: an antiproliferative aminopeptidase inhibitor that leads to amino acid deprivation in human leukemic cells. Cancer Res 68:6669–6679. doi:10.1158/0008-5472.CAN-07-6627

    PubMed  CAS  Google Scholar 

  • Laplante M, Sabatini DM (2009) mTOR signaling at a glance. J Cell Sci 122:3589–3594. doi:10.1242/jcs.051011

    PubMed Central  PubMed  CAS  Google Scholar 

  • Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149:274–293. doi:10.1016/j.cell.2012.03.017

    PubMed Central  PubMed  CAS  Google Scholar 

  • Larsen SL, Pedersen LO, Buus S, Stryhn A (1996) T cell responses affected by aminopeptidase N (CD13)-mediated trimming of major histocompatibility complex class II-bound peptides. J Exp Med 184:183–189

    PubMed  CAS  Google Scholar 

  • Lecker SH, Goldberg AL, Mitch WE (2006) Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. J Am Soc Nephrol 17:1807–1819. doi:10.1681/ASN.2006010083

    PubMed  CAS  Google Scholar 

  • Lee S (2009) Cobalt chloride-induced downregulation of puromycin-sensitive aminopeptidase suppresses the migration and invasion of PC-3 Cells. J Microbiol Biotechnol 19:530–536. doi:10.4014/jmb.0807.438

    PubMed  CAS  Google Scholar 

  • Lee P, Lin C, Liu C (2003) Acute leukemia with myeloid, B-, and natural killer cell differentiation. Arch Pathol Lab Med 127:93–95

    Google Scholar 

  • Lee J, Song S, Seok J, Jha B, Han E, Song H-O, Yu H-S, Hong Y, Kong H-H, Chung D (2010) M17 leucine aminopeptidase of the human malaria parasite Plasmodium vivax. Mol Biochem Parasitol 170:45–48. doi:10.1016/j.molbiopara.2009.11.003

    PubMed  CAS  Google Scholar 

  • Löwenberg B, Morgan G, Ossenkoppele GJ, Burnett AK, Zachée P, Dührsen U, Dierickx D, Müller-Tidow C, Sonneveld P, Krug U, Bone E, Flores N, Richardson AF, Hooftman L, Jenkins C, Zweegman S, Davies F (2010) Phase I/II clinical study of tosedostat, an inhibitor of aminopeptidases, in patients with acute myeloid leukemia and myelodysplasia. J Clin Oncol 28:4333–4338. doi:10.1200/JCO.2009.27.6295

    PubMed  Google Scholar 

  • Lowther WT, Matthews BW (2002) Metalloaminopeptidases: common functional themes in disparate structural surroundings. Chem Rev 102:4581–4608

    PubMed  CAS  Google Scholar 

  • Luan Y, Ma C, Sui Z, Wang X, Feng J, Liu N, Jing F, Wang Y, Li M, Fang H, Xu W (2011) LYP3, a new bestatin derivative for aminopeptidase N inhibition. Med Chem 7:32–36

    PubMed  CAS  Google Scholar 

  • Martínez JM, Prieto I, Ramírez MJ, Cueva C, Alba F, Ramírez M (1999) Aminopeptidase activities in breast cancer tissue. Clin Chem 45:1797–1802

    PubMed  Google Scholar 

  • Matsushima M, Takahashi T, Ichinose M, Miki K, Kurokawa K, Takahashi K (1991) Structural and immunological evidence fort he identity of prolyl aminopeptidase with leucyl aminopeptidase. Biochem Biophys Res Cummun 178:1459–1464

    CAS  Google Scholar 

  • Mehta A, Jordanova E, Corver W, Van Wezel T, Uh H, Kenter G, Fleuren GJ (2009) Single nucleotide polymorphisms in antigen processing machinery component ERAP1 significantly associate with clinical outcome in cervical carcinoma. Genes Chromosom Cancer 48:410–418. doi:10.1002/gcc

    PubMed  CAS  Google Scholar 

  • Menrad A, Speicher D, Wacker J, Herlyn M (1993) Biochemical and functional characterization of aminopeptidase N expressed by human melanoma cells. Cancer Res 53:1450–1455

