Commonly used caspase inhibitors designed based on substrate specificity profiles lack selectivity

Berger, Alicia B.; Sexton, Kelly B.; Bogyo, Matthew

doi:10.1038/sj.cr.7310112

Cited by 110 publications

(106 citation statements)

References 9 publications

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“…Other studies have demonstrated that the caspase 9 inhibitor Z-LEHD-FMK (fluoromethylketone) prevented TRAIL-induced apoptosis in HCT116 cells (Ozoren et al, 2000;Kim et al, 2004). However, the selectivity of FMK-based small molecule caspase inhibitors (especially Z-LEHD-FMK) is highly debatable (Berger et al, 2006). We found that inhibiting caspase 9 activity using a more specific siRNA strategy failed to rescue apoptosis induced by FLIP siRNA in our panel of CRC cell lines.…”

Section: Discussionmentioning

confidence: 57%

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

et al. 2008

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Death receptors can directly (type I cells) or indirectly induce apoptosis by activating mitochondrial-regulated apoptosis (type II cells). The level of caspase 8 activation is thought to determine whether a cell is type I or II, with type II cells less efficient at activating this caspase following death receptor activation. FLICE-inhibitory protein (FLIP) blocks death receptor-mediated apoptosis by inhibiting caspase 8 activation; therefore, we assessed whether silencing FLIP could convert type II cells into type I. FLIP silencing-induced caspase 8 activation in Bax wild-type and null HCT116 colorectal cancer cells; however, complete caspase 3 processing and apoptosis were only observed in Bax wild-type cells. Bax-null cells were also more resistant to chemotherapy and tumor necrosis factor-related apoptosis inducing ligand and, unlike the Bax wild-type cells, were not sensitized to these agents by FLIP silencing. Further analyses indicated that release of second mitochondrial activator of caspases from mitochondria and subsequent inhibition of X-linked inhibitor of apoptosis protein (XIAP) was required to induce full caspase 3 processing and apoptosis following FLIP silencing. These results indicate that silencing FLIP does not necessarily bypass the requirement for mitochondrial involvement in type II cells. Furthermore, targeting FLIP and XIAP may represent a therapeutic strategy for the treatment of colorectal tumors with defects in mitochondrial-regulated apoptosis.

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Section: Discussionmentioning

confidence: 57%

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

et al. 2008

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“…In addition, we cannot exclude the possibility that the caspase-inhibitor cross reacts and blocks other matrix-degrading enzymes. 22 Because only low levels of cleaved caspase-3 are histologically detected on the cell membrane in vivo, we think that other matrix-degrading enzymes probably play a part in aneurysm progression. Even more, the number of elastic lamellear interruptions is considerably fewer than anticipated in the areas surrounding apoptotic SMCs.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Caspase Activity Contributes to Aortic Wall Remodeling and Early Aneurysm Development in a Murine Model of Marfan Syndrome

Emrich

Okamura

Dalal

et al. 2015

ATVB

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C1039G/+ascending SMCs showed that apoptotic SMCs have increased elastolytic potential compared with viable cells, mostly because of caspase activity. Moreover, in vitro (1) cell membrane isolation, (2) immunofluorescence staining, and (3) scanning electron microscopy studies illustrate that caspases are expressed on the exterior cell surface of apoptotic SMCs. Conclusions-Caspase inhibition attenuates aneurysm development in an

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“…2,[8][9][10][11] Unfortunately, most of them lack selectivity and cannot be used for selectively targeting or analyzing particular enzymes in complex biological environments. [12][13][14][15] This is entirely because of the overlapping specificities of the caspases on their preferred natural amino acid sequences. To address this problem we designed and synthesized a Hybrid Combinatorial Substrate Library (HyCoSuL) containing 19 natural amino acids (omitting cysteine) and 110 unnatural amino acids.…”

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confidence: 99%

Unnatural amino acids increase sensitivity and provide for the design of highly selective caspase substrates

et al. 2014

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Traditional combinatorial peptidyl substrate library approaches generally utilize natural amino acids, limiting the usefulness of this tool in generating selective substrates for proteases that share similar substrate specificity profiles. To address this limitation, we synthesized a Hybrid Combinatorial Substrate Library (HyCoSuL) with the general formula of Ac-P4-P3-P2-Asp-ACC, testing the approach on a family of closely related proteases -the human caspases. The power of this library for caspase discrimination extends far beyond traditional PS-SCL approach, as in addition to 19 natural amino acids we also used 110 diverse unnatural amino acids that can more extensively explore the chemical space represented by caspase-active sites. Using this approach we identified and employed peptide-based substrates that provided excellent discrimination between individual caspases, allowing us to simultaneously resolve the individual contribution of the apical caspase-9 and the executioner caspase-3 and caspase-7 in the development of cytochrome-c-dependent apoptosis for the first time.

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Commonly used caspase inhibitors designed based on substrate specificity profiles lack selectivity

Cited by 110 publications

References 9 publications

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

Enhanced Caspase Activity Contributes to Aortic Wall Remodeling and Early Aneurysm Development in a Murine Model of Marfan Syndrome

Unnatural amino acids increase sensitivity and provide for the design of highly selective caspase substrates

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