Synthesis of a novel legumain-cleavable colchicine prodrug with cell-specific toxicity

Smith, Robert L.; Åstrand, Ove Alexander Høgmoen; Nguyen, Luan Minh; Elvestrand, Tina; Hagelin, Gunnar; Solberg, Rigmor; Johansen, Harald Thidemann; Rongved, Pål

doi:10.1016/j.bmc.2014.04.056

Cited by 19 publications

(10 citation statements)

References 31 publications

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“…Due to high legumain expression in solid tumors and correlation with poor prognosis, legumain has been suggested as a prognostic marker in various cancers [57,115,230,[295][296][297][298][299]. For cancer treatment, several legumain-cleavable prodrugs have successfully been constructed based on a legumain-cleavable peptide linked to a cytotoxic drug (doxorubicin, etoposide, auristatin or colchicine), thus utilizing high legumain expression for cancer drug delivery [115,[300][301][302][303].…”

Section: Clinical Relevance Of Legumainmentioning

confidence: 99%

Glycosylation is important for legumain localization and processing to active forms but not for cystatin E/M inhibitory functions

et al. 2017

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Section: Clinical Relevance Of Legumainmentioning

confidence: 99%

Glycosylation is important for legumain localization and processing to active forms but not for cystatin E/M inhibitory functions

et al. 2017

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“…Now, we have reached the level of theranostics (Lee and Kim 2012;Mikhaylov et al 2014), which comprises therapeutic molecules that are targeted to a desired site of action relying on antibody-based immunogenic recognition of the target cell or tissue. Hence, features of the pathologically altered tissue site known from diagnostics are used to deliver therapeutic molecules in a trojan horse-like manner to the desired site of action, where they may be released, for instance, by proteolytic cleavage such as in probody-based targeting of specific cancers and in using TAT-liposomes (Desnoyers et al 2013;Liu et al 2003;Liu et al 2012;Mikhaylov et al 2011;Smith et al 2014). Another example is provided by the recently FDA-approved anti-cancer drug Adcetris® (brentuximab vedotin) in which CD30 antibodies direct the toxic payload to the tumor cells, where it is released in its active form by proteolytic cleavage mediated only at the site of delivery and is facilitated by over-expressed cancer-specific proteases (Newland et al 2013;Sanderson et al 2005).…”

Section: The Protease Family Businessmentioning

confidence: 99%

“…Likewise, active legumain is thought to be rapidly inactivated if left unstabilized and upon exposure to neutral pH (Dall and Brandstetter 2012;Overbye et al 2011). When secreted from cells, the presence of the endogenous inhibitors cystatins C and E/M, and to a lesser extent cystatin F, is known to strongly restrict the proteolytic activity of extracellular legumain (Alvarez-Fernandez et al 1999;Smith et al 2014;Wallin et al 2013). Type II cystatin presence has accordingly been shown to inhibit cysteine cathepsin-and legumainpromoted invasion of cancer cells (Briggs et al 2010;Vigneswaran et al 2006).…”

Section: Endo-lysosomal Cysteine Peptidases: Myths and Common Questionsmentioning

confidence: 99%

Proteolysis mediated by cysteine cathepsins and legumain—recent advances and cell biological challenges

et al. 2014

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Proteases play essential roles in protein degradation, protein processing, and extracellular matrix remodeling in all cell types and tissues. They are also involved in protein turnover for maintenance of homeostasis and protein activation or inactivation for cell signaling. Proteases range in function and specificity, with some performing distinct substrate cleavages, while others accomplish proteolysis of a wide range of substrates. As such, different cell types use specialized molecular mechanisms to regulate the localization of proteases and their function within the compartments to which they are destined. Here, we focus on the cysteine family of cathepsin proteases and legumain, which act predominately within the endo-lysosomal pathway. In particular, recent knowledge on cysteine cathepsins and their primary regulator legumain is scrutinized in terms of their trafficking to endo-lysosomal compartments and other less recognized cellular locations. We further explore the mechanisms that regulate these processes and point to pathological cases which arise from detours taken by these proteases. Moreover, the emerging biological roles of specific forms and variants of cysteine cathepsins and legumain are discussed. These may be decisive, pathogenic, or even deadly when localizing to unusual cellular compartments in their enzymatically active form, because they may exert unexpected effects by alternative substrate cleavage. Hence, we propose future perspectives for addressing the actions of cysteine cathepsins and legumain as well as their specific forms and variants. The increasing knowledge in non-canonical aspects of cysteine cathepsin- and legumain-mediated proteolysis may prove valuable for developing new strategies to utilize these versatile proteases in therapeutic approaches.

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“…Therefore, linkers presenting asparagine or aspartic acid residues, selectively hydrolysable by this enzyme, have been used to develop enzyme-sensitive prodrugs. To date, both low MW molecules containing legumain-cleavable linkers [128][129][130] and polymeric conjugates [131] have been synthesized using peptides containing the alanine-alanine-asparagine sequence (Ala-Ala-Asn). Recently, Lin et al presented hyaluronic acid (HA) legumain-sensitive nanogel, based on the same AAN peptide, for the delivery of Doxorubicin with a high targeting efficiency, both in vitro and in vivo [132].…”

Section: Legumain-sensitive Conjugatesmentioning

confidence: 99%

Two-step polymer- and liposome-enzyme prodrug therapies for cancer: PDEPT and PELT concepts and future perspectives

Scomparin

Florindo

Tiram

et al. 2017

Advanced Drug Delivery Reviews

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Polymer-directed enzyme prodrug therapy (PDEPT) and polymer enzyme liposome therapy (PELT) are two-step therapies developed to provide anticancer drugs site-selective intratumoral accumulation and release. Nanomedicines, such as polymer-drug conjugates and liposomal drugs, accumulate in the tumor site due to extravasation-dependent mechanism (enhanced permeability and retention - EPR - effect), and further need to cross the cellular membrane and release their payload in the intracellular compartment. The subsequent administration of a polymer-enzyme conjugate able to accumulate in the tumor tissue and to trigger the extracellular release of the active drug showed promising preclinical results. The development of polymer-enzyme, polymer-drug conjugates and liposomal drugs had undergone a vast advancement over the past decades. Several examples of enzyme mimics for in vivo therapy can be found in the literature. Moreover, polymer therapeutics often present an enzyme-sensitive mechanism of drug release. These nanomedicines can thus be optimal substrates for PDEPT and this review aims to provide new insights and stimuli toward the future perspectives of this promising combination.

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Synthesis of a novel legumain-cleavable colchicine prodrug with cell-specific toxicity

Cited by 19 publications

References 31 publications

Glycosylation is important for legumain localization and processing to active forms but not for cystatin E/M inhibitory functions

Glycosylation is important for legumain localization and processing to active forms but not for cystatin E/M inhibitory functions

Proteolysis mediated by cysteine cathepsins and legumain—recent advances and cell biological challenges

Two-step polymer- and liposome-enzyme prodrug therapies for cancer: PDEPT and PELT concepts and future perspectives

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