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LOXL2 Inhibitors and Breast Cancer Progression

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LOXL2 Inhibitors and Breast Cancer Progression antioxidants Review LOXL2 Inhibitors and Breast Cancer Progression Sandra Ferreira 1 , Nuno Saraiva 1 , Patrícia Rijo 1,2 and Ana S. Fernandes 1,* 1 CBIOS, Universidade Lusófona’s Research Center for Biosciences & Health Technologies, Campo Grande 376, 1749-024 Lisbon, Portugal; [email protected] (S.F.); [email protected] (N.S.); [email protected] (P.R.) 2 Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, Portugal * Correspondence: [email protected]; Tel.: +351-217-515-500 (ext. 627) Abstract: LOX (lysyl oxidase) and lysyl oxidase like-1–4 (LOXL 1–4) are amine oxidases, which catalyze cross-linking reactions of elastin and collagen in the connective tissue. These amine oxidases also allow the cross-link of collagen and elastin in the extracellular matrix of tumors, facilitating the process of cell migration and the formation of metastases. LOXL2 is of particular interest in cancer biology as it is highly expressed in some tumors. This protein also promotes oncogenic transformation and affects the proliferation of breast cancer cells. LOX and LOXL2 inhibition have thus been suggested as a promising strategy to prevent metastasis and invasion of breast cancer. BAPN (β-aminopropionitrile) was the first compound described as a LOX inhibitor and was obtained from a natural source. However, novel synthetic compounds that act as LOX/LOXL2 selective inhibitors or as dual LOX/LOX-L inhibitors have been recently developed. In this review, we describe LOX enzymes and their role in promoting cancer development and metastases, with a special focus on LOXL2 and breast cancer progression. Moreover, the recent advances in the development of LOXL2 inhibitors are also addressed. Overall, this work contextualizes and explores the importance of LOXL2 inhibition as a promising novel complementary and effective therapeutic Citation: Ferreira, S.; Saraiva, N.; approach for breast cancer treatment. Rijo, P.; Fernandes, A.S. LOXL2 Inhibitors and Breast Cancer Keywords: BAPN; breast cancer; cell invasion; EMT; lysyl-oxidase; lysyl-oxidase like 2; metas- Progression. Antioxidants 2021, 10, tases; inhibitors 312. https://doi.org/10.3390/ antiox10020312 Academic Editor: Cinzia Domenicotti 1. Introduction Received: 29 December 2020 LOX (lysyl oxidase or protein lysine 6-oxidase) and lysyl oxidase like-1 through 4 Accepted: 16 February 2021 (LOXL1–LOXL4) are copper-dependent amine oxidases that covalently cross-link collagen Published: 19 February 2021 and elastin in the extracellular matrix (ECM) [1,2]. These enzymes are expressed in various tissues and organs, such as skin, aorta, heart, lung, liver, cartilage, kidney, stomach, Publisher’s Note: MDPI stays neutral small intestine, colon, retina, ovary, testis, and brain [3]. LOX/LOXL proteins have been with regard to jurisdictional claims in implicated in the pathogenesis of various diseases, including cancer. Therefore, inhibitors published maps and institutional affil- of these enzymes have been developed for therapeutic purposes. In this work, the impact iations. of LOX/LOXL enzymes in cancer progression and the state of the art of the development of inhibitors are reviewed. 2. Historical Perspective Copyright: © 2021 by the authors. The discovery of LOX enzymes was initially associated with the toxic effects described Licensee MDPI, Basel, Switzerland. for the inhibitor β-aminopropionitrile (BAPN; Figure1). Reports on BAPN can be found in This article is an open access article the literature since the 1950s [4]. BAPN is a potent irreversible inhibitor of LOX enzymes distributed under the terms and that severely disrupts cross-linkage of collagen and elastin [5]. This natural compound was conditions of the Creative Commons originally found in sweet peas, Lathyrus odoratus L. The ingestion of seeds or food products Attribution (CC BY) license (https:// of these genus spp. is associated with toxic effects, namely with lathyrism. This condition creativecommons.org/licenses/by/ is characterized by skeletal and tissue deformities, growth malformations, and vascular 4.0/). Antioxidants 2021, 10, 312. https://doi.org/10.3390/antiox10020312 https://www.mdpi.com/journal/antioxidants AntioxidantsAntioxidants 20212021,, 1010,, 312312 22 of 1618 alterationsespecially by that inhibition result from of collagen connective and tissue elastin disruption, cross-linking especially [5]. Hippocrates by inhibition was of collagenthe first andto describe elastin the cross-linking deleterious [5 effect]. Hippocrates of lathyrism, was which the first caused to describe paralysis the of deleterious the legs after effect the ofconsumption lathyrism, whichof certain caused species paralysis