    PubMed  CAS  Google Scholar 

  • Mina-Osorio P (2008) The moonlighting enzyme CD13: old and new functions to target. Trends Mol Med 14:361–371. doi:10.1016/j.molmed.2008.06.003

    PubMed  CAS  Google Scholar 

  • Moore HE, Davenport EL, Smith EM, Muralikrishnan S, Dunlop AS, Walker BA, Krige D, Drummond AH, Hooftman L, Morgan GJ, Davies FE (2009) Aminopeptidase inhibition as a targeted treatment strategy in myeloma. Mol Cancer Ther 8:762–770. doi:10.1158/1535-7163.MCT-08-0735

    PubMed  CAS  Google Scholar 

  • Nguyen TT, Chang S-C, Evnouchidou I, York IA, Zikos C, Rock KL, Goldberg AL, Stratikos E, Stern LJ (2011) Structural basis for antigenic peptide precursor processing by the endoplasmic reticulum aminopeptidase ERAP1. Nat Struct Mol Biol 18:604–613. doi:10.1038/nsmb.2021

    PubMed Central  PubMed  CAS  Google Scholar 

  • Oi N, Jeong C-H, Nadas J, Cho Y-Y, Pugliese A, Bode AM, Dong Z (2010) Resveratrol, a red wine polyphenol, suppresses pancreatic cancer by inhibiting leukotriene ahydrolase. Cancer Res 70:9755–9764. doi:10.1158/0008-5472.CAN-10-2858

    PubMed  CAS  Google Scholar 

  • Pasqualini R, Koivunen E, Kain R (2000) Aminopeptidase N Is a receptor for tumor-homing peptides and a target for inhibiting angiogenesis. Cancer Res 60:722–727

    PubMed  CAS  Google Scholar 

  • Pei K-L, Yuan Y, Qin S-H, Wang Y, Zhou L, Zhang H-L, Qu X-J, Cui S-X (2012) CIP-13F, a novel aminopeptidase N (APN/CD13) inhibitor, inhibits Lewis lung carcinoma growth and metastasis in mice. Cancer Chemother Pharmacol 69:1029–1038. doi:10.1007/s00280-011-1799-1

    PubMed  CAS  Google Scholar 

  • Pérez I, Varona A, Blanco L, Gil J (2009) Increased APN/CD13 and acid aminopeptidase activities in head and neck squamous cell carcinoma. Head Neck 10:1335–1340. doi:10.1002/h

    Google Scholar 

  • Peters GJ, Jansen G (2001) Antimetabolites. In: Souhami RL, Tannock I, Hohenberger P, Horiot JC (eds) Oxford textbook of oncology, vol 1, chapter 4.16, 2nd edn. Oxford University Press, Oxford, pp 663–713

    Google Scholar 

  • Piedfer M, Dauzonne D, Tang R, N’Guyen J, Billard C, Bauvois B (2011) Aminopeptidase-N/CD13 is a potential proapoptotic target in human myeloid tumor cells. FASEB J 25:2831–2842. doi:10.1096/fj.11-181396

    PubMed  CAS  Google Scholar 

  • Pulido-Cejudo G, Conway B, Proulx P, Brown R, Izaguirre C (1997) Bestatin-mediated inhibition of leucine aminopeptidase may hinder HIV infection. Antiviral Res 36:167–177

    PubMed  CAS  Google Scholar 

  • Rackley RR, Yang B, Pretlow TG, Abdul-Karim FW, Lewis TJ, McNamara N, Delmoro CM, Bradley EL, Kursh E, Resnick MI (1991) Differences in the leucine aminopeptidase activity in extracts from human prostatic carcinoma and benign prostatic hyperplasia. Cancer 68:587–593

    PubMed  CAS  Google Scholar 

  • Radmark O, Shimizus T, Jornvall H, Samuelsson B (1984) Leukotriene A4 hydrolase in human leukocytes. Purification and properties. J Biol Chem 259:12339–12345

    PubMed  CAS  Google Scholar 

  • Rao M, Li Q, Feng L, Xia X, Ruan L, Sheng X, Ge M (2011) A new aminopeptidase inhibitor from streptomyces strain HCCB10043 found by UPLC-MS. Anal Bioanal Chem 401:699–706. doi:10.1007/s00216-011-5093-1

    PubMed  CAS  Google Scholar 

  • Reid AHM, Protheroe A, Attard G, Hayward N, Vidal L, Spicer J, Shaw HM, Bone EA, Carter J, Hooftman L, Harris A, De Bono JS (2009) A first-in-man phase I and pharmacokinetic study on CHR-2797 (Tosedostat), an inhibitor of M1 aminopeptidases, in patients with advanced solid tumors. Clin Cancer Res 15:4978–4985. doi:10.1158/1078-0432.CCR-09-0306

    PubMed  CAS  Google Scholar 

  • Reits E, Griekspoor A, Neijssen J, Groothuis T, Jalink K, Van Veelen P, Janssen H, Calafat J, Drijfhout JW, Neefjes J (2003) Peptide diffusion, protection, and degradation in nuclear and cytoplasmic compartments before antigen presentation by MHC class I. Immunity 18:97–108

    PubMed  CAS  Google Scholar 

  • Rock K, Goldberg A (1999) Degradation of cell proteins and the generation of MHC class I-presented peptides. Annu Rev Immunol 17:739–779. doi:10.1146/annurev.immunol.17.1.739

    PubMed  CAS  Google Scholar 

  • Rock K, York I, Goldberg A (2004) Post-proteasomal antigen processing for major histocompatibility complex class I presentation. Nat Immunol 5:670–677. doi:10.1038/ni1089

    PubMed  CAS  Google Scholar 

  • Rutenburg A, Goldbarg J, Pineda E (1958) Leucine aminopeptidase activity; observations in patients with cancer of the pancreas and other diseases. N Engl J Med 259:469–472

    PubMed  CAS  Google Scholar 

  • Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM (2008) The rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320(5882):1496–1501. doi:10.1126/science.1157535

    PubMed Central  PubMed  CAS  Google Scholar 

  • Sanderink GJ, Artur Y, Siest G (1988) Human aminopeptidases: a review of the literature. J Clin Chem Clin Biochem 26:795–807

    PubMed  CAS  Google Scholar 

  • Santos A, Langner J, Herrmann M, Riemann D (2000) Aminopeptidase N/CD13 is directly linked to signal transduction pathways in monocytes. Cell Immunol 201:22–32. doi:10.1006/cimm.2000.1629

    PubMed  CAS  Google Scholar 

  • Saric T, Chang S-C, Hattori A, York IA, Markant S, Rock KL, Tsujimoto M, Goldberg AL (2002) An IFN-gamma-induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I-presented peptides. Nat Immunol 3:1169–1176. doi:10.1038/ni859

    PubMed  CAS  Google Scholar 

  • Saric T, Graef CI, Goldberg AL (2004) Pathway for degradation of peptides generated by proteasomes: a key role for thimet oligopeptidase and other metallopeptidases. J Biol Chem 279:46723–46732. doi:10.1074/jbc.M406537200

    PubMed  CAS  Google Scholar 

  • Sato Y (2004) Role of aminopeptidase in angiogenesis. Biol Pharm Bull 27:772–776

    PubMed  CAS  Google Scholar 

  • Saveanu L, Carroll O, Lindo V, Del Val M, Lopez D, Lepelletier Y, Greer F, Schomburg L, Fruci D, Niedermann G, Van Endert PM (2005) Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum. Nat Immunol 6:689–697. doi:10.1038/ni1208

    PubMed  CAS  Google Scholar 

  • Sawafuji K, Miyakawa Y, Weisberg E, Griffin JD, Ikeda Y, Kizaki M (2003) Aminopeptidase inhibitors inhibit proliferation and induce apoptosis of K562 and STI571-resistant K562 cell lines through the MAPK and GSK-3beta pathways. Leuk Lymphoma 44:1987–1996. doi:10.1080/1042819031000122033

    PubMed  CAS  Google Scholar 

  • Scornik O, Botbol V (2001) Bestatin as an experimental tool in mammals. Curr Drug Metab 2:67–85

    PubMed  CAS  Google Scholar 

  • Scott L, Lamb J, Smith S, Wheatley DN (2000) Single amino acid (arginine) deprivation: rapid and selective death of cultured transformed and malignant cells. Br J Cancer 83:800–810. doi:10.1054/bjoc.2000.1353

    PubMed Central  PubMed  CAS  Google Scholar 

  • Sengupta S, Horowitz PM, Karsten SL, Jackson GR, Geschwind DH, Fu Y, Berry RW, Binder LI (2006) Degradation of tau protein by puromycin-sensitive aminopeptidase in vitro. Biochemistry 45:15111–15119. doi:10.1021/bi061830d

    PubMed  CAS  Google Scholar 

  • Serwold T, Gonzalez F, Kim J, Jacob R, Shastri N (2002) ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum. Nature 419:480–483. doi:10.1038/nature01074

    PubMed  CAS  Google Scholar 

  • Stoltze L, Schirle M, Schwarz G, Schröter C, Thompson MW, Hersh LB, Kalbacher H, Stevanovic S, Rammensee HG, Schild H (2000) Two new proteases in the MHC class I processing pathway. Nat Immunol 1:413–818. doi:10.1038/80852

    PubMed  CAS  Google Scholar 

  • Su L, Cao J, Jia Y, Zhang X, Fang H, Xu W (2012a) Development of synthetic aminopeptidase N/CD13 inhibitors to overcome cancer metastasis and angiogenesis. ACS Med Chem Lett 3:959–964. doi:10.1021/ml3000758

    CAS  Google Scholar 

  • Su L, Jia Y, Zhang L, Xu Y, Fang H, Xu W (2012b) Design, synthesis and biological evaluation of novel amino acid ureido derivatives as aminopeptidase N/CD13 inhibitors. Bioorg Med Chem 20:3807–3815. doi:10.1016/j.bmc.2012.04.035

    PubMed  CAS  Google Scholar 

  • Taylor A (1993) Aminopeptidases: structure and function. FASEB J 32:290–298

    Google Scholar 

  • Tholander F, Muroya A, Roques B-P, Fournié-Zaluski M-C, Thunnissen MMGM, Haeggström JZ (2008) Structure-based dissection of the active site chemistry of leukotriene A4 hydrolase: implications for M1 aminopeptidases and inhibitor design. Chem Biol 15:920–929. doi:10.1016/j.chembiol.2008.07.018

    PubMed  CAS  Google Scholar 

  • Thunnissen M, Nordlund P, Haeggström JZ (2001) Crystal structure of human leukotriene A 4 hydrolase, a bifunctional enzyme in inflammation. Nat Struct Biol 8:131–135

    PubMed  CAS  Google Scholar 

  • Tobler A, Constam DB, Schmitt-Gräff A, Malipiero U, Schlapbach R, Fontana A (1997) Cloning of the human puromycin-sensitive aminopeptidase and evidence for expression in neurons. J Neurochem 68:889–897

    PubMed  CAS  Google Scholar 

  • Tokuhara T, Hattori N, Ishida H, Hirai T, Higashiyama M, Kodama K, Miyake M (2006) Clinical significance of aminopeptidase N in non-small cell lung cancer. Clin Cancer Res 12:3971–3978. doi:10.1158/1078-0432.CCR-06-0338

    PubMed  CAS  Google Scholar 

  • Towne C, York I, Neijssen J (2008) Puromycin-sensitive aminopeptidase limits MHC class I presentation in dendritic cells but does not affect CD8 T cell responses during viral infections. J Immunol 180:1704–1712

    PubMed  CAS  Google Scholar 

  • Tsukamoto H, Shibata K, Kajiyama H, Terauchi M, Nawa A, Kikkawa F (2008) Aminopeptidase N (APN)/CD13 inhibitor, Ubenimex, enhances radiation sensitivity in human cervical cancer. BMC Cancer 8:74. doi:10.1186/1471-2407-8-74

    PubMed Central  PubMed  Google Scholar 

  • Umezawa H, Aoyagi T, Suda H (1976) Bestatin, an inhibitor of aminopeptidase B, produced by actinomycetes. J Antibiot XXIX:97–99

    Google Scholar 

  • van Hensbergen Y, Broxterman H, Hanemaaijer R, Jorna AS, Van Lent NA, Verheul HM, Pinedo HM, Hoekman K (2002) Soluble aminopeptidase N/CD13 in malignant and nonmalignant effusions and intratumoral fluid. Clin Cancer Res 8:3747–3754

    PubMed  Google Scholar 

  • van Herpen CM, Eskens FA, De Jonge M, Desar I, Hooftman L, Bone EA, Timmer-Bonte JN, Verweij J (2010) A phase Ib dose-escalation study to evaluate safety and tolerability of the addition of the aminopeptidase inhibitor tosedostat (CHR-2797) to paclitaxel in patients with advanced solid tumours. Br J Cancer 103:1362–1368. doi:10.1038/sj.bjc.6605917

    PubMed Central  PubMed  Google Scholar 

  • Varona A, Blanco L, López JI, Gil J, Agirregoitia E, Irazusta J, Larrinaga G (2007) Altered levels of acid, basic, and neutral peptidase activity and expression in human clear cell renal cell carcinoma. Am J Physiol Renal Physiol 292:F780–F788. doi:10.1152/ajprenal.00148.2006

    PubMed  CAS  Google Scholar 

  • Wakita A, Ohtake S, Takada S, Yagasaki F, Komatsu H, Miyazaki Y, Kubo K, Kimura Y, Takeshita A, Adachi Y, Kiyoi H, Yamaguchi T, Yoshida M, Ohnishi K, Miyawaki S, Naoe T, Ueda R, Ohno R (2012) Randomized comparison of fixed-schedule versus response-oriented individualized induction therapy and use of ubenimex during and after consolidation therapy for elderly patients with acute myeloid leukemia: the JALSG GML200 Study. Int J Hematol 96:84–93. doi:10.1007/s12185-012-1105-y

    PubMed  CAS  Google Scholar 

  • Watanabe Y, Shibata K, Kikkawa F (2003) Adipocyte-derived leucine aminopeptidase suppresses angiogenesis in human endometrial carcinoma via renin-angiotensin system. Clin Cancer Res 9:6497–6503

    PubMed  CAS  Google Scholar 

  • Wickström M, Larsson R, Nygren P, Gullbo J (2011) Aminopeptidase N (CD13) as a target for cancer chemotherapy. Cancer Sci 102:501–508. doi:10.1111/j.1349-7006.2010.01826.x

    PubMed  Google Scholar 

  • Willighagen R, Planteydt H (1959) Aminopeptidase activity in cancer cells. Nature 183:263–264

    PubMed  CAS  Google Scholar 

  • Xu Y, Lai LT, Gabrilove JL, Scheinberg DA (1998) Antitumor activity of actinonin in vitro and in vivo. Clin Cancer Res 4:171–176

    PubMed  CAS  Google Scholar 

  • Yamamoto Y, Li YH, Ushiyama I, Nishimura A, Ohkubo I, Nishi K (2000) Puromycin-sensitive alanyl aminopeptidase from human liver cytosol: purification and characterization. Forensic Sci Int 113:143–146

    PubMed  CAS  Google Scholar 

  • Yewdell J, Princiotta M (2004) Proteasomes get by with lots of help from their friends. Immunity 20:362–363

    PubMed  CAS  Google Scholar 

  • York IA, Chang S-C, Saric T, Keys JA, Favreau JM, Goldberg AL, Rock KL (2002) The ER aminopeptidase ERAP1 enhances or limits antigen presentation by trimming epitopes to 8–9 residues. Nat Immunol 3:1177–1184. doi:10.1038/ni860

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by grants CCA/VICI-07/36 to GJ, and CCA2012-1-08 to GJ, GO and GJP.

Conflict of interest

The authors do not have a conflict of interest.

Author information

Affiliations

  1. Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Rm 1.42, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

    Sarina M. Hitzerd & Godefridus J. Peters

  2. Department of Rheumatology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

    Sue Ellen Verbrugge & Gerrit Jansen

  3. Department of Hematology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

    Gert Ossenkoppele

Authors
  1. Sarina M. Hitzerd
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sue Ellen Verbrugge
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gert Ossenkoppele
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gerrit Jansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Godefridus J. Peters
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Godefridus J. Peters.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hitzerd, S.M., Verbrugge, S.E., Ossenkoppele, G. et al. Positioning of aminopeptidase inhibitors in next generation cancer therapy. Amino Acids 46, 793–808 (2014). https://doi.org/10.1007/s00726-013-1648-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-013-1648-0

Keywords

  • Amino acids
  • Aminopeptidases
  • Aminopeptidase inhibitors
  • Bestatin
  • Tosedostat