A cleavage-site-directed inhibitor of interleukin-1<i>β</i>-converting enzyme-like proteases inhibits apoptosis in primary cultures of rat hepatocytes

Cain, Kelvin; Inayat-Hussain, Salmaan H.; Couet, Carole; Cohen, Gerald M.

doi:10.1042/bj3140027

Cited by 81 publications

(62 citation statements)

References 33 publications

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“…Pre-treatment of hepatocytes with broad spectrum caspase inhibitor, z-VAD-FMK and more specific inhibition of caspase-3 (Ac-DEVD-CHO or z-DEVD-FMK), caspase-8 (z-IETD-FMK) and caspase-9 (z-LEHD-FMK) has provided evidence in the same way as had been reported in previously studied cell types and cell lines (Cain et al 1996;Jones et al 1998;Blom et al 1999;Woo et al 1999;Albright et al 2003). Similarly, we show in the present study that staurosporine-induced apoptosis can be blocked by treatment with caspase inhibitors.…”

Section: Discussionsupporting

confidence: 74%

Apoptosis and Its Suppression in Hepatocytes Culture

Mukwena

Al‐Rubeai

2004

Cytotechnology

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In order to achieve the goal of developing extracorporeal liver support devices, it is necessary to optimise bioprocess environment such that viability and function are maximised. Optimising culture medium composition and controlling the constitution of the cellular microenvironment within the bioreactor have for many years been considered vital to achieving these aims. Coupled to this is the need to understand apoptosis, the prime suspect in the demise of animal cultures, including those of hepatocytes. Results presented here show that absent nutrients including glucose and amino acids play a substantial part in the induction of apoptosis. The use of chemical apoptosis inhibitors was utilised to investigate key components of hepatic apoptosis where caspases, predominantly caspase 8, were implicated in staurosporine (STS)-induced HepZ apoptosis. Caspase 9 and 3 activation although recorded was of less significance. Interestingly, these results were not consistent with those of mitochondrial membrane depolarisation where inhibition of caspase activation appeared to drive depolarisation. Inhibition of mitochondrial permeability transition and use of anti-oxidants was unsuccessful in reducing apoptosis, caspase activation and mitochondrial membrane depolarisation. In further studies, the anti-apoptotic gene bcl-2 was over-expressed in HepZ, resulting in a cell line that was more robust and resistant to death induced by glucose and cystine deprivation and treatment with STS. Bcl-2 did not however show significant cytoprotectivity where apoptosis was stimulated by deprivation of glutamine and serum. Overall, results indicated that although apoptosis can be curbed by use of chemical inhibitors and genetic manipulation, their success is dependent on apoptotic stimuli.

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Section: Discussionsupporting

confidence: 74%

Apoptosis and Its Suppression in Hepatocytes Culture

Mukwena

Al‐Rubeai

2004

Cytotechnology

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“…These results ~dggested that the TLCK target was not part of a common t ffector mechanism but that it had an important function either 1 ositively or negatively regulating apoptosis dependent on the cell type. In contrast the ability of Z-VAD.FMK to inhibit ;'poptosis induced by diverse stimuli in several different systems ( 19,40,44 and the present study] support the hypothesis that ; is inhibiting a common mediator of apoptosis. This common I mediator of apoptosis in both the nematode and mammals ,#ppears to be a ted-3/ICE-like cysteine protease [13-201.…”

Section: Parp Proteolysissupporting

confidence: 80%

An interleukin‐1β‐converting enzyme‐like protease is a common mediator of apoptosis in thymocytes

1995

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“…Cain et al [33] demonstrated that YVAD-CMK inhibited apoptosis of rat hepatocytes induced by transforming growth factor β1 and staurosporine, and these results suggested that an ICE-like protease is involved in the induction of apoptosis in these cells. Given the results with human hepatoma cells in the present study, it is suggested that different apoptotic signals may show different preferences in the activation of caspases.…”

Section: Discussionmentioning

confidence: 99%

Activation of caspase-3-like proteases in apoptosis induced by sphingosine and other long-chain bases in Hep3B hepatoma cells

Hung

Chang

Chuang

1999

Biochemical Journal

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Sphingosine and other long-chain bases (including sphinganine, dimethylsphingosine and stearylamine), but not octylamine (a short-chain analogue of sphinganine), induced apoptosis in Hep3B hepatoma cells. Because both -and -erythrosphingosine and stearylamine exert potent apoptotic effects on Hep3B cells, it is possible that these long-chain bases may activate apoptosis by inhibiting protein kinase C (PKC) activity. However, pretreatment with the PKC activator PMA could not rescue cells from apoptosis triggered by long-chain bases. Therefore the involvement of PKC in this apoptotic process requires further characterization. We also investigated whether these long-chain bases might be metabolized into ceramide in order to elicit their apoptotic action. We found that long-chain bases acted independently of ceramide in the induction of apoptosis, since addition of fumonisin B1, a fungal agent which effectively inhibits ceramide synthesis from sphingosine, did not protect against apoptosis. Additionally, we found that sphingosine-

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A cleavage-site-directed inhibitor of interleukin-1β-converting enzyme-like proteases inhibits apoptosis in primary cultures of rat hepatocytes

Cited by 81 publications

References 33 publications

Apoptosis and Its Suppression in Hepatocytes Culture

Apoptosis and Its Suppression in Hepatocytes Culture

An interleukin‐1β‐converting enzyme‐like protease is a common mediator of apoptosis in thymocytes

Activation of caspase-3-like proteases in apoptosis induced by sphingosine and other long-chain bases in Hep3B hepatoma cells

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