CA074 methyl ester: A proinhibitor for intracellular cathepsin B

Buttle, David J.; Murata, Mitsuo; Knight, Christopher G.; Barrett, Alan J.

doi:10.1016/0003-9861(92)90290-d

Cited by 189 publications

(173 citation statements)

References 24 publications

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“…To investigate this we tested several protease inhibitors including the broad spectrum cysteine protease inhibitor leupeptin (25 lM), the cathepsin B/L specific inhibitor CA074ME (10 lM) [14,15], and the cathepsin D inhibitor pepstatin A (1 lg/ml). Although pepstatin A had no effect on acid ceramidase downregulation, leupeptin and CA074ME almost completely reversed acid ceramidase downregulation in desipramine treated cells (Fig.…”

Section: Desipramine Induces the Downregulation Of Acid Ceramidasementioning

confidence: 99%

New insights on the use of desipramine as an inhibitor for acid ceramidase

et al. 2006

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Treatment of different cancer cell lines with desipramine induced a time-and dose-dependent downregulation of acid ceramidase. Desipramine's effect on acid ceramidase appeared specific for amphiphilic agents (desipramine, chlorpromazine, and chloroquine) but not other lysomotropic agents such as ammonium chloride and bafilomycin A1, and was not transcriptionally regulated. The cathepsin B/L inhibitor, CA074ME, but not the cathepsin D inhibitor, pepstatin A, blocked desipramine's effect on acid ceramidase. Desipramine led to a more pronounced downregulation of sphingosine compared to ceramide suggesting acid ceramidase inhibition is important to desipramine's mechanism of action. This study reveals a new mechanism of action for desipramine.

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Section: Desipramine Induces the Downregulation Of Acid Ceramidasementioning

confidence: 99%

New insights on the use of desipramine as an inhibitor for acid ceramidase

et al. 2006

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“…GILIN and LAN-5 cells were treated for up to 72 hr with 100 M E-64 or 10 M CA074Me (2 inhibitors of CB 18,19 ) or 100 M pepstatin A (an inhibitor of CD 20 ). These concentrations of cathepsin inhibitors were chosen based on previous work from this and other laboratories demonstrating the effective inhibition of lysosomal protein degradation.…”

Section: Inhibition Of Either Lysosomal Cathepsin B or D Is Incompatimentioning

confidence: 99%

“…The long incubation time required for pepstatin A to exert its cytotoxic effect is in agreement with the low rate of intracellular accumulation of this inhibitor in cultured cells. 21 CA074Me, which is highly membrane-permeable and highly specific for CB, 19 readily exerted its effects, causing about 40% cell loss within 24 hr and almost complete death of the cultures by 48 hr of treatment. In this experimental condition CA074Me caused cell death primarily by necrosis, as assessed by flow cytometry (not shown).…”

Section: Inhibition Of Either Lysosomal Cathepsin B or D Is Incompatimentioning

confidence: 99%

Lysosomal proteases as potential targets for the induction of apoptotic cell death in human neuroblastomas

Castino¹,

Pace²,

Démoz³

et al. 2001

Intl Journal of Cancer

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Neuroblastoma is the most common type of cancer in infants. In children this tumor is particularly aggressive; despite various new therapeutic approaches, it is associated with poor prognosis. Given the importance of endosomallysosomal proteolysis in cellular metabolism, we hypothesized that inhibition of lysosomal protease would impact negatively on neuroblastoma cell survival. Treatment with E-64 or CA074Me (2 specific inhibitors of cathepsin B) or with pepstatin A (a specific inhibitor of cathepsin D) was cytotoxic for 2 neuroblastoma cell lines having different degrees of malignancy. Cell death was associated with condensation and fragmentation of chromatin and externalization of plasma membrane phosphatidylserine, 2 hallmarks of apoptosis. Concomitant inhibition of the caspase cascade protected neuroblastoma cells from cathepsin inhibitor-induced cytotoxicity. These data indicate that prolonged inhibition of the lysosomal proteolytic pathway is incompatible with cell survival, leading to apoptosis of neuroblastoma cells, and that the cathepsin-mediated and caspase-mediated proteolytic systems are connected and cooperate in the regulation of such an event. Since modern antitumor chemotherapy is aimed at restoring the normal rate of apoptosis in neoplastic tissues, the demonstration that endosomal-lysosomal cathepsins are involved in this process may constitute a basis for novel strategies that include cathepsin inhibitors in the therapeutic regimen. © 2002 Wiley-Liss, Inc. Key words: apoptosis; neuroblastoma; caspases; cathepsins; protease inhibitorsAltered regulation of cell survival and death, including apoptosis, is considered an important factor in tumor development and progression, as well as in the response to antineoplastic therapy. 1,2 The molecular pathways controlling apoptosis include a complex network of intracellular proteases that act in an orderly sequence on cellular substrates and lead to characteristic modifications of cell morphology with eventual DNA cleavage and apoptotic body formation. Several proteolytic systems have been shown to participate in the apoptotic process, depending on the cell type and stimuli adopted. With few exceptions, the caspase system seems to be the most universally involved one. 3,4 Recently, proteases resident within the endosomal-lysosomal compartment (cathepsins) have also been associated with apoptosis. 5-9 These studies demonstrated the need for a cathepsin-mediated proteolytic event in the apoptotic pathway triggered by cytokines or antiblastic drugs. In addition, the active participation of the autophagic proteolytic pathway, particularly of lysosomal cathepsins B and D (CB, CD), has been envisaged in rat pheochromocytoma PC12 cell death after nutrient and serum factor deprivation. In this model of caspasedependent apoptosis, CD acted as a death factor, whereas CB acted as a pro-survival factor. 10 We followed an opposite approach, assuming that the endosomal-lysosomal proteolytic pathway serves crucial functions for cell viability. Indeed, experiments usi...

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“…Some success has been obtained using E-64 analogs developed for the specific inhibition of cathepsin B [10]. In this case selectivity is achieved through interaction with the 'occluding loop' of cathepsin B, a structural feature particular to this enzyme [11,12]. Selective inhibition of cathepsin B has also been observed with a 56 amino acid peptide derived from the proregion of the enzyme [13].…”

Section: Introductionmentioning

confidence: 99%

Delineating functionally important regions and residues in the cathepsin B propeptide for inhibitory activity

Chen¹,

Plouffe²,

Ménard³

et al. 1996

FEBS Letters

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Synthetic peptides derived from the proregion of rat cathepsin B were used to identify functionally important regions and residues for cathepsin B inhibition. Successive 5 amino acid deletions of a 56 amino acid propeptide from both the N-and Ctermini has allowed the identification of two regions important for inhibitory activity: the NTTWQ (residues 21p-25p) and CGTVL (42p--46p) regions. Alanine scanning of residues within these two regions indicates that Trp-24p and Cys-42p contribute strongly to inhibition, their replacement by Ala resulting in 160-and 140-fold increases in Ki, respectively.

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CA074 methyl ester: A proinhibitor for intracellular cathepsin B

Cited by 189 publications

References 24 publications

New insights on the use of desipramine as an inhibitor for acid ceramidase

New insights on the use of desipramine as an inhibitor for acid ceramidase

Lysosomal proteases as potential targets for the induction of apoptotic cell death in human neuroblastomas

Delineating functionally important regions and residues in the cathepsin B propeptide for inhibitory activity

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