Cysteine cathepsins: their role in tumor progression and recent trends in the development of imaging probes

Löser, Reik; Pietzsch, Jens

doi:10.3389/fchem.2015.00037

Cited by 66 publications

(74 citation statements)

References 260 publications

(293 reference statements)

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“…50 Cathepsin L and B are both upregulated in glioma cells. 51, 52 A cathepsin-L specific cleavable activity based probe labeled with a NIR Cy5.5 fluorophore (excitation 675 nM, emission 694 nM), named GB119, has been developed to label glioma cells with increased cathepsin-L activity (Table 1).…”

Section: Targeted Fluorescent Molecular Imaging Agentsmentioning

confidence: 99%

Fluorescent-Guided Surgical Resection of Glioma with Targeted Molecular Imaging Agents: A Literature Review

et al. 2016

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The median life expectancy following a diagnosis of glioblastoma (GBM) is 15 months. While chemotherapeutics may someday cure GBM by killing the highly dispersive malignant cells, the most important contribution that clinicians can currently offer to improve survival is by maximizing the extent of resection and providing concurrent chemo-radiation, which has become standard. Strides have been made in this area with the advent and implementation of methods of improved intraoperative tumor visualization. One of these techniques, optical fluorescent imaging with targeted molecular imaging agents, allows the surgeon to view fluorescently labeled tumor tissue during surgery with the use of special microscopy – thereby highlighting where to resect, and indicating when tumor-free margins have been obtained. This advantage is especially important at the difficult to observe margins where tumor cells infiltrate normal tissue. Targeted fluorescent agents also may be valuable for identifying tumor versus non-tumor tissue. In this review, we briefly summarize non-targeted fluorescent tumor imaging agents before discussing several novel targeted fluorescent agents being developed for glioma imaging in the context of fluorescent guided surgery or live molecular navigation. Many of these agents are currently undergoing preclinical testing. As the agents become available, however, it is necessary to understand the strengths and weaknesses of each.

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Section: Targeted Fluorescent Molecular Imaging Agentsmentioning

confidence: 99%

Fluorescent-Guided Surgical Resection of Glioma with Targeted Molecular Imaging Agents: A Literature Review

et al. 2016

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“…8,9 His110 and His111 of the occluding loop contribute to the exopeptidase activity by providing an appropriately spaced acceptor to bind the Cterminal carboxyl group of a peptide substrate. 2,3,10,11 Low pH values of around 4−5 are connected with the exopeptidase activity of cathepsin B, while the endopeptidase activity increases with a rising pH value. This effect was suggested to result from the protonation/deprotonation state of the residues involved in the stabilizing salt bridges.…”

mentioning

confidence: 99%

Cathepsin B Inhibitors: Combining Dipeptide Nitriles with an Occluding Loop Recognition Element by Click Chemistry

Schmitz

Bartz

et al. 2016

ACS Med. Chem. Lett.

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An active site mapping of human cathepsin B with dipeptide nitrile inhibitors was performed for a combinatorial approach by introducing several points of diversity and stepwise optimizing the inhibitor structure. To address the occluding loop of cathepsin B by a carboxylate moiety, click chemistry to generate linker-connected molecules was applied. Inhibitor 17 exhibited K i values of 41.3 nM, 27.3 nM, or 19.2 nM, depending on the substrate and pH of the assay. Kinetic data were discussed with respect to the conformational selection and induced fit models. KEYWORDS:Copper-catalyzed azide−alkyne cycloaddition, cysteine proteases, human cathepsin B, nitrile inhibitors C athepsin B is a papain-like cysteine protease that is ubiquitously expressed and involved in various physiological processes. 1 In nontumor cells, it is localized within endosomes/lysosomes, while in transformed cells it adopts a peripheral distribution in the cytoplasm and is, moreover, associated with the plasma membrane. 2,3 At the surface of invasive tumor cells, cathepsin B was found to bind to annexin II or caveolin-1, the structural protein of caveolae. Caveolae serve as a platform for a proteolytic cascade for the degradation of the extracellular matrix (ECM), executed by several proteases, including cathepsin B. 2−4 Cathepsin B affects the ECM either directly by extracellular proteolytic degradation of its components or indirectly via activation of other proteases. Partially degraded ECM components can be internalized to intracellular endosomal/lysosomal vesicles where the proteolysis is continued. This ECM breakdown remodels the tumor environment, promotes tumor invasion, and enables angiogenesis and metastasis. Cathepsin B also contributes to angiogenesis by degrading metalloprotease inhibitors and releasing growth factors that are bound to ECM components. 2,5,6 The crucial roles of cathepsin B at multiple points of the tumor development have been established in several in vitro and in vivo models and cathepsin B was proposed to be a prognostic marker in patients with various types of cancer. 1,2,7 Cathepsin B shows endopeptidase and exopeptidase activity, a unique feature for cysteine cathepsins, arousing from a flexible structural element, referred to as the occluding loop. The occluding loop is a 19−20 amino acid section that blocks the active site cleft at the end of the primed site. This event leaves only space for two amino acid residues of the substrate C-terminal of the scissile bond, that is, in the P1′ and P2′ positions. In this socalled closed conformation, two salt bridges, His110-Asp22 and Arg116-Asp224, hold the occluding loop over the primed subsites of the substrate binding cleft, preventing extended binding of large endopeptidase substrates and conferring an exopeptidase activity to cathepsin B. Mutations of His110 and Asp22 or the deletion of 12 amino acids of the occluding loop to enforce an open conformation reduced the exopeptidase activity of cathepsin B in favor of its endopeptidase activity. 8,9 His110...

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“…Endogenous inhibitors of cysteine cathepsins, however, are not selective and would cause severe off-target side effects during therapeutic treatment. Several small synthetic molecules have been reported to specifically inhibit cathepsins in cancer cells [172][173][174]. Their effects have been followed with respect to the degradation of ECM, while their impact on cysteine cathepsins involved in signal transduction pathways has been neglected.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Lysosomal cysteine peptidases – Molecules signaling tumor cell death and survival

Pišlar

Nanut

Kos

2015

Seminars in Cancer Biology

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Cysteine cathepsins: their role in tumor progression and recent trends in the development of imaging probes

Cited by 66 publications

References 260 publications

Fluorescent-Guided Surgical Resection of Glioma with Targeted Molecular Imaging Agents: A Literature Review

Fluorescent-Guided Surgical Resection of Glioma with Targeted Molecular Imaging Agents: A Literature Review

Cathepsin B Inhibitors: Combining Dipeptide Nitriles with an Occluding Loop Recognition Element by Click Chemistry

Lysosomal cysteine peptidases – Molecules signaling tumor cell death and survival

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