of peas. of the In legs 1883, after the the phenomenon consumption of of certainlathyrism species was ofdescribed peas. In 1883,by Louis the phenomenon Astier. Since of lathyrism then, several was described researchers by Louis have Astier. described Since then,the severalconsequences researchers of the have ingestion described of certain the consequences plants on connective of the ingestion tissue disorders, of certain especially plants on connectiveon collagen tissue and elastin disorders, cross-linking especially [5]. on collagen and elastin cross-linking [5]. Figure 1. Chemical structure of β-aminopropionitrile (BAPN). In the latelate 1960s,1960s, LOXLOX enzymesenzymes werewere identifiedidentified whilewhile studyingstudying thethe rolerole ofof collagencollagen and elastin elastin cross-link cross-link associated associated with with bone bone loss loss [6,7]. [6, 7Pinnell]. Pinnell and andMartin, Martin, 1968 1968[7] detected [7] de- tectedan enzyme an enzyme that converts that converts peptide-bound peptide-bound lysine lysine to allysine to allysine in embryonic in embryonic chick chick bone. bone. The Theauthors authors demonstrated demonstrated that that the theenzyme enzyme was was inhibited inhibited by by the the lathyrogen lathyrogen BAPN. ThisThis compound showed showed inin vitro vitro andand inin vivo vivo inhibitioninhibition of of collagen collagen and and elastin elastin cross-linking cross-linking by Antioxidants 2021, 10, 312 byblocking blocking the the lysine-to-allysi lysine-to-allysinene conversion. conversion. The The authors authors concluded concluded that that this enzymaticenzymatic 3 of 18 inactivation promotedpromoted the the primary primary lesion lesion of lathyrism.of lathyrism. It was It thewas first the time first that time the that enzyme the responsibleenzyme responsible for converting for converting lysyl residues lysyl toresidues allysyl to residues allysyl was residues identified was [identified7,8]. Although [7,8]. LOXAlthough is known LOX since is known the late since 1960s, the thelate 3D 1960s, crystalline the 3D structure crystalline of humanstructure lysyl of human oxidase-like lysyl 2oxidase-like (Figure2A) 2 was (Figure only 2A) obtained was only in 2018 obtained [9]. in 2018 [9]. A LOXL2 SRCR3 Ca SRCR4 Zn Catalytic Domain B FigureFigure 2. 2. StructureStructure of LOXLOX proteins. proteins. (A ()A Crystal) Crystal structure structure of human of human LOXL2 LOXL2 in a precursor in a precursor state state obtainedobtained by by Zhang Zhang etet al.al. (2018)(2018) [ 9[9].]. The The SRCR SRCR domains domains 3 and 3 and 4 are 4 coloredare colored in red in and red orange, and orange, respectively;respectively; the the catalytic domain domain is is colored colored in blue.in blue. The The glycosyl glycosyl groups groups at Asn-644 at Asn-644 are shown. are shown. Zinc Zinc andand calcium calcium ionsions are are represented represented as purple, as purple, blue and bl greenue and spheres, green respectively. spheres, Imagerespectively. was prepared Image was preparedwith PDB with (PDBID PDB 5ZE3) (PDBID [10]. 5ZE3) (B) Schematic [10]. (B representation) Schematic representation of the structure of and the homology structure of and human homology ofLOX human isoenzymes. LOX isoenzymes. Due to similarities Due to in thesimilarities domain arrangement,in the domain LOX arrangement, and LOXL1 represent LOX and one LOXL1 representLOX subfamily, one LOX whereas subfamily, LOXL2-4 whereas constitute LOXL another2-4 constitute LOX subfamily. another LOX subfamily. Antioxidants 2021, 10, 312 4 of 18 3. LOX Enzymes Antioxidants 2021, 10, 312 3 of 16 The mammalian lysyl oxidase family of proteins is encoded by five genes: LOX, LOXL1, LOXL2, LOXL3, and LOXL4. These genes encode proteins with the conserved C- terminal region that includes a copper binding site, lysine tyrosylquinone (LTQ) cofactor 3.residues, LOX Enzymes and a cytokine receptor-like (CRL) domain [1,11]. The diverse N-terminal pro- peptideThe mammalianregions determine lysyl oxidase the classification family of proteins intois two encoded subfamilies by five genes:consistingLOX ,of LOX and LOXL1, LOXL2, LOXL3, and LOXL4. These genes encode proteins with the conserved C-terminalLOXL1, and region LOXL2–LOXL4. that includes a copperThe prodomains binding site, lysinein LOX tyrosylquinone and LOXL1 (LTQ) enable cofac- their secretion toras residues,pro-enzymes, and a cytokinewhich receptor-likeare then activated (CRL) domain extracellularly [1,11]. The diversein a process N-terminal that involves pro-peptideproteolytic regionscleavage. determine LOXL2, the classificationLOXL3, and into LOXL4 two subfamilies contain consisting four scavenger of LOX receptor andcysteine-rich LOXL1, and domains LOXL2–LOXL4. (SRCR) The that prodomains are